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1
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Hu X, Li Y, Liu X. Sitagliptin phosphate ameliorates chronic inflammation in diabetes mellitus via modulating macrophage polarization. Front Endocrinol (Lausanne) 2025; 16:1544684. [PMID: 40260283 PMCID: PMC12010097 DOI: 10.3389/fendo.2025.1544684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/11/2025] [Indexed: 04/23/2025] Open
Abstract
Aim To investigate the effect and mechanism of Sitagliptin phosphate on inflammation and macrophage polarization in a mouse model of type 2 diabetes. Methods In vitro, Raw264.7 cells were cultured with a high concentration of glucose (HG) and sitagliptin phosphate (SIG). The levels of inflammatory factors and the regulation of macrophage polarization were investigated, and the differentially expressed genes between HG and HG+SIG intervention were analyzed and enriched through transcriptomics. In vivo, C57BL/6J male mice were treated with HFD+STZ to establish a type 2 diabetes mouse model were investigated the effects of regulation of macrophage polarization in the pancreas and visceral adipose tissue. Results In vitro cell experiments and transcriptomics showed that Sitagliptin phosphate decreased the secretion of inflammatory factors IL-6 and TNF-α induced by high-glucose, and increased secretion of anti-inflammatory factor IL-10 by enhancing macrophage polarization. In vivo, the body weight and abdominal visceral fat weight, the ratio of visceral fat weight to body weight and fasting blood glucose were significantly increased in the DM group compared with the Control (P<0.05), Sitagliptin phosphate treatments reversed the changes in the DM group. Moreover, histological analysis showed that compared with the Control group, the size of visceral adipocytes, hepatocyte lipid deposition and the ratio of M1/M2 macrophage were higher in the DM group, which were reversed by Sitagliptin phosphate treatments (P<0.05), insulin treatments did not have a significant effect (P>0.05). Mechanistically, Western blot showed that compared with the normal group, HG upregulated the expression of mTORc1 protein, P-65 phosphorylation and P-65 protein expression in Raw264.7 cells (P<0.05), downregulated the expression of IKKβ (P<0.05) and PPAR-γ proteins (P<0.05), Sitagliptin phosphate and insulin treatments rescued these changes. Conclusion These results indicated that Sitagliptin phosphate reduced high glucose-induced inflammation by improving the imbalance of macrophage polarization via modulating the mTORc1/ PPAR-γ/NF-κB in vitro and in vivo.
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Affiliation(s)
| | | | - Xinyue Liu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China
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Piccirillo F, Mastroberardino S, Nusca A, Frau L, Guarino L, Napoli N, Ussia GP, Grigioni F. Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets. Int J Mol Sci 2023; 24:10164. [PMID: 37373310 PMCID: PMC10299555 DOI: 10.3390/ijms241210164] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.
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Affiliation(s)
- Francesco Piccirillo
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Sara Mastroberardino
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Annunziata Nusca
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Lorenzo Frau
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Lorenzo Guarino
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Nicola Napoli
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Endocrinology and Diabetes Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Gian Paolo Ussia
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Francesco Grigioni
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
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Demaria TM, Crepaldi LD, Costa-Bartuli E, Branco JR, Zancan P, Sola-Penna M. Once a week consumption of Western diet over twelve weeks promotes sustained insulin resistance and non-alcoholic fat liver disease in C57BL/6 J mice. Sci Rep 2023; 13:3058. [PMID: 36810903 PMCID: PMC9942638 DOI: 10.1038/s41598-023-30254-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/20/2023] [Indexed: 02/24/2023] Open
Abstract
The Western diet (high in fat and sucrose) consumption is a highly prevalent feature in the whole world, mainly due to the increasing consumption of ultra-processed foods (UPF), which are cheaper and easier-to-eat, as compared to fresh and highly nutritive meals. Epidemiological studies have associated UPF consumption with development of obesity, non-alcoholic fat liver disease (NAFLD) and insulin resistance. For molecular studies, mice fed with Western diets have been used to characterize signaling pathways involved in these diet-induced pathologies. However, these studies fed mice continuously with the diets, which is not compatible with what occurs in real life, when consumption is occasional. Here, we fed mice once-a-week with a high fat, high sucrose (HFHS) diet and compared these animals with those fed continuously with HFHS diet or with a standard diet. Our results show that after a single day of consuming HFHS, animals presented impaired oral glucose tolerance test (oGTT) as compared to control group. Although this impairment was reversed after 24 h consuming regular diet, repetition of HFHS consumption once-a-week aggravated the picture such as after 12-weeks, oGTT impairment was not reversed after 6 days under control diet. Liver steatosis, inflammation, impaired insulin signaling pathway and endoplasmic reticulum stress are similar comparing animals that consumed HFHS once-a-week with those that continuously consumed HFHS, though weekly-fed animals did not gain as much weight. Therefore, we conclude that regimen of one day HFHS plus 6 days normal diet over 12 weeks is sufficient to induce insulin resistance and NAFLD in mice.
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Affiliation(s)
- Thainá Magalhães Demaria
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Leticia Diniz Crepaldi
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Emylle Costa-Bartuli
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Jessica Ristow Branco
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Patricia Zancan
- grid.8536.80000 0001 2294 473XThe Metabolizsm’ Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ 21941-902 Brazil
| | - Mauro Sola-Penna
- The Metabolizsm' Group, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
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Aroor A, DeMarco VG, Whaley-Connell AT, Jia G, Yang Y, Sharma N, Naz H, Hans C, Hayden MR, Hill MA, Sowers JR, Manrique-Acevedo C, Lastra G. Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice. Am J Physiol Regul Integr Comp Physiol 2023; 324:R90-R101. [PMID: 36440901 PMCID: PMC9799154 DOI: 10.1152/ajpregu.00274.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/17/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022]
Abstract
Widespread consumption of diets high in fat and fructose (Western diet, WD) has led to increased prevalence of obesity and diastolic dysfunction (DD). DD is a prominent feature of heart failure with preserved ejection fraction (HFpEF). However, the underlying mechanisms of DD are poorly understood, and treatment options are still limited. We have previously shown that deletion of the cell-specific mineralocorticoid receptor in endothelial cells (ECMR) abrogates DD induced by WD feeding in female mice. However, the specific role of ECMR activation in the pathogenesis of DD in male mice has not been clarified. Therefore, we fed 4-wk-old ECMR knockout (ECMRKO) male mice and littermates (LM) with either a WD or chow diet (CD) for 16 wk. WD feeding resulted in DD characterized by increased left ventricle (LV) filling pressure (E/e') and diastolic stiffness [E/e'/LV inner diameter at end diastole (LVIDd)]. Compared with CD, WD in LM resulted in increased myocardial macrophage infiltration, oxidative stress, and increased myocardial phosphorylation of Akt, in concert with decreased phospholamban phosphorylation. WD also resulted in focal cardiomyocyte remodeling, characterized by areas of sarcomeric disorganization, loss of mitochondrial electron density, and mitochondrial fragmentation. Conversely, WD-induced DD and associated biochemical and structural abnormalities were prevented by ECMR deletion. In contrast with our previously reported observations in females, WD-fed male mice exhibited enhanced Akt signaling and a lower magnitude of cardiac injury. Collectively, our data support a critical role for ECMR in obesity-induced DD and suggest critical mechanistic differences in the genesis of DD between males and females.
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Affiliation(s)
- Annayya Aroor
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Vincent G DeMarco
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Adam T Whaley-Connell
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Division of Nephrology, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Guanghong Jia
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Yan Yang
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Neekun Sharma
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Huma Naz
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Chetan Hans
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Melvin R Hayden
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Michael A Hill
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - James R Sowers
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Camila Manrique-Acevedo
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Guido Lastra
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
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Han B, Zhang L, Hou Y, Zhong J, Hettinga K, Zhou P. Phosphoproteomics reveals that camel and goat milk improve glucose homeostasis in HDF/STZ-induced diabetic rats through activation of hepatic AMPK and GSK3-GYS axis. Food Res Int 2022; 157:111254. [DOI: 10.1016/j.foodres.2022.111254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 12/22/2022]
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Pathak R, Kumar A, Palfrey HA, Stone KP, Raju NR, Gettys TW, Murthy SN. Prolonged effects of DPP-4 inhibitors on steato-hepatitic changes in Sprague-Dawley rats fed a high-cholesterol diet. Inflamm Res 2022; 71:711-722. [PMID: 35578028 PMCID: PMC10154130 DOI: 10.1007/s00011-022-01572-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/28/2022] [Accepted: 04/03/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects. METHODS Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods. RESULTS Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1β) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile. CONCLUSIONS The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.
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Affiliation(s)
- Rashmi Pathak
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA.,Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, 70803, USA
| | - Avinash Kumar
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA.,Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.,Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA
| | - Henry A Palfrey
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA
| | - Kirsten P Stone
- Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Narayan R Raju
- Pathology Research Laboratory Inc, South San Francisco, CA, USA
| | - Thomas W Gettys
- Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Subramanyam N Murthy
- Department of Environmental Toxicology, Southern University and A&M College, 209, Lee Hall, Baton Rouge, LA, 70813, USA.
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Patarrão RS, Duarte N, Coelho I, Ward J, Ribeiro RT, Meneses MJ, Andrade R, Costa J, Correia I, Boavida JM, Duarte R, Gardete-Correia L, Medina JL, Pell J, Petrie J, Raposo JF, Macedo MP, Penha-Gonçalves C. Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion. Diabetologia 2022; 65:861-871. [PMID: 35190847 PMCID: PMC8960640 DOI: 10.1007/s00125-021-05638-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/26/2021] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. METHODS We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. RESULTS In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10-7) and C-peptide release responses (rs2300757, p=6.86x10-5) upon OGTT. Association with blood glucose levels was stronger at 30 min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the DPP4 gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. CONCLUSIONS/INTERPRETATION These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes.
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Affiliation(s)
- Rita S Patarrão
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Nádia Duarte
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Inês Coelho
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Joey Ward
- Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK
| | - Rogério T Ribeiro
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
- Departamento de Ciências Médicas, Instituto de Biomedicina (iBiMED), Universidade de Aveiro, Aveiro, Portugal
| | - Maria João Meneses
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | - Rita Andrade
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | - João Costa
- Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Isabel Correia
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | - José Manuel Boavida
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | - Rui Duarte
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | - Luís Gardete-Correia
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | | | - Jill Pell
- Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK
| | - John Petrie
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
| | - João F Raposo
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
- Sociedade Portuguesa de Diabetologia, Lisbon, Portugal
| | - Maria Paula Macedo
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal.
