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Khunti K, Zaccardi F, Amod A, Aroda VR, Aschner P, Colagiuri S, Mohan V, Chan JCN. Glycaemic control is still central in the hierarchy of priorities in type 2 diabetes management. Diabetologia 2025; 68:17-28. [PMID: 39155282 PMCID: PMC11663178 DOI: 10.1007/s00125-024-06254-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 07/15/2024] [Indexed: 08/20/2024]
Abstract
A panel of primary care and diabetes specialists conducted focused literature searches on the current role of glycaemic control in the management of type 2 diabetes and revisited the evolution of evidence supporting the importance of early and intensive blood glucose control as a central strategy to reduce the risk of adverse long-term outcomes. The optimal approach to type 2 diabetes management has evolved over time as the evidence base has expanded from data from trials that established the role of optimising glycaemic control to recent data from cardiovascular outcomes trials (CVOTs) demonstrating organ-protective effects of newer glucose-lowering drugs (GLDs). The results from these CVOTs were derived mainly from people with type 2 diabetes and prior cardiovascular and kidney disease or multiple risk factors. In more recent years, earlier diagnosis in high-risk individuals has contributed to the large proportion of people with type 2 diabetes who do not have complications. In these individuals, a legacy effect of early and optimal control of blood glucose and cardiometabolic risk factors has been proven to reduce cardiovascular and kidney disease events and all-cause mortality. As there is a lack of RCTs investigating the potential synergistic effects of intensive glucose control and organ-protective effects of newer GLDs, this article re-evaluates the evolution of the scientific evidence and highlights the importance of integrating glycaemic control as a pivotal early therapeutic goal in most people with type 2 diabetes, while targeting existing cardiovascular and kidney disease. We also emphasise the importance of implementing multifactorial management using a multidisciplinary approach to facilitate regular review, patient empowerment and the possibility of tailoring interventions to account for the heterogeneity of type 2 diabetes.
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Affiliation(s)
- Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK.
| | | | - Aslam Amod
- Department of Endocrinology, Nelson Mandela School of Medicine and Life Chatsmed Garden Hospital, Durban, South Africa
| | - Vanita R Aroda
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Pablo Aschner
- Endocrinology Unit, Javeriana University and San Ignacio University Hospital, Bogotá, Colombia
| | - Stephen Colagiuri
- Boden Collaboration, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Viswanathan Mohan
- Department of Diabetology, Dr Mohan's Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
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Ma G, Zhang S, Yu B. Impact of Dipeptidyl Peptidase-4 Inhibitors on Aminotransferases Levels in Patients with Type 2 Diabetes Mellitus With Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trial. CURRENT THERAPEUTIC RESEARCH 2024; 102:100768. [PMID: 39831144 PMCID: PMC11741081 DOI: 10.1016/j.curtheres.2024.100768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/26/2024] [Indexed: 01/22/2025]
Abstract
Background Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are highly prevalent diseases that constitute enormous public health problems. The efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors in blood glucose control in T2DM patients with NAFLD has been established, but little is known about its effect on liver enzyme levels. Objective This meta-analysis aimed to evaluate the influences of DPP-4 inhibitors on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in patients with T2DM and NAFLD. Methods To identify the relevant studies, we searched PubMed, Embase, the Cochrane Library, Wanfang Data, and China National Knowledge Infrastructure. Means differences in liver enzymes and metabolic outcomes were meta-analyzed using a random-effects model, with subgroup analyses by gender, age, area, follow-up duration, and type of DPP-4 inhibitor. Quality assessment of the included studies was conducted using the revised Cochrane risk of bias tool. Results A total of 1323 patients from 16 studies were included in this meta-analysis. The results of analysis of DPP-4 inhibitors showed that the mean difference was -6.19 (95% confidence interval [CI]: -9.45 to -2.92) for ALT and -5.17 (95% CI: -8.10 to -2.23) for AST; this effect was statistically significant from the placebo group which indicates the beneficial effect on liver enzymes. Subgroup analysis revealed that while there were no significant gender differences in enzyme reductions, individuals over 55 years old experienced more pronounced decreases in ALT. Notably, Asian studies showed significant reductions in liver enzymes, contrasting with the minor variations observed in Euramerican regions, and the effectiveness of DPP-4 inhibitors was particularly pronounced during shorter follow-up periods, with effects diminishing over time. Regarding secondary outcomes, there was a notable improvement in gamma-glutamyl transpeptidase, with a mean reduction, and in HbA1c levels, indicating improved glycemic control. Homeostatic model assessment for insulin resistance levels also improved, reflecting better insulin sensitivity. Additionally, adverse event analysis confirmed that DPP-4 inhibitors were well-tolerated with a favorable safety profile. Conclusions DPP-4 inhibitors appear to enhance glycemic control and improve liver enzyme levels, suggesting a potentially effective therapeutic approach for managing T2DM/NAFLD and highlighting their broader metabolic benefits.