- Departamento de Ciências Médicas, Instituto de Biomedicina (iBiMED), Universidade de Aveiro, Aveiro, Portugal.
- Sociedade Portuguesa de Diabetologia, Lisbon, Portugal.
| | - Carlos Penha-Gonçalves
- Instituto Gulbenkian de Ciência, Oeiras, Portugal.
- Associação Protectora dos Diabéticos de Portugal/Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal.
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Muroya S, Zhang Y, Otomaru K, Oshima K, Oshima I, Sano M, Roh S, Ojima K, Gotoh T. Maternal Nutrient Restriction Disrupts Gene Expression and Metabolites Associated with Urea Cycle, Steroid Synthesis, Glucose Homeostasis, and Glucuronidation in Fetal Calf Liver. Metabolites 2022; 12:metabo12030203. [PMID: 35323646 PMCID: PMC8949217 DOI: 10.3390/metabo12030203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/23/2022] Open
Abstract
This study aimed to understand the mechanisms underlying the effects of maternal undernutrition (MUN) on liver growth and metabolism in Japanese Black fetal calves (8.5 months in utero) using an approach that integrates metabolomics and transcriptomics. Dams were fed 60% (low-nutrition; LN) or 120% (high-nutrition; HN) of their overall nutritional requirements during gestation. We found that MUN markedly decreased the body and liver weights of the fetuses; metabolomic analysis revealed that aspartate, glycerol, alanine, gluconate 6-phosphate, and ophthalmate levels were decreased, whereas UDP-glucose, UDP-glucuronate, octanoate, and 2-hydroxybutyrate levels were decreased in the LN fetal liver (p ≤ 0.05). According to metabolite set enrichment analysis, the highly different metabolites were associated with metabolisms including the arginine and proline metabolism, nucleotide and sugar metabolism, propanoate metabolism, glutamate metabolism, porphyrin metabolism, and urea cycle. Transcriptomic and qPCR analyses revealed that MUN upregulated QRFPR and downregulated genes associated with the glucose homeostasis (G6PC, PCK1, DPP4), ketogenesis (HMGCS2), glucuronidation (UGT1A1, UGT1A6, UGT2A1), lipid metabolism (ANGPTL4, APOA5, FADS2), cholesterol and steroid homeostasis (FDPS, HSD11B1, HSD17B6), and urea cycle (CPS1, ASS1, ASL, ARG2). These metabolic pathways were extracted as relevant terms in subsequent gene ontology/pathway analyses. Collectively, these results indicate that the citrate cycle was maintained at the expense of activities of the energy metabolism, glucuronidation, steroid hormone homeostasis, and urea cycle in the liver of MUN fetuses.
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Affiliation(s)
- Susumu Muroya
- Division of Animal Products Research, NARO Institute of Livestock and Grassland Science (NILGS), Ibaraki, Tsukuba 305-0901, Japan;
- Correspondence: (S.M.); (T.G.)
| | - Yi Zhang
- Department of Agricultural Sciences and Natural Resources, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-8580, Japan; (Y.Z.); (I.O.)
| | - Kounosuke Otomaru
- Joint Faculty of Veterinary Medicine, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-8580, Japan;
| | - Kazunaga Oshima
- Division of Year-Round Grazing Research, NARO Western Region Agricultural Research Center, 60 Yoshinaga, Ohda 694-0013, Shimane, Japan;
| | - Ichiro Oshima
- Department of Agricultural Sciences and Natural Resources, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-8580, Japan; (Y.Z.); (I.O.)
| | - Mitsue Sano
- Faculty of Human Culture, University of Shiga Prefecture, 2500 Hassaka-cho, Hikone 522-8533, Shiga, Japan;
| | - Sanggun Roh
- Graduate School of Agricultural Science, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Miyagi, Japan;
| | - Koichi Ojima
- Division of Animal Products Research, NARO Institute of Livestock and Grassland Science (NILGS), Ibaraki, Tsukuba 305-0901, Japan;
| | - Takafumi Gotoh
- Department of Agricultural Sciences and Natural Resources, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-8580, Japan; (Y.Z.); (I.O.)
- Correspondence: (S.M.); (T.G.)
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9
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Cariou B. The metabolic triad of non-alcoholic fatty liver disease, visceral adiposity and type 2 diabetes: Implications for treatment. Diabetes Obes Metab 2022; 24 Suppl 2:15-27. [PMID: 35014161 DOI: 10.1111/dom.14651] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 01/06/2022] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with visceral obesity, insulin resistance, type 2 diabetes (T2D) and has been often considered as the hepatic expression of the metabolic syndrome (MetS). Epidemiological studies highlight a bidirectional relationship of NAFLD with T2D in which NAFLD increases the risk of incident T2D and T2D increases the risk of severe non-alcoholic steatohepatitis (NASH) and liver fibrosis. Regarding the molecular determinants of NAFLD, we specifically focused in this review on adipocyte dysfunction as a key molecular link between visceral adipose tissue, MetS and NAFLD. Notably, the subcutaneous white adipose tissue expandability appears a critical adaptive buffering mechanism to prevent lipotoxicity and its related metabolic complications, such as NAFLD and T2D. There is a clinical challenge to consider therapeutic strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis. Strategies that promote significant and sustained weight loss (~10% of total body weight) such as metabolic and bariatric surgery or incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP or GLP-1/glucagon receptor co-agonists) are among the most efficient ones. In addition, insulin sensitizers such as PPARγ (pioglitazone) and pan-PPARs agonists (lanifibranor) have shown some beneficial effects on both NASH and liver fibrosis. Since NASH is a complex and multifactorial disease, it is conceivable that targeting different pathways, not only insulin resistance but also inflammation and fibrotic processes, is required to achieve NASH resolution.
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Affiliation(s)
- Bertrand Cariou
- Université de Nantes, Inserm, CNRS, CHU Nantes, l'institut du thorax, Nantes, France
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10
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Yin H, Shi A, Wu J. Platelet-Activating Factor Promotes the Development of Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2022; 15:2003-2030. [PMID: 35837578 PMCID: PMC9275506 DOI: 10.2147/dmso.s367483] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterised by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signalling pathway needs further investigation. In this paper, we review the relevant literature in recent years and discuss the role played by PAF in NAFLD development. It is important to elucidate the pathogenesis of NAFLD and to find effective interventions for treatment.
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Affiliation(s)
- Hang Yin
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
| | - Anhua Shi
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
| | - Junzi Wu
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
- Correspondence: Junzi Wu; Anhua Shi, Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China, Tel/Fax +86 187 8855 7524; +86 138 8885 0813, Email ;
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11
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Abstract
Sodium glucose cotransporter 2 (SGLT-2) inhibitors are the latest class of antidiabetic medications. They prevent glucose reabsorption in the proximal convoluted tubule to decrease blood sugar. Several animal studies revealed that SGLT-2 is profoundly involved in the inflammatory response, fibrogenesis, and regulation of numerous intracellular signaling pathways. Likewise, SGLT-2 inhibitors markedly attenuated inflammation and fibrogenesis and improved the function of damaged organ in animal studies, observational studies, and clinical trials. SGLT-2 inhibitors can decrease blood pressure and ameliorate hypertriglyceridemia and obesity. Likewise, they improve the outcome of cardiovascular diseases such as heart failure, arrhythmias, and ischemic heart disease. SGLT-2 inhibitors are associated with lower cardiovascular and all-cause mortality as well. Meanwhile, they protect against nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, acute kidney injury, and improve micro- and macroalbuminuria. SGLT-2 inhibitors can reprogram numerous signaling pathways to improve NAFLD, cardiovascular diseases, and renal diseases. For instance, they enhance lipolysis, ketogenesis, mitochondrial biogenesis, and autophagy while they attenuate the renin-angiotensin-aldosterone system, lipogenesis, endoplasmic reticulum stress, oxidative stress, apoptosis, and fibrogenesis. This review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases and dissects the underlying molecular mechanisms in detail. This narrative review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases using the results of latest observational studies, clinical trials, and meta-analyses. Thereafter, it dissects the underlying molecular mechanisms involved in the clinical effects of SGLT-2 inhibitors on these diseases.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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12
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Khatatbeh M, Momani W, Altaani Z, Al Saad R, Al Bourah AR. Fast Food Consumption, Liver Functions, and Change in Body Weight Among University Students: A Cross-Sectional Study. Int J Prev Med 2021; 12:109. [PMID: 34760120 PMCID: PMC8551780 DOI: 10.4103/ijpvm.ijpvm_194_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 03/17/2021] [Indexed: 11/14/2022] Open
Abstract
Background: Over the past decades, the consumption of fast foods has increased worldwide and became favored by people of most age groups. The objective of this research was to assess the impact of fast foods on liver enzyme levels and body weight. Methods: A cross-sectional study was conducted at Yarmouk University/Jordan using survey questionnaire and enquired university students about their dietary habits, in addition to laboratory investigations of liver enzymes. Results: In the cross-tabulation analysis, only age and body mass index (BMI) were significantly associated with alanine aminotransferase (ALT) enzyme level. However, all differences between aspartate aminotransferase (AST) level and other variables were statistically insignificant. The AST/ALT ratio was calculated and revealed significant statistical association with BMI of participants (P = 0.001). Change in body weight during one year was significantly associated with eating fast food (P = 0.031), drinking beverages with fast food meals (P = 0.001), and ALT level (P = 0.026). However, this association was statistically insignificant with AST level. Conclusions: Fast food consumption among university students in Jordan was not significantly associated with increasing levels of ALT and AST liver enzymes. However, eating fast food and drinking soft drinks were associated with increasing body weight, which is expected to have adverse effect on liver functions in the long term.
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Affiliation(s)
- Moawiah Khatatbeh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Waleed Momani
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Zaid Altaani
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Reem Al Saad
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Abdul Rahman Al Bourah
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
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13
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Qin J, Guo S, Yang J, Qazi IH, Pan B, Lv T, Zang S, Fang Y, Zhou G. Melatonin Promotes in vitro Development of Vitrified-Warmed Mouse GV Oocytes, Potentially by Modulating Phosphorylation of Drp1. Front Vet Sci 2021; 8:752001. [PMID: 34631868 PMCID: PMC8497800 DOI: 10.3389/fvets.2021.752001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/30/2021] [Indexed: 12/03/2022] Open
Abstract
Previous studies have shown that melatonin can mitigate cryopreservation-induced mitochondrial dysfunction in oocytes; however, the underlying molecular mechanism remains unclear. The objective of the present study was to investigate whether melatonin can improve the mitochondrial function during in vitro maturation of vitrified-warmed mouse germinal vesicle (GV) oocytes by modulating phosphorylation of dynamin related protein 1 (Drp1). Vitrification/warming procedures resulted in the following: (1) After cryopreservation of mouse GV oocytes, the phosphorylation level of Drp1 at Ser616 (p-Drp1 Ser616) in metaphase II (MII) oocytes was increased (P < 0.05). Furthermore, the rates of in vitro maturation, cleavage and blastocyst formation after parthenogenetic activation were decreased (P < 0.05). (2) In MII oocytes, the expression levels of translocase of the mitochondrial outer membrane 20 (TOMM20), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) content, and mRNA levels of mitochondrial biogenesis-related genes (Sirt1, Pgc-1α, Tfam) were all decreased (P < 0.05), and (3) Reactive oxygen species (ROS) level, early apoptosis level, Cytochrome C release and mRNA levels of pro-apoptotic related genes (Bax, Caspase9, Caspase3) in MII oocytes were all increased (P < 0.05). The results of this study further revealed that negative impacts of GV oocyte cryopreservation were mitigated by supplementation of warming and in vitro maturation media with 10−7mol /L melatonin or 2 x 10−5mol/L Mdivi-1 (Drp1 inhibitor). Therefore, we concluded that 10−7mol/L melatonin improved mitochondrial function, reduced oxidative stress and inhibited apoptosis by regulating phosphorylation of Drp1, thereby enhancing in vitro development of vitrified-warmed mouse GV oocytes.
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Affiliation(s)
- Jianpeng Qin
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Shichao Guo
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Jinyu Yang
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Izhar Hyder Qazi
- Department of Veterinary Anatomy and Histology, Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Sakrand, Pakistan
| | - Bo Pan
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Tianyi Lv
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Shengqin Zang
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Yi Fang
- Department of Grassland Resources and Animal Husbandry, Jilin Provincial Key Laboratory of Grassland Farming, Northeast Institute of Geography and Agoecology, Chinese Academy of Sciences, Changchun, China
| | - Guangbin Zhou
- Department of Animal Science, Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
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Huang X, Khoong Y, Han C, Su D, Ma H, Gu S, Li Q, Zan T. Targeting Dermal Fibroblast Subtypes in Antifibrotic Therapy: Surface Marker as a Cellular Identity or a Functional Entity? Front Physiol 2021; 12:694605. [PMID: 34335301 PMCID: PMC8319956 DOI: 10.3389/fphys.2021.694605] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/16/2021] [Indexed: 02/01/2023] Open
Abstract
Fibroblasts are the chief effector cells in fibrotic diseases and have been discovered to be highly heterogeneous. Recently, fibroblast heterogeneity in human skin has been studied extensively and several surface markers for dermal fibroblast subtypes have been identified, holding promise for future antifibrotic therapies. However, it has yet to be confirmed whether surface markers should be looked upon as merely lineage landmarks or as functional entities of fibroblast subtypes, which may further complicate the interpretation of cellular function of these fibroblast subtypes. This review aims to provide an update on current evidence on fibroblast surface markers in fibrotic disorders of skin as well as of other organ systems. Specifically, studies where surface markers were treated as lineage markers and manipulated as functional membrane proteins are both evaluated in parallel, hoping to reveal the underlying mechanism behind the pathogenesis of tissue fibrosis contributed by various fibroblast subtypes from multiple angles, shedding lights on future translational researches.
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Affiliation(s)
- Xin Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yimin Khoong
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chengyao Han
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dai Su
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Ma
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuchen Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tao Zan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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15
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Shin CY, Lee HY, Kim GH, Park SY, Choi WS, Sohn UD. Effects of the Combination of Evogliptin and Leucine on Insulin Resistance and Hepatic Steatosis in High-Fat Diet-Fed Mice. Biomol Ther (Seoul) 2021; 29:419-426. [PMID: 33814417 PMCID: PMC8255144 DOI: 10.4062/biomolther.2021.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/09/2021] [Accepted: 02/27/2021] [Indexed: 12/20/2022] Open
Abstract
In this study, we aimed to investigate the effects of 8 weeks of treatment with a combination of evogliptin and leucine, a branched-chain amino acid, in mice with high-fat diet (HFD)-induced diabetes. Treatment with evogliptin alone or in combination with leucine reduced the body weight of the mice, compared to the case for those from the HFD control group. Long-term treatment with evogliptin alone or in combination with leucine resulted in a significant reduction in glucose intolerance; however, leucine alone did not affect postprandial glucose control, compared to the case for the mice from the HFD control group. Furthermore, the combination of evogliptin and leucine prevented HFD-induced insulin resistance, which was associated with improved homeostasis model assessment for insulin resistance, accompanied by markedly reduced liver fat deposition, hepatic triglyceride content, and plasma alanine aminotransferase levels. The combination of evogliptin and leucine increased the gene expression levels of hepatic peroxisome proliferator-activated receptor alpha, whereas those of the sterol regulatory element-binding protein 1 and stearoyl-CoA desaturase 1 were not altered, compared to the case in the HFD-fed mice (p<0.05). Thus, our results suggest that the combination of evogliptin and leucine may be beneficial for treating patients with type 2 diabetes and hepatic steatosis; however, further studies are needed to delineate the molecular mechanisms underlying the action of this combination.
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Affiliation(s)
- Chang Yell Shin
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hak Yeong Lee
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Gil Hyung Kim
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Sun Young Park
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Won Seok Choi
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Uy Dong Sohn
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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16
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Hapala I, Griac P, Holic R. Metabolism of Storage Lipids and the Role of Lipid Droplets in the Yeast Schizosaccharomyces pombe. Lipids 2020; 55:513-535. [PMID: 32930427 DOI: 10.1002/lipd.12275] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/14/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022]
Abstract
Storage lipids, triacylglycerols (TAG), and steryl esters (SE), are predominant constituents of lipid droplets (LD) in fungi. In several yeast species, metabolism of TAG and SE is linked to various cellular processes, including cell division, sporulation, apoptosis, response to stress, and lipotoxicity. In addition, TAG are an important source for the generation of value-added lipids for industrial and biomedical applications. The fission yeast Schizosaccharomyces pombe is a widely used unicellular eukaryotic model organism. It is a powerful tractable system used to study various aspects of eukaryotic cellular and molecular biology. However, the knowledge of S. pombe neutral lipids metabolism is quite limited. In this review, we summarize and discuss the current knowledge of the homeostasis of storage lipids and of the role of LD in the fission yeast S. pombe with the aim to stimulate research of lipid metabolism and its connection with other essential cellular processes. We also discuss the advantages and disadvantages of fission yeast in lipid biotechnology and recent achievements in the use of S. pombe in the biotechnological production of valuable lipid compounds.
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Affiliation(s)
- Ivan Hapala
- Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava, Slovakia
| | - Peter Griac
- Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava, Slovakia
| | - Roman Holic
- Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava, Slovakia
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17
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Fan SM, Shi XY, Fan YP, Yang LL, Yao J, Feng PM. Efficacy and safety of incretin-based therapies in patients with nonalcoholic fatty liver disease: A protocol for a systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e20695. [PMID: 32629641 PMCID: PMC7337581 DOI: 10.1097/md.0000000000020695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is seriously affecting the general health due to its high prevalence and associated risk of liver-related consequences and extrahepatic chronic complications. New drugs are urgently needed for the treatment of NAFLD. The purpose of this meta-analysis is to assess the efficacy of incretin-based therapies in patients with NAFLD. METHODS We will search 4 databases for relative studies: PubMed, Cochrane Library, Embase, and Web of Science databases and identified all reports of randomized controlled trials (RCTs) published from inception to July 2020. Two authors will independently scan the searched articles, extract the data from included articles, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Fixed-effects model or random-effects model will be used to calculate pooled estimates of weighted mean difference (WMD) with 95% confidence intervals (CIs) or odds ratio (OR) with 95% CIs. RESULTS This systematic review aims to examine the effect of incretin-based therapies on liver histology, liver fat content, liver enzymes, and adverse events in patients with NAFLD. CONCLUSIONS These findings will provide guidance to clinicians and patients on the use of incretin-based therapies for NAFLD.
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Affiliation(s)
- Si-min Fan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Xiao-yan Shi
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Yan-ping Fan
- School of Medicine, Xi’an Jiaotong University, Xi’an, Shanxi Province, P.R. China
| | - Lin-lin Yang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Jia Yao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
| | - Pei-min Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province
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18
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Dougherty JA, Guirguis E, Thornby KA. A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease. Ann Pharmacother 2020; 55:65-79. [PMID: 32571083 DOI: 10.1177/1060028020935105] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To evaluate glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl-peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT) inhibitors to treat nondiabetic and type 2 diabetes mellitus (T2DM) nonalcoholic fatty liver disease (NAFLD) as it relates to improvement in hepatosteatosis (HS) or steatohepatitis (SH). DATA SOURCES MEDLINE and CINAHL were searched from inception through May 1, 2020. Search terms included nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, fatty liver, dipeptidyl-peptidase IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose transporter 2 inhibitors. STUDY SELECTION AND DATA EXTRACTION Full-text observational and randomized controlled studies in English were included. Patients diagnosed with NAFLD, treated with GLP-1 RAs, DPP-4 inhibitors, and SGLT2 inhibitors, with measures to evaluate HS or SH were evaluated. DATA SYNTHESIS Eight GLP-1 RA trials were reviewed; 7 GLP-1 RA trials showed improvement in HS. Two studies demonstrated improvement in liver histology in patients with SH. Seven SGLT2 inhibitor studies were reviewed; 6 studies demonstrated improvements in NAFLD. Five studies showed improvements in HS, whereas 1 displayed improvement in liver histology in NASH. Six studies that included DPP-4 inhibitors were evaluated, and only 2 demonstrated improvement in NASH. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Based on evidence reviewed, GLP-1 RAs and SGLT2 inhibitors decreased HS and SH in NAFLD patients, whereas DPP-4 inhibitor therapy was not effective for patients with HS. CONCLUSIONS Based on study data utilizing imaging studies and biopsy results, GLP-1 RAs or SGLT2 inhibitors can benefit NAFLD T2DM patients. Clinical trials with larger patient populations may augment these results.