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Affiliation(s)
- Gang Ma
- Department of hepatobiliary surgery, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, China
| | - Song Zhang
- Departmant of Pharmacy, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, China
| | - Baozhong Yu
- Clinical trial institutions, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, China
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Briceño-Islas G, Mojica L, Urías-Silvas JE. Functional chia (Salvia hispanica L.) co-product protein hydrolysate: An analysis of biochemical, antidiabetic, antioxidant potential and physicochemical properties. Food Chem 2024; 460:140406. [PMID: 39047480 DOI: 10.1016/j.foodchem.2024.140406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/22/2024] [Accepted: 07/07/2024] [Indexed: 07/27/2024]
Abstract
Protein hydrolysates with antioxidant potential have been reported to act as adjuvants in preventing and treating type-2 diabetes (T2D). This work investigated the biochemical, antidiabetic, antioxidant potential, and physicochemical properties of chia meal protein hydrolysate (CMPH). Bands smaller than 14 kDa were observed in the electrophoretic profile. The predominant amino acids were hydrophobic and aromatic. CMPH had the potential to inhibit α-amylase (IC50: 1.76 ± 0.13 mg/mL), α-glucosidase (IC50: 0.42 ± 0.13 mg/mL), and DPP-IV (IC50: 0.46 ± 0.14 mg/mL). Antioxidant activity for ABTS (IC50: 0.236 mg/mL), DPPH (8.83 ± 0.52%), and ORAC (IC25: 0.115 mg/mL). Against chia meal protein isolate (CMPI), CMPH has a broad solubility (pH 2-12.46). Particle size (624.5 ± 247.3 nm), low PDI (0.22 ± 0.06), ζ-potential (-31.1 ± 2.5 mV), and surface hydrophobicity (11,183.33 ± 2024.11) and the intrinsic fluorescence peak of CMPH was lower than that of CMPI. CMPH represents an alternative to add value to the agri-food co-product of the chia seed oil industry, generating food ingredients with outstanding antidiabetic and antioxidant potential.
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Affiliation(s)
- Gislane Briceño-Islas
- Food Technology, Center for Research and Assistance in Technology and Design of the State of Jalisco, A.C. (CIATEJ), Camino Arenero 1227, El Bajío Arenal, 45019 Zapopan, Jalisco, Mexico
| | - Luis Mojica
- Food Technology, Center for Research and Assistance in Technology and Design of the State of Jalisco, A.C. (CIATEJ), Camino Arenero 1227, El Bajío Arenal, 45019 Zapopan, Jalisco, Mexico
| | - Judith E Urías-Silvas
- Food Technology, Center for Research and Assistance in Technology and Design of the State of Jalisco, A.C. (CIATEJ), Camino Arenero 1227, El Bajío Arenal, 45019 Zapopan, Jalisco, Mexico.
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Liu J, Guo B, Liu Q, Zhu G, Wang Y, Wang N, Yang Y, Fu S. Cellular Senescence: A Bridge Between Diabetes and Microangiopathy. Biomolecules 2024; 14:1361. [PMID: 39595537 PMCID: PMC11591988 DOI: 10.3390/biom14111361] [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: 08/28/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
Cellular senescence is a state of permanent cell cycle arrest and plays an important role in many vascular lesions. This study found that the cells of diabetic patients have more characteristics of senescence, which may cause microvascular complications. Cell senescence, as one of the common fates of cells, links microangiopathy and diabetes. Cell senescence in a high-glucose environment can partially elucidate the mechanism of diabetic microangiopathy, and various types of cellular senescence induced by it can promote the progression of diabetic microangiopathy. Still, the molecular mechanism of microangiopathy-related cellular senescence has not yet been clearly studied. Building on recent research evidence, we herein summarize the fundamental mechanisms underlying the development of cellular senescence in various microangiopathies associated with diabetes. We gradually explain how cellular senescence serves as a key driver of diabetic microangiopathy. At the same time, the treatment of basic senescence mechanisms such as cellular senescence may have a great impact on the pathogenesis of the disease, may be more effective in preventing the development of diabetic microangiopathy, and may provide new ideas for the clinical treatment and prognosis of diabetic microangiopathy.