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Affiliation(s)
- John A Dougherty
- Palm Beach Atlantic University: Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL, USA
| | - Erenie Guirguis
- Palm Beach Atlantic University: Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL, USA
| | - Krisy-Ann Thornby
- Palm Beach Atlantic University: Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL, USA
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19
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Li YP, Xiao J, Liang X, Pei Y, Han XF, Li CX, Tian H. DPP-4 inhibition resembles exercise in preventing type 2 diabetes development by inhibiting hepatic protein kinase C ε expression in a mouse model of hyperinsulinemia. J Int Med Res 2020; 48:300060520934635. [PMID: 32588693 PMCID: PMC7323281 DOI: 10.1177/0300060520934635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/26/2020] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE Interventions for hyperinsulinemia (HINS), an early indicator of type 2 diabetes mellitus (T2DM), can significantly reduce the T2DM risk. This study aims to determine how dipeptidyl peptidase-4 (DPP-4) inhibition prevents HINS progression to T2DM through ameliorating hepatic steatosis. METHODS KKay mice were used as a HINS model and they underwent exercise or received a DPP-4 inhibitor, MK0626. Hepatic steatosis was examined and liver diacylglycerol levels were determined. Human hepatic cells (LO2) were treated with MK0626 or transfected with DPP-4 siRNA. Protein kinase C ε isoform (PKCε) and DPP-4 expression and insulin receptor substrate 1 (IRS-1) phosphorylation were assessed using immunohistochemistry and western blot. RESULTS KKay mice developed HINS spontaneously at 7 weeks of age. Similar to exercise, MK0626 ameliorated hepatic steatosis and reduced the liver triglyceride and diacylglycerol content. Both exercise and MK0626 suppressed diacylglycerol-induced PKCε expression and restored insulin signaling, which was shown by tyrosine phosphorylation of IRS-1, in the livers of KKay mice. Additionally, silencing DPP-4 or MK0626 treatment decreased PKCε expression in LO2 cells. CONCLUSIONS Our data demonstrate that DPP-4 inhibition resembles exercise and effectively delays T2DM onset by suppressing hepatic PKCε expression in the HINS mouse model.
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Affiliation(s)
- Yu-peng Li
- Tianjin Medical University Chu Hsien-I Memorial Hospital (Tianjin Medical University Metabolic Diseases Hospital), Tianjin, China. NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Jing Xiao
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Xu Liang
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China; Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Yu Pei
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-fei Han
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Chen-xi Li
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
| | - Hui Tian
- Military Postgraduate Medical College, Second Medical Center of PLA General Hospital, Beijing, China
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Goedeke L, Perry RJ, Shulman GI. Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes. Annu Rev Pharmacol Toxicol 2020; 59:65-87. [PMID: 30625285 DOI: 10.1146/annurev-pharmtox-010716-104727] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.
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Affiliation(s)
- Leigh Goedeke
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA; , ,
| | - Rachel J Perry
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA; , , .,Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Gerald I Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA; , , .,Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA
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21
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Liu Y, Xu F, Jiang P. Effect of sitagliptin on expression of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1 α and irisin in a rat model of type 2 diabetes mellitus. J Int Med Res 2020; 48:300060519885569. [PMID: 32364035 PMCID: PMC7218978 DOI: 10.1177/0300060519885569] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 10/07/2019] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To evaluate the effect of sitagliptin on skeletal muscle expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), irisin, and phosphoadenylated adenylate activated protein kinase (p-AMPK) in a rat model of type 2 diabetes mellitus (T2DM). METHODS A high-fat diet/streptozotocin T2DM rat model was established. Rats were divided into T2DM, low-dose sitagliptin (ST1), high-dose sitagliptin (ST2), and normal control groups (NC). PGC-1α, irisin, and p-AMPK protein levels in skeletal muscle were measured by western blot, and PCG-1α and Fndc5 mRNA levels were assessed by reverse transcription-polymerase chain reaction. RESULTS Fasting plasma glucose (FPG), fasting insulin (FIns), homeostatic model assessment-insulin resistance (HOMA-IR), and tumor necrosis factor-α (TNF-α) were significantly up-regulated in the T2DM compared with the other groups, and FPG, FIns, total cholesterol, triglycerides, TNF-α, and HOMA-IR were significantly down-regulated in the ST2 compared with the ST1 group. PGC-1α, irisin, and p-AMPK expression levels decreased successively in the ST2, ST1, and DM groups compared with the NC, and were all significantly up-regulated in the ST2 compared with the ST1 group. CONCLUSION Down-regulation of PGC-1α and irisin in skeletal muscle may be involved in T2DM. Sitagliptin can dose-dependently up-regulate PCG-1α and irisin, potentially improving insulin resistance and glycolipid metabolism and inhibiting inflammation.
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MESH Headings
- AMP-Activated Protein Kinase Kinases
- Animals
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/etiology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/etiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diet, High-Fat/adverse effects
- Dose-Response Relationship, Drug
- Down-Regulation
- Fibronectins/analysis
- Fibronectins/metabolism
- Glycolipids/metabolism
- Humans
- Hypoglycemic Agents/administration & dosage
- Male
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/immunology
- Muscle, Skeletal/metabolism
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/analysis
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
- Protein Kinases/analysis
- Protein Kinases/metabolism
- Rats
- Sitagliptin Phosphate/administration & dosage
- Streptozocin/toxicity
- Up-Regulation
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Affiliation(s)
- Yuntao Liu
- Department of Endocrinology, Affiliated Renhe Hospital of China Three Gorges University, The Second Clinical Medical College of China Three Gorges University, Yichang, China
| | - Feng Xu
- Yichang Hospital of Traditional Chinese Medicine, Clinical Medical College of Traditional Chinese Medicine, China Three Gorges University, Yichang, China
| | - Pan Jiang
- Department of Endocrinology, Affiliated Renhe Hospital of China Three Gorges University, The Second Clinical Medical College of China Three Gorges University, Yichang, China
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22
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Yang M, Ma X, Xuan X, Deng H, Chen Q, Yuan L. Liraglutide Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Local Renin-Angiotensin System. Front Pharmacol 2020; 11:432. [PMID: 32322207 PMCID: PMC7156971 DOI: 10.3389/fphar.2020.00432] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
The renin-angiotensin system (RAS) is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and represents a potential therapeutic target for NAFLD. Glucagon-like peptide-1 (GLP-1) signaling has been shown to regulate the RAS within various local tissues. In this study, we aimed to investigate the functional relationship between GLP-1 and the local RAS in the liver during NAFLD. Wild-type and ACE2 knockout mice were used to establish a high-fat-induced NAFLD model. After the mice were treated with liraglutide (a GLP-1 analogue) for 4 weeks, the key RAS component genes were up-regulated in the liver of NAFLD mice. Liraglutide treatment regulated the RAS balance, preventing a reduction in fatty acid oxidation gene expression and increasing gluconeogenesis and the expression of inflammation-related genes caused by NAFLD, which were impaired in ACE2 knockout mice. Liraglutide-treated HepG2 cells exhibited activation of the ACE2/Ang1-7/Mas axis, increased fatty acid oxidation gene expression, and decreased inflammation, which could be reversed by A779 and AngII. These results indicate that the local RAS in the liver becomes overactivated in response to NAFLD. Moreover, ACE2 knockout increases the severity of liver steatosis. Liraglutide has a negative and antagonistic effect on the ACE/AngII/AT1R axis, a positive impact on the ACE2/Ang1-7/Mas axis, and is mediated through the PI3K/AKT pathway. This may represent a potential new mechanism by which liraglutide improves NAFLD.
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Affiliation(s)
- Mengying Yang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyi Ma
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiuping Xuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongjun Deng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Yuan
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Kawakubo M, Tanaka M, Ochi K, Watanabe A, Saka-Tanaka M, Kanamori Y, Yoshioka N, Yamashita S, Goto M, Itoh M, Shirakawa I, Kanai S, Suzuki H, Sawada M, Ito A, Ishigami M, Fujishiro M, Arima H, Ogawa Y, Suganami T. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Sci Rep 2020; 10:983. [PMID: 31969650 PMCID: PMC6976646 DOI: 10.1038/s41598-020-57935-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 01/08/2020] [Indexed: 01/24/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism–independent effects of anagliptin on NASH and HCC development.
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Affiliation(s)
- Mitsuhiro Kawakubo
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Miyako Tanaka
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. .,Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Kozue Ochi
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Akiko Watanabe
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Marie Saka-Tanaka
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yohei Kanamori
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Naoki Yoshioka
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoko Yamashita
- Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan
| | - Moritaka Goto
- Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan
| | - Michiko Itoh
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Kanagawa Institute of Industrial Science and Technology, Kawasaki, Japan
| | - Ibuki Shirakawa
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Sayaka Kanai
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiromi Suzuki
- Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Makoto Sawada
- Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ayaka Ito
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Ogawa
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Japan Agency for Medical Research and Development, CREST, Tokyo, Japan
| | - Takayoshi Suganami
- Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. .,Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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24
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Patel BM, Goyal RK. Liver and insulin resistance: New wine in old bottle!!! Eur J Pharmacol 2019; 862:172657. [DOI: 10.1016/j.ejphar.2019.172657] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 09/02/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022]
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25
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Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep 2019; 1:312-328. [PMID: 32039382 PMCID: PMC7001557 DOI: 10.1016/j.jhepr.2019.07.002] [Citation(s) in RCA: 292] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 06/14/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD is prevalent in obese individuals, but may also affect non-obese insulin-resistant individuals. NAFLD is associated with a 2- to 3-fold increased risk of developing type 2 diabetes (T2D), which may be higher in patients with more severe liver disease - fibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion, increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review, we discuss the altered pathophysiological mechanisms that underlie the development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH.
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Affiliation(s)
- Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, The University of Florida, and Malcom Randall Veterans Administration Medical Center, Gainesville, Florida
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26
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Cusi K. Incretin-Based Therapies for the Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes. Hepatology 2019; 69:2318-2322. [PMID: 31006135 DOI: 10.1002/hep.30670] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/16/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida, Gainesville, FL.,Malcom Randall Veterans Administration Medical Center, Gainesville, FL
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27
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Tanimura Y, Aoi W, Mizushima K, Higashimura Y, Naito Y. Combined treatment of dipeptidyl peptidase-4 inhibitor and exercise training improves lipid profile in KK/Ta mice. Exp Physiol 2019; 104:1051-1060. [PMID: 31020720 DOI: 10.1113/ep087449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 04/24/2019] [Indexed: 12/18/2022]
Abstract
NEW FINDINGS What is the central question of this study? Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice. What is the main finding and its importance? The combination of a DPP-4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36. ABSTRACT The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP-4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP-4 inhibitor, enhances the preventive effect of exercise-induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high-fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K-A, KK/Ta mice with alogliptin (0.01%); K-Ex, KK/Ta mice with exercise training (3 days week-1 , 15-20 m min-1 for 30 min); and K-Ex+A, KK/Ta mice with alogliptin and exercise training (n = 8 or 9 mice per group). After 8 weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K-Ex+A group than in the K group. The liver expression level of PPAR-γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K-Ex+A and B groups than in the K group. Thus, combined therapy of a DPP-4 inhibitor with exercise training was effective against high-fat diet-induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP-4 inhibitor.
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Affiliation(s)
- Yuko Tanimura
- Faculty of Human Health, Aichi Toho University, Meito-ku, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Wataru Aoi
- Division of Applied Life Sciences, Graduate School and Life and Environmental Science, Kyoto Prefectural University, Sakyo-ku, Kyoto, Japan
| | - Katsura Mizushima
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Yasuki Higashimura
- Department of Bioresources and Environmental Science, Ishikawa Prefectural University, Nonoichi, Japan
| | - Yuji Naito
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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28
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Zhu B, Li Y, Xiang L, Zhang J, Wang L, Guo B, Liang M, Chen L, Xiang L, Dong J, Liu M, Mei W, Li H, Xiang G. Alogliptin improves survival and health of mice on a high-fat diet. Aging Cell 2019; 18:e12883. [PMID: 30644630 PMCID: PMC6413659 DOI: 10.1111/acel.12883] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 10/08/2018] [Accepted: 11/01/2018] [Indexed: 12/14/2022] Open
Abstract
Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long‐term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high‐fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.
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Affiliation(s)
- Biao Zhu
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Yixiang Li
- Department of Hematology and Medical Oncology, School of Medicine; Emory University; Atlanta Georgia
| | | | - Jiajia Zhang
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Li Wang
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Bei Guo
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Minglu Liang
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Wuhan China
| | - Long Chen
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Wuhan China
| | - Lin Xiang
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Jing Dong
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Min Liu
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Wen Mei
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Huan Li
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
| | - Guangda Xiang
- Department of Endocrinology; Wuhan General Hospital of Chinese People's Liberation Army; Wuhan China
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29
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Dipeptidyl dipeptidase-4 inhibitor recovered ischemia through an increase in vasculogenic endothelial progenitor cells and regeneration-associated cells in diet-induced obese mice. PLoS One 2019; 14:e0205477. [PMID: 30889182 PMCID: PMC6424405 DOI: 10.1371/journal.pone.0205477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 02/18/2019] [Indexed: 01/21/2023] Open
Abstract
Metabolic syndrome (MS), overlapping type 2 diabetes, hyperlipidemia, and/or hypertension, owing to high-fat diet, poses risk for cardiovascular disease. A critical feature associated with such risk is the functional impairment of endothelial progenitor cells (EPCs). Dipeptidyl dipeptidase-4 inhibitors (DPP-4 i) not only inhibit degradation of incretins to control blood glucose levels, but also improve EPC bioactivity and induce anti-inflammatory effects in tissues. In the present study, we investigated the effects of such an inhibitor, MK-06266, in an ischemia model of MS using diet-induced obese (DIO) mice. EPC bioactivity was examined in MK-0626-administered DIO mice and a non-treated control group, using an EPC colony-forming assay and bone marrow cKit+ Sca-1+ lineage-cells, and peripheral blood-mononuclear cells. Our results showed that, in vitro, the effect of MK-0626 treatment on EPC bioactivities and differentiation was superior compared to the control. Furthermore, microvascular density and pericyte-recruited arteriole number increased in MK-0626-administered mice, but not in the control group. Lineage profiling of isolated cells from ischemic tissues revealed that MK-0626 administration has an inhibitory effect on unproductive inflammation. This occurred via a decrease in the influx of total blood cells and pro-inflammatory cells such as neutrophils, total macrophages, M1, total T-cells, cytotoxic T-cells, and B-cells, with a concomitant increase in number of regeneration-associated cells, such as M2/M ratio and Treg/T-helper. Laser Doppler analysis revealed that at day 14 after ischemic injury, blood perfusion in hindlimb was greater in MK-0626-treated DIO mice, but not in control. In conclusion, the DPP-4 i had a positive effect on EPC differentiation in MS model of DIO mice. Following ischemic injury, DPP-4 i sharply reduced recruitment of pro-inflammatory cells into ischemic tissue and triggered regeneration and reparation, making it a promising therapeutic agent for MS treatment.
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30
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Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds. Transl Res 2019; 205:51-63. [PMID: 30452888 PMCID: PMC7252504 DOI: 10.1016/j.trsl.2018.10.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 09/29/2018] [Accepted: 10/25/2018] [Indexed: 12/23/2022]
Abstract
In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM-MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM-MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes.
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31
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Rameshrad M, Razavi BM, Ferns GAA, Hosseinzadeh H. Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning. ACTA ACUST UNITED AC 2019; 27:341-360. [PMID: 30674032 DOI: 10.1007/s40199-019-00238-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Despite advances in our understanding of metabolic syndrome (MetS) and the treatment of each of its components separately, currently there is no single therapy approved to manage it as a single condition. Since multi-drug treatment increases drug interactions, decreases patient compliance and increases health costs, it is important to introduce single therapies that improve all of the MetS components. EVIDENCE ACQUISITION We conducted a PubMed, Scopus, Google Scholar, Web of Science, US FDA, utdo.ir and clinicaltrial.gov search, gathered the most relevant preclinical and clinical studies that have been published since 2010, and discussed the beneficial effects of dipeptidyl peptidase (DPP)-4 inhibitors to prevent and treat different constituent of the MetS as a single therapy. Furthermore, the pharmacology of DPP-4 inhibitors, focusing on pharmacodynamics, pharmacokinetics, drug interactions and their side effects are also reviewed. RESULTS DPP-4 inhibitors or gliptins are a new class of oral anti-diabetic drugs that seem safe drugs with no severe side effects, commonly GI disturbance, infection and inflammatory bowel disease. They increase mass and function of pancreatic β-cells, and insulin sensitivity in liver, muscle and adipose tissue. It has been noted that gliptin therapy decreases dyslipidemia. DPP-4 inhibitors increase fatty oxidation, and cholesterol efflux, and decrease hepatic triglyceride synthase and de novo lipogenesis. They delay gastric emptying time and lead to satiety. Besides, gliptin therapy has anti-inflammatory and anti-atherogenic impacts, and improves endothelial function and reduces vascular stiffness. CONCLUSION The gathered data prove the efficacy of DPP-4 inhibitors in managing MetS in some levels beyond anti-diabetic effects. This review could be a lead for designing new DPP-4 inhibitors with greatest effects on MetS in future. Introducing drugs with polypharmacologic effects could increase the patient's compliance and decrease the health cost that there is not in multi-drug therapy. Graphical abstract ᅟ.
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Affiliation(s)
- Maryam Rameshrad
- Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Mayfield House, Falmer, Brighton, West Sussex, BN1 9PH, UK
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Dipeptidyl peptidase-4 inhibition protects the liver of insulin-resistant female rats against triglyceride accumulation by suppressing uric acid. Biomed Pharmacother 2018; 110:869-877. [PMID: 30557836 DOI: 10.1016/j.biopha.2018.12.036] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/20/2018] [Accepted: 12/07/2018] [Indexed: 02/07/2023] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibition has been shown to exert beneficial effects against insulin resistance (IR) and type 2 diabetes. Combined oral contraceptive (COC) treatment is associated with impaired glucose and lipid metabolism but the mechanisms are elusive. We therefore, hypothesized that DPP-4 inhibition ameliorates COC-induced glucose dysregulation and hepatic triglyceride (TG) accumulation through adenosine deaminase (ADA) /xanthine oxidase (XO) /uric acid-dependent pathway. Female Wistar rats received (po) vehicle and COC (1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel; po) with or without DPP-4 inhibitor (sitagliptin; 100 mg/kg; po) for 8 weeks (n = 6/group). Glucose dysmetabolism was assessed by elevated fasting blood glucose, impaired oral glucose tolerance test and homeostatic model assessment of IR. Treatment with COC led to increased plasma fasting glucose, triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, IR and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic TG, TG/HDL-cholesterol ratio, malondialdehyde, uric acid (plasma; 25.2 ± 0.6 mg/dl; hepatic 128.9 ± 8.0 mg/100 mg tissue), lactate dehydrogenase, DPP-4, ADA and XO (plasma;10.5 ± 1.1 U/L; hepatic 21.2 ± 1.4 U/g protein) activities. Likewise, COC led to reduction in nitric oxide level. However, DPP-4 inhibition significantly ameliorated these alterations induced by COC treatment through suppression of uric acid (plasma; 15.1 ± 1.0 mg/dl, hepatic; 75.6 ± 5.0 mg/100 mg tissue), XO (plasma; 4.1 ± 0.9 U/L, hepatic; 8.7 ± 0.4 U/g protein), ADA and DPP-4 activities suggesting their involvement in glucose dysregulation and hepatic TG accumulation induced by COC treatment. Therefore, DPP-4 inhibition would impact positively on cardiometabolic disorders, at least in part, through XO, ADA and uric acid suppression.