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Affiliation(s)
- Jiahui Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Buyu Guo
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Qianqian Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Guomao Zhu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Yaqi Wang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Na Wang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Yichen Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (J.L.); (B.G.); (Q.L.); (G.Z.); (Y.W.); (N.W.); (Y.Y.)
| | - Songbo Fu
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Province Clinical Research Center for Endocrine Disease, Lanzhou 730000, China
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Roy S, Ghosh A, Majie A, Karmakar V, Das S, Dinda SC, Bose A, Gorain B. Terpenoids as potential phytoconstituent in the treatment of diabetes: From preclinical to clinical advancement. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155638. [PMID: 38728916 DOI: 10.1016/j.phymed.2024.155638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/21/2024] [Accepted: 04/13/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy. PURPOSES The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems. STUDY DESIGN An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions. METHODS Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation. RESULTS Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data. CONCLUSION This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders.
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Affiliation(s)
- Sukanta Roy
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Arya Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Ankit Majie
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Varnita Karmakar
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Sourav Das
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Subas Chandra Dinda
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Anirbandeep Bose
- School of Medical Science, Adamas University, Barbaria, Jagannathpur, Kolkata, India.
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
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Sivaraman SA, Sabareesh V. An Update on Dipeptidyl Peptidase-IV Inhibiting Peptides. Curr Protein Pept Sci 2024; 25:267-285. [PMID: 38173201 DOI: 10.2174/0113892037287976231212104607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/30/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024]
Abstract
Diabetes is a chronic metabolic disorder. According to the International Diabetes Federation, about 537 million people are living with diabetes. The two types of diabetes are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), among which the population affected by T2DM is relatively higher. A major reason for T2DM is that insulin stimulation is hampered due to the inactivation of incretin hormones. Dipeptidyl peptidase-IV (DPP-IV) is a serine protease that is directly involved in the inactivation of incretin hormones, e.g., glucagon-like peptide-1 (GLP-1). Therefore, the inhibition of DPP-IV can be a promising method for managing T2DM, in addition to other enzyme inhibition strategies, such as inhibition of α-amylase and α -glucosidase. Currently, about 12 different gliptin drugs are available in the market that inhibit DPP-IV in a dose-dependent manner. Instead of gliptins, 'peptides' can also be employed as an alternative and promising way to inhibit DPP-IV. Peptide inhibitors of DPP-IV have been identified from various plants and animals. Chemically synthesized peptides have also been experimented for inhibiting DPP-IV. Most peptides have been analysed by biochemical assays, whereas some in vitro assays have also been reported. Molecular docking analysis has been applied to comprehend the mechanism of inhibition. In this review, certain aspects of natural as well as synthetic peptides are described that have been proven to inhibit DPP-IV.
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Affiliation(s)
- Sachithanantham Annapoorani Sivaraman
- Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632 014, India
- School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632 014, India
| | - Varatharajan Sabareesh
- Centre for Bio-Separation Technology (CBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632 014, India
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Satyadev N, Rivera MI, Nikolov NK, Fakoya AOJ. Exosomes as biomarkers and therapy in type 2 diabetes mellitus and associated complications. Front Physiol 2023; 14:1241096. [PMID: 37745252 PMCID: PMC10515224 DOI: 10.3389/fphys.2023.1241096] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate new therapeutic targets as well as methodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications.