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Zhu B, Li Y, Mei W, He M, Ding Y, Meng B, Zhao H, Xiang G. Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism. Vascul Pharmacol 2018; 115:55-63. [PMID: 30447331 DOI: 10.1016/j.vph.2018.11.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 10/22/2018] [Accepted: 11/13/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Perivascular adipose tissue (PVAT) regulates vascular function in a paracrine manner and the vasodilatory effect of PVAT on vessels is completely abolished in obesity. In addition, autophagy is required for maintaining biological function of PVAT and has been shown to be inhibited in obesity. The aim of this study was to explore whether alogliptin improves endothelial function by promoting autophagy in PVAT in obese mice. METHODS C57BL/6 mice were maintained on high fat diet with or without alogliptin intervention for 3 months. Vasorelaxation function of thoracic aorta with or without PVAT was determined. Autophagy related protein level of p62 and LC3B, along with phosphorylated mTOR (p-mTOR) were evaluated. In addition, the effects of alogliptin on autophagy were also investigated in cultured adipocytes. RESULTS The presence of PVAT significantly impaired endothelium-dependent vasodilation in obese mice and alogliptin intervention corrected this defect. Autophagy in PVAT was decreased in obese mice and alogliptin intervention activated autophagy. Activating autophagy in PVAT improved endothelium-dependent vasodilation while blocking it in PVAT impaired vasodilation function. Further, addition of glucagon-like peptide-1 (GLP-1) but not alogliptin alone activated autophagy. Moreover, GLP-1 and alogliptin co-treatment did not show additive effect on activating autophagy. CONCLUSIONS These results revealed that promoting autophagy in PVAT improved endothelial function in response to alogliptin intervention. Additionally, the beneficial effect of alogliptin intervention on PVAT was GLP-1 dependent.
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Affiliation(s)
- Biao Zhu
- Graduate School, Southern Medical University, Shatai Nan Road 1023, Guangzhou 510515, Guangdong Province, China; Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China
| | - Yixiang Li
- Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Wen Mei
- Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China
| | - Mingjuan He
- Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China
| | - Yan Ding
- Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China
| | - Biying Meng
- Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China
| | - Hui Zhao
- Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China
| | - Guangda Xiang
- Graduate School, Southern Medical University, Shatai Nan Road 1023, Guangzhou 510515, Guangdong Province, China; Department of Endocrinology, Wuhan General Hospital of Chinese People's Liberation Army, Wuluo Road 627, Wuhan 430070, Hubei Province, China.
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Spradley FT, Smith JA, Alexander BT, Anderson CD. Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. Am J Physiol Endocrinol Metab 2018; 315:E795-E814. [PMID: 29509436 PMCID: PMC6293166 DOI: 10.1152/ajpendo.00394.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intrauterine growth restriction (IUGR) is linked to increased risk for chronic disease. Placental ischemia and insufficiency in the mother are implicated in predisposing IUGR offspring to metabolic dysfunction, including hypertension, insulin resistance, abnormalities in glucose homeostasis, and nonalcoholic fatty liver disease (NAFLD). It is unclear whether these metabolic disturbances contribute to the developmental origins of exaggerated cardiovascular-renal disease (CVRD) risk accompanying IUGR. IUGR impacts the pancreas, adipose tissue, and liver, which are hypothesized to program for hepatic insulin resistance and subsequent NAFLD. NAFLD is projected to become the major cause of chronic liver disease and contributor to uncontrolled type 2 diabetes mellitus, which is a leading cause of chronic kidney disease. While NAFLD is increased in experimental models of IUGR, lacking is a full comprehension of the mechanisms responsible for programming of NAFLD and whether this potentiates susceptibility to liver injury. The use of well-established and clinically relevant rodent models, which mimic the clinical characteristics of IUGR, metabolic disturbances, and increased blood pressure in the offspring, will permit investigation into mechanisms linking adverse influences during early life and later chronic health. The purpose of this review is to propose mechanisms, including those proinflammatory in nature, whereby IUGR exacerbates the pathogenesis of NAFLD and how these adverse programmed outcomes contribute to exaggerated CVRD risk. Understanding the etiology of the developmental origins of chronic disease will allow investigators to uncover treatment strategies to intervene in the mother and her offspring to halt the increasing prevalence of metabolic dysfunction and CVRD.
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Affiliation(s)
- Frank T Spradley
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Jillian A Smith
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Barbara T Alexander
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
- Department of Physiology and Biophysics, The University of Mississippi Medical Center , Jackson, Mississippi
| | - Christopher D Anderson
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, School of Medicine, The University of Mississippi Medical Center , Jackson, Mississippi
- Cardiovascular-Renal Research Center, The University of Mississippi Medical Center , Jackson, Mississippi
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Saxagliptin regulates M1/M2 macrophage polarization via CaMKKβ/AMPK pathway to attenuate NAFLD. Biochem Biophys Res Commun 2018; 503:1618-1624. [DOI: 10.1016/j.bbrc.2018.07.090] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 07/19/2018] [Indexed: 01/13/2023]
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Omolekulo TE, Areola ED, Badmus OO, Michael OS, Kim I, Olatunji LA. Inhibition of adenosine deaminase and xanthine oxidase by valproic acid abates hepatic triglyceride accumulation independent of corticosteroids in female rats treated with estrogen-progestin. Can J Physiol Pharmacol 2018; 96:1092-1103. [PMID: 30001502 DOI: 10.1139/cjpp-2018-0231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Elevated circulating uric acid has been postulated to play an important pathophysiological role in estrogen-progestin combined oral contraceptive (COC)-induced hypertension and endothelial dysfunction. We hypothesized that disruption of glucoregulation and liver triglyceride (TG) accumulation induced by COC use would be abated by valproic acid (VPA) treatment through suppression of adenosine deaminase (ADA) and xanthine oxidase (XO) activities. Female Wistar rats aged 9-10 weeks were treated with a combination of estrogen-progestin COC steroids (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel; p.o.) with or without VPA (100.0 mg/kg; p.o.) daily for 6 weeks. The result shows that the disrupted glucoregulation and associated elevated hepatic ADA activity, plasma and hepatic XO activity, uric acid (UA), TG/HDL-cholesterol, total cholesterol, and malondialdehyde induced by COC treatment were attenuated by VPA treatment. However, VPA did not have any effect on plasma aldosterone, corticosterone, ADA, circulating and hepatic free fatty acid. Our results demonstrate that suppression of plasma and hepatic XO activities, along with hepatic ADA activity and UA by VPA treatment, protects against disrupted glucoregulation and increased liver TG by COC independent of elevated corticosteroids. The findings imply that VPA would provide protection against the development of cardiometabolic disorder via inhibition of the ADA/XO/UA-mediated pathway.
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Affiliation(s)
- Tolulope Eniola Omolekulo
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel Damilare Areola
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Olufunto Olayinka Badmus
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.,b Department of Public Health, Kwara State University, Malete, Nigeria
| | - Olugbenga Samuel Michael
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.,c Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University, Iwo, Nigeria
| | - Inkyeom Kim
- d Cardiovascular Research Institute and Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Lawrence Aderemi Olatunji
- a HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
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Fan S, Wang Y, Wang C, Jin H, Wu Z, Lu J, Zhang Z, Sun C, Shan Q, Wu D, Zhuang J, Sheng N, Xie Y, Li M, Hu B, Fang J, Zheng Y, Qin W. Hepatocyte-specific deletion of LASS2 protects against diet-induced hepatic steatosis and insulin resistance. Free Radic Biol Med 2018; 120:330-341. [PMID: 29626628 DOI: 10.1016/j.freeradbiomed.2018.04.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/23/2018] [Accepted: 04/03/2018] [Indexed: 02/06/2023]
Abstract
Homo sapienslongevity assurance homolog 2 of yeast LAG1 (LASS2) is expressed mostly in human liver. Here, we explored roles of LASS2 in pathogenesis of hepatic steatosis. Hepatocyte-specific LASS2 knockout (LASS2-/-) mice were generated using Cre-LoxP system. LASS2-/- and wild-type (WT) mice were fed with chow or high-fat diet (HFD). We found LASS2-/- mice were resistant to HFD-induced hepatic steatosis and insulin resistance. In HFD-fed mice, LASS2 deficiency significantly inhibited p38 MAPK and ERK1/ERK2 signaling in mouse liver. This effect was mediated by a significant increase of V-ATPase activity and a decrease of ROS level. We also observed that elevated expression of LASS2 in mouse hepatocyte cell line AML12 obviously decreased V-ATPase activity and increased ROS level by activation of p38 MAPK and ERK1/ERK2 signaling. Our findings indicate that LASS2 plays an important role in the pathogenesis of diet-induced hepatic steatosis and is a potential novel target for prevention and intervention of liver diseases.
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Affiliation(s)
- Shaohua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Yanyan Wang
- Department of Medical Ultrasonics, The Affiliated First People's Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Haojie Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Zheng Wu
- Department of Radiotherapy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Zifeng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Chunhui Sun
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Qun Shan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Dongmei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Juan Zhuang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Ning Sheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Ying Xie
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Mengqiu Li
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Bin Hu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China
| | - Jingyuan Fang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Yuanlin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Xuzhou, Jiangsu 221116, China.
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
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Wang JS, Hung YJ, Lu YC, Tsai CL, Yang WS, Lee TI, Hsiao YC, Sheu WHH. Difference between observed and predicted glycated hemoglobin at baseline and treatment response to vildagliptin-based dual oral therapy in patients with type 2 diabetes. Diabetes Res Clin Pract 2018; 138:119-127. [PMID: 29444447 DOI: 10.1016/j.diabres.2018.02.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/22/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022]
Abstract
AIM We aimed to investigate the association of difference between observed and predicted glycated hemoglobin (dopHbA1c) and HbA1c reduction after vildagliptin-based oral therapy in patients with type 2 diabetes (T2D). METHODS This was a prospective observational study. Adults ≥ 20 years old with T2D and HbA1c ≧7% treated with oral anti-diabetic drugs (OADs) were eligible if their OADs were shifted to vildagliptin-based dual oral therapy. Fasting plasma glucose (FPG) and HbA1c were recorded at baseline, week 12, and week 24. To determine baseline dopHbA1c, a predicted HbA1c was calculated by inserting baseline FPG into a regression equation (HbA1c = FPG ∗ 0.0225 + 4.3806) developed from linear relationship between HbA1c and FPG in an independent cohort of 3239 outpatients with T2D (dopHbA1c = observed HbA1c - predicted HbA1c). Patients were assigned to low (≦0) or high (>0) dopHbA1c group according to their baseline dopHbA1c levels. The study endpoint was changes from baseline to week 24 in HbA1c levels. RESULTS A total of 1224 patients were enrolled. Patients with a dopHbA1c >0 had a greater HbA1c reduction after vildagliptin-based dual oral therapy than those with a dopHbA1c ≦0 (-1.5 ± 2.0 vs. -0.4 ± 1.0%, p < 0.001). Baseline dopHbA1c was positively associated with HbA1c reduction from baseline to week 24 (β coefficient 0.883, 95% CI 0.811 to 0.955, p < 0.001), and the association remained significant after adjustment for confounders. CONCLUSIONS In T2D patients with an HbA1c ≧7%, a higher baseline dopHbA1c was associated with a greater HbA1c reduction after shifting to vildagliptin-based dual oral therapy.
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Affiliation(s)
- Jun-Sing Wang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan
| | - Yung-Chuan Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine for International Students, I-Shou University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Lin Tsai
- Division of Endocrinology and Metabolism, Department of Internal medicine, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
| | - Wei-Shiung Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ting-I Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of General Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ya-Chun Hsiao
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital Hsinchu branch, Hsinchu, Taiwan
| | - Wayne Huey-Herng Sheu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Medical Technology, College of Life Science, National Chung-Hsing University, Taichung, Taiwan; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
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Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5045182. [PMID: 29721506 PMCID: PMC5867538 DOI: 10.1155/2018/5045182] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022]
Abstract
Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD), high fat diet (HFD), and HFD administered with vildagliptin (50 mg/Kg) (V-HFD). After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission electron microscopy, real-time PCR for gene expression levels, and western blots for protein expression levels. ER stress was induced in HepG2 cells with palmitic acid and the effects of vildagliptin were investigated. Results. HFD mice showed increased liver weight/body weight (20.27%) and liver triglycerides (314.75%) compared to CD mice, but these decreased by 9.27% and 21.83%, respectively, in V-HFD mice. In the liver, HFD induced the expression of ER stress indicators significantly, which were obviously decreased by vildagliptin. In vitro, the expressions of molecular indicators of ER stress were reduced in HepG2 when vildagliptin was administered. Conclusions. Vildagliptin alleviates hepatic ER stress in a mouse high fat diet model. In HepG2 cells, vildagliptin directly reduced ER stress. Therefore, vildagliptin may be a potential agent for nonalcoholic fatty liver disease.
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Tobita H, Sato S, Yazaki T, Mishiro T, Ishimura N, Ishihara S, Kinoshita Y. Alogliptin alleviates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease by promoting CPT1a expression via Thr172 phosphorylation of AMPKα in the liver. Mol Med Rep 2018; 17:6840-6846. [PMID: 29512720 DOI: 10.3892/mmr.2018.8673] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/06/2018] [Indexed: 11/05/2022] Open
Abstract
Pioglitazone (PIO) has been reported to be effective for nonalcoholic fatty liver disease (NAFLD) and alogliptin (ALO) may have efficacy against NAFLD progression in patients with type 2 diabetes mellitus (T2DM). The present study examined the effectiveness of ALO in a rodent model of NAFLD and diabetes mellitus. KK‑Ay mice were used to produce an NAFLD model via administration of a choline‑deficient (CD) diet. To examine the effects of alogliptin, KK‑Ay mice were provided with a CD diet with 0.03% ALO and/or 0.02% PIO orally for 8 weeks. Biochemical parameters, pathological alterations and hepatic mRNA levels associated with fatty acid metabolism were assessed. Severe hepatic steatosis was observed in KK‑Ay mice fed with a CD diet, which was alleviated by the administration of ALO and/or PIO. ALO administration increased the hepatic carnitine palmitoyltransferase 1a (CPT1a) mRNA expression level and enhanced the Thr172 phosphorylation of AMP‑activated protein kinase α (AMPKα) in the liver. PIO administration tended to decrease the hepatic fatty acid synthase mRNA expression level and increase the serum adiponectin level. Homeostasis model of assessment‑insulin resistance values tended to improve with ALO and PIO administration. ALO and PIO alleviated hepatic steatosis in KK‑Ay mice fed with a CD diet. ALO increased hepatic mRNA expression levels associated with fatty acid oxidation. In addition, the results of the present study suggested that ALO promotes CPT1a expression via Thr172 phosphorylation of AMPKα.
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Affiliation(s)
- Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
| | - Tomotaka Yazaki
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
| | - Tsuyoshi Mishiro
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
| | - Norihisa Ishimura
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
| | - Shunnji Ishihara
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
| | - Yoshikazu Kinoshita
- Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
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High fructose diet-induced metabolic syndrome: Pathophysiological mechanism and treatment by traditional Chinese medicine. Pharmacol Res 2018; 130:438-450. [PMID: 29471102 DOI: 10.1016/j.phrs.2018.02.020] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/09/2018] [Accepted: 02/14/2018] [Indexed: 02/08/2023]
Abstract
Fructose is a natural monosaccharide broadly used in modern society. Over the past few decades, epidemiological studies have demonstrated that high fructose intake is an etiological factor of metabolic syndrome (MetS). This review highlights research advances on fructose-induced MetS, especially the underlying pathophysiological mechanism as well as pharmacotherapy by traditional Chinese medicine (TCM), using the PubMed, Web of science, China National Knowledge Infrastructure, China Science and Technology Journal and Wanfang Data. This review focuses on de novo lipogenesis (DNL) and uric acid (UA) production, two unique features of fructolysis different from glucose glycolysis. High level of DNL and UA production can result in insulin resistance, the key pathological event in developing MetS, mostly through oxidative stress and inflammation. Some other pathologies like the disturbance in brain and gut microbiota in the development of fructose-induced MetS in the past years, are also discussed. In management of MetS, TCM is an excellent representative in alternative and complementary medicine with a complete theory system and substantial herbal remedies. TCMs against MetS or MetS components, including Chinese patent medicines, TCM compound formulas, single TCM herbs and active compounds of TCM herbs, are reviewed on their effects and molecular mechanisms. TCMs with hypouricemic activity, which specially target fructose-induced MetS, are highlighted. And new technologies and strategies (such as high-throughput assay and systems biology) in this field are further discussed. In summary, fructose-induced MetS is a multifactorial disorder with the underlying complex mechanisms. Current clinical and pre-clinical evidence supports the potential of TCMs in management of MetS. Additionally, TCMs may show some advantages against complex MetS as their holistic feature through multiple target actions. However, further work is needed to confirm the effectivity and safety of TCMs by high-standard clinical trials, clarify the molecular mechanisms, and develop new anti-MetS drugs by development and application of optimized and feasible strategies and methods.
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Bouchi R, Fukuda T, Takeuchi T, Nakano Y, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T, Ogawa Y. Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes. Diabetes Metab Res Rev 2018; 34. [PMID: 29054111 DOI: 10.1002/dmrr.2957] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 07/30/2017] [Accepted: 10/10/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Activation of dipeptidyl peptidase 4 has been reported to be associated with impairment of insulin signalling in skeletal muscle, presumably leading to loss of muscle function. This study was aimed to investigate whether the use of dipeptidyl peptidase 4 inhibitors (DPP4i) could attenuate the progressive loss of muscle mass in patients with type 2 diabetes. METHODS A total 105 patients with type 2 diabetes (mean age 62 ± 12 years; 39% female) were studied in this retrospective observational study. To reduce the bias due to confounding variables, propensity-score matching analysis was performed. Change in skeletal muscle index measured by the whole body dual-energy X-ray absorptiometry at 1-year follow-up was evaluated. One-year changes in visceral and subcutaneous fat area and liver attenuation index were also determined by abdominal computed tomography. RESULTS Overall, 37 of 105 (35.2%) patients were treated with DPP4i. The estimated change in skeletal muscle index in patients with DPP4i was significantly higher than that in patients without (0.05 ± 0.06 vs -0.10 ± 0.04 kg, P = .046). In a propensity-matched population (N = 48), the same finding was observed (0.04 ± 0.03 in DPP4i versus -0.12 ± 0.03 kg in non-DPP4i, P = .033). There were no significant differences in changes of visceral and subcutaneous fat area and liver attenuation index between patients with DPP4i and those without. CONCLUSIONS Our data suggest the potential of DPP4i to prevent the progressive loss of muscle mass with ageing in patients with type 2 diabetes.
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Affiliation(s)
- Ryotaro Bouchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuya Fukuda
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takato Takeuchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yujiro Nakano
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masanori Murakami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Isao Minami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hajime Izumiyama
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Center for Medical Welfare and Liaison Services, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koshi Hashimoto
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanobu Yoshimoto
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshihiro Ogawa
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
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Long Z, Cao M, Su S, Wu G, Meng F, Wu H, Liu J, Yu W, Atabai K, Wang X. Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide. Free Radic Biol Med 2017; 113:71-83. [PMID: 28942246 PMCID: PMC5927376 DOI: 10.1016/j.freeradbiomed.2017.09.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/06/2017] [Accepted: 09/18/2017] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder that is closely associated with insulin resistance and type 2 diabetes. Previous studies have suggested that hepatocyte nuclear factor 1b (HNF1b) ameliorates insulin resistance. However, the role of HNF1b in the regulation of lipid metabolism and hepatic steatosis remains poorly understood. We found that HNF1b expression was decreased in steatotic livers. We injected mice with lentivirus (LV) expressing HNF1b shRNA to generate mice with hepatic knockdown of HNF1b. We also injected high fat (HF) diet-induced obese and db/db diabetic mice with LV expressing HNF1b to overexpress HNF1b. Knockdown of HNF1b increased hepatic lipid contents and induced insulin resistance in mice and in hepatocytes. Knockdown of HNF1b worsened HF diet-induced increases in hepatic lipid contents, liver injury and insulin resistance in mice and PA-induced lipid accumulation and impaired insulin signaling in hepatocytes. Moreover, overexpression of HNF1b alleviated HF diet-induced increases in hepatic lipid content and insulin resistance in mice. Knockdown of HNF1b increased expression of genes associated with lipogenensis and endoplasmic reticulum (ER) stress. DPP4 and NOX1 expression was increased by knockdown of HNF1b and HNF1b directly bound with the promoters of DPP4 and NOX1. Overexpression of DPP4 or NOX1 was associated with an increase in lipid droplets in hepatocytes and decreased expression of DPP4 or NOX1 suppressed the effects of knockdown of HNF1b knockdown on triglyceride (TG) formation and insulin signaling. Knockdown of HNF1b increased superoxide level and decreased glutathione content, which was inhibited by downregulation of DPP4 and NOX1. N-acetylcysteine (NAC) suppressed HNF1b knockdown-induced ER stress, TG formation and insulin resistance. Palmitic acid (PA) decreased HNF1b expression which was inhibited by NAC. Taken together, these studies demonstrate that HNF1b plays an essential role in controlling hepatic TG homeostasis and insulin sensitivity by regulating DPP4/NOX1mediated generation of superoxide.
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Affiliation(s)
- Zi Long
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Meng Cao
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Shuhao Su
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Guangyuan Wu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Fansen Meng
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Hao Wu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Jiangzheng Liu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Weihua Yu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Kamran Atabai
- Cardiovascular Research Institute, University of California, San Francisco, United States; Department of Medicine, University of California, San Francisco, United States
| | - Xin Wang
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
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Baumeier C, Schlüter L, Saussenthaler S, Laeger T, Rödiger M, Alaze SA, Fritsche L, Häring HU, Stefan N, Fritsche A, Schwenk RW, Schürmann A. Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease. Mol Metab 2017; 6:1254-1263. [PMID: 29031724 PMCID: PMC5641684 DOI: 10.1016/j.molmet.2017.07.016] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 07/26/2017] [Accepted: 07/31/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. METHODS Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity. RESULTS Subjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content. CONCLUSIONS Our results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling.
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Affiliation(s)
- Christian Baumeier
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Luisa Schlüter
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany
| | - Sophie Saussenthaler
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Thomas Laeger
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Maria Rödiger
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Stella Amelie Alaze
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany
| | - Louise Fritsche
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Hans-Ulrich Häring
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Norbert Stefan
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Andreas Fritsche
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Robert Wolfgang Schwenk
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Annette Schürmann
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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Petersen MC, Shulman GI. Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance. Trends Pharmacol Sci 2017; 38:649-665. [PMID: 28551355 DOI: 10.1016/j.tips.2017.04.004] [Citation(s) in RCA: 268] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 04/19/2017] [Accepted: 04/20/2017] [Indexed: 12/22/2022]
Abstract
Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance.
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Affiliation(s)
- Max C Petersen
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Gerald I Shulman
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
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Zhang DM, Jiao RQ, Kong LD. High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions. Nutrients 2017; 9:E335. [PMID: 28353649 PMCID: PMC5409674 DOI: 10.3390/nu9040335] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 03/15/2017] [Accepted: 03/24/2017] [Indexed: 02/06/2023] Open
Abstract
High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption.
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Affiliation(s)
- Dong-Mei Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, China.
| | - Rui-Qing Jiao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, China.
| | - Ling-Dong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, China.
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Zhang Z, Chen X, Lu P, Zhang J, Xu Y, He W, Li M, Zhang S, Jia J, Shao S, Xie J, Yang Y, Yu X. Incretin-based agents in type 2 diabetic patients at cardiovascular risk: compare the effect of GLP-1 agonists and DPP-4 inhibitors on cardiovascular and pancreatic outcomes. Cardiovasc Diabetol 2017; 16:31. [PMID: 28249585 PMCID: PMC5333444 DOI: 10.1186/s12933-017-0512-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/21/2017] [Indexed: 02/06/2023] Open
Abstract
Background Incretin-based agents, including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 agonists (GLP-1As), work via GLP-1 receptor for hyperglycemic control directly or indirectly, but have different effect on cardiovascular (CV) outcomes. The present study is to evaluate and compare effects of incretin-based agents on CV and pancreatic outcomes in patients with type 2 diabetes mellitus (T2DM) and high CV risk. Methods Six prospective randomized controlled trials (EXMAINE, SAVOR-TIMI53, TECOS, ELIXA, LEADER and SUSTAIN-6), which included three trials for DPP-4Is and three trials for GLP-1As, with 55,248 participants were selected to assess the effect of different categories of incretin-based agents on death, CV outcomes (CV mortality, major adverse CV events, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization), pancreatic events (acute pancreatitis and pancreatic cancer) as well as on hypoglycemia. Results When we evaluated the combined effect of six trials, the results suggested that incretin-based treatment had no significant effect on overall risks of CV and pancreatic outcomes compared with placebo. However, GLP-1As reduced all-cause death (RR = 0.90, 95% CI 0.82–0.98) and CV mortality (RR = 0.84, 95% CI 0.73–0.97), whereas DPP-4Is had no significant effect on CV outcomes but elevated the risk for acute pancreatitis (OR = 1.76, 95% CI 1.14–2.72) and hypoglycemia (both any and severe hypoglycemia), while GLP-1As lowered the risk of severe hypoglycemia. Conclusions GLP-1As decreased risks of all-cause and CV mortality and severe hypoglycemia, whereas DPP-4Is had no effect on CV outcomes but increased risks in acute pancreatitis and hypoglycemia. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0512-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zeqing Zhang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Xi Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Puhan Lu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Jianhua Zhang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Yongping Xu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Wentao He
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Mengni Li
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Shujun Zhang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Jing Jia
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Shiying Shao
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Junhui Xie
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Yan Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Xuefeng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, People's Republic of China.
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Rufinatscha K, Radlinger B, Dobner J, Folie S, Bon C, Profanter E, Ress C, Salzmann K, Staudacher G, Tilg H, Kaser S. Dipeptidyl peptidase-4 impairs insulin signaling and promotes lipid accumulation in hepatocytes. Biochem Biophys Res Commun 2017; 485:366-371. [PMID: 28213130 DOI: 10.1016/j.bbrc.2017.02.071] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 02/13/2017] [Indexed: 02/07/2023]
Abstract
Dipeptidyl-peptidase 4 [DPP-4) has evolved into an important target in diabetes therapy due to its role in incretin hormone metabolism. In contrast to its systemic effects, cellular functions of membranous DPP-4 are less clear. Here we studied the role of DPP-4 in hepatic energy metabolism. In order to distinguish systemic from cellular effects we established a cell culture model of DPP-4 knockdown in human hepatoma cell line HepG2. DPP-4 suppression was associated with increased basal glycogen content due to enhanced insulin signaling as shown by increased phosphorylation of insulin-receptor substrate 1 (IRS-1), protein kinase B/Akt and mitogen-activated protein kinases (MAPK)/ERK, respectively. Additionally, glucose-6-phosphatase cDNA expression was significantly decreased in DPP-4 deficiency. Reduced triglyceride content in DPP-4 knockdown cells was paralleled by enhanced expressions of peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase -1 (CPT-1) while sterol regulatory element-binding protein 1c (SREBP-1c) expression was significantly decreased. Our data suggest that hepatic DPP-4 induces a selective pathway of insulin resistance with reduced glycogen storage, enhanced glucose output and increased lipid accumulation in the liver. Hepatic DPP-4 might be a novel target in fatty liver disease in patients with glucose intolerance.
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Affiliation(s)
- Kerstin Rufinatscha
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Bernhard Radlinger
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Jochen Dobner
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Sabrina Folie
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Claudia Bon
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Clinica Medica 3, Padua University Hospital, Padua, Italy
| | - Elisabeth Profanter
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Claudia Ress
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Karin Salzmann
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Gabriele Staudacher
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Susanne Kaser
- Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria; Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
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Meyers A, Chourey K, Weiskittel TM, Pfiffner S, Dunlap JR, Hettich RL, Dalhaimer P. The protein and neutral lipid composition of lipid droplets isolated from the fission yeast, Schizosaccharomyces pombe. J Microbiol 2017; 55:112-122. [PMID: 28120187 DOI: 10.1007/s12275-017-6205-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 10/04/2016] [Accepted: 10/20/2016] [Indexed: 12/17/2022]
Abstract
Lipid droplets consist of a core of neutral lipids surrounded by a phospholipid monolayer with bound proteins. Much of the information on lipid droplet function comes from proteomic and lipodomic studies that identify the components of droplets isolated from organisms throughout the phylogenetic tree. Here, we add to that important inventory by reporting lipid droplet factors from the fission yeast, Schizosaccharomyces pombe. Unique to this study was the fact that cells were cultured in three different environments: 1) late log growth phase in glucose-based media, 2) stationary phase in glucosebased media, and 3) late log growth phase in media containing oleic acid. We confirmed colocalization of major factors with lipid droplets using live-cell fluorescent microscopy. We also analyzed droplets from each of the three conditions for sterol ester (SE) and triacylglycerol (TAG) content, along with their respective fatty acid compositions. We identified a previously undiscovered lipid droplet protein, Vip1p, which affects droplet size distribution. The results provide further insight into the workings of these ubiquitous organelles.
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Affiliation(s)
- Alex Meyers
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, TN, 37996-2200, USA
| | - Karuna Chourey
- Oak Ridge National Laboratory, Oak Ridge, TN, 37831, USA
| | - Taylor M Weiskittel
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, TN, 37996-2200, USA
| | - Susan Pfiffner
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, 37996, USA
| | - John R Dunlap
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, 37996, USA.,Advanced Microscopy and Imaging Center, University of Tennessee, Knoxville, TN, 37996, USA
| | | | - Paul Dalhaimer
- Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, TN, 37996-2200, USA. .,Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, 37996, USA. .,Institute of Biomedical Engineering, University of Tennessee, Knoxville, TN, 37996, USA.
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Nistala R, Savin V. Diabetes, hypertension, and chronic kidney disease progression: role of DPP4. Am J Physiol Renal Physiol 2017; 312:F661-F670. [PMID: 28122713 DOI: 10.1152/ajprenal.00316.2016] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 01/18/2017] [Accepted: 01/20/2017] [Indexed: 12/11/2022] Open
Abstract
The protein dipeptidyl peptidase 4 (DPP4) is a target in diabetes management and reduction of associated cardiovascular risk. Inhibition of the enzymatic function and genetic deletion of DPP4 is associated with tremendous benefits to the heart, vasculature, adipose tissue, and the kidney in rodent models of obesity, diabetes and hypertension, and associated complications. The recently concluded, "Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53" trial revealed a reduction in proteinuria in chronic kidney disease patients (stages 1-3). These results have spurred immense interest in the nonenzymatic and enzymatic role of DPP4 in the kidney. DPP4 is expressed predominantly in the glomeruli and S1-S3 segments of the nephron and to a lesser extent in other segments. DPP4 is known to facilitate absorption of cleaved dipeptides and regulate the function of the sodium/hydrogen exchanger-3 in the proximal tubules. DPP4, also known as CD26, has an important role in costimulation of lymphocytes via caveolin-1 on antigen-presenting cells in peripheral blood. Herein, we present our perspectives for the ongoing interest in the role of DPP4 in the kidney.
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Affiliation(s)
- Ravi Nistala
- Division of Nephrology and Hypertension, Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri; and
| | - Virginia Savin
- Department of Nephrology, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri
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