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Affiliation(s)
- Nihal Satyadev
- Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Milagros I. Rivera
- University of Medicine and Health Sciences, Basseterre, St. Kitts and Nevis
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Effects of Initial Combinations of Gemigliptin Plus Metformin Compared with Glimepiride Plus Metformin on Gut Microbiota and Glucose Regulation in Obese Patients with Type 2 Diabetes: The INTESTINE Study. Nutrients 2023; 15:nu15010248. [PMID: 36615904 PMCID: PMC9824054 DOI: 10.3390/nu15010248] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/02/2022] [Accepted: 12/06/2022] [Indexed: 01/06/2023] Open
Abstract
The efficacy and safety of medications can be affected by alterations in gut microbiota in human beings. Among antidiabetic medications, incretin-based therapy such as dipeptidyl peptidase 4 inhibitors might affect gut microbiomes, which are related to glucose metabolism. This was a randomized, controlled, active-competitor study that aimed to compare the effects of combinations of gemigliptin−metformin vs. glimepiride−metformin as initial therapies on gut microbiota and glucose homeostasis in drug-naïve patients with type 2 diabetes. Seventy drug-naïve patients with type 2 diabetes (mean age, 52.2 years) with a glycated hemoglobin (HbA1c) level ≥7.5% were assigned to either gemigliptin−metformin or glimepiride−metformin combination therapies for 24 weeks. Changes in gut microbiota, biomarkers linked to glucose regulation, body composition, and amino acid blood levels were investigated. Although both treatments decreased the HbA1c levels significantly, the gemigliptin−metformin group achieved HbA1c ≤ 7.0% without hypoglycemia or weight gain more effectively than did the glimepiride−metformin group (59% vs. 24%; p < 0.05). At the phylum level, the Firmicutes/Bacteroidetes ratio tended to decrease after gemigliptin−metformin therapy (p = 0.065), with a notable depletion of taxa belonging to Firmicutes, including Lactobacillus, Ruminococcus torques, and Streptococcus (all p < 0.05). However, regardless of the treatment modality, a distinct difference in the overall gut microbiome composition was noted between patients who reached the HbA1c target goal and those who did not (p < 0.001). Treatment with gemigliptin−metformin resulted in a higher achievement of the glycemic target without hypoglycemia or weight gain, better than with glimepiride−metformin; these improvements might be related to beneficial changes in gut microbiota.
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Paul RK, Ahmad I, Patel H, Kumar V, Raza K. Phytochemicals from Amberboa ramosa as potential DPP-IV inhibitors for the management of Type-II Diabetes Mellitus: Inferences from In-silico Investigations. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Munteanu C, Rotariu M, Turnea MA, Anghelescu A, Albadi I, Dogaru G, Silișteanu SC, Ionescu EV, Firan FC, Ionescu AM, Oprea C, Onose G. Topical Reappraisal of Molecular Pharmacological Approaches to Endothelial Dysfunction in Diabetes Mellitus Angiopathy. Curr Issues Mol Biol 2022; 44:3378-3397. [PMID: 36005129 PMCID: PMC9406839 DOI: 10.3390/cimb44080233] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is a frequent medical problem, affecting more than 4% of the population in most countries. In the context of diabetes, the vascular endothelium can play a crucial pathophysiological role. If a healthy endothelium-which is a dynamic endocrine organ with autocrine and paracrine activity-regulates vascular tone and permeability and assures a proper balance between coagulation and fibrinolysis, and vasodilation and vasoconstriction, then, in contrast, a dysfunctional endothelium has received increasing attention as a potential contributor to the pathogenesis of vascular disease in diabetes. Hyperglycemia is indicated to be the major causative factor in the development of endothelial dysfunction. Furthermore, many shreds of evidence suggest that the progression of insulin resistance in type 2 diabetes is parallel to the advancement of endothelial dysfunction in atherosclerosis. To present the state-of-the-art data regarding endothelial dysfunction in diabetic micro- and macroangiopathy, we constructed this literature review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We interrogated five medical databases: Elsevier, PubMed, PMC, PEDro, and ISI Web of Science.
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Affiliation(s)
- Constantin Munteanu
- Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa” Iași, 700454 Iași, Romania; (M.R.); (M.-A.T.)
- Neuromuscular Rehabilitation Division, Teaching Emergency Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania;
| | - Mariana Rotariu
- Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa” Iași, 700454 Iași, Romania; (M.R.); (M.-A.T.)
| | - Marius-Alexandru Turnea
- Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa” Iași, 700454 Iași, Romania; (M.R.); (M.-A.T.)
| | - Aurelian Anghelescu
- Neuromuscular Rehabilitation Division, Teaching Emergency Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania;
- Faculty of Midwives and Nursing, University of Medicine and Pharmacy “Carol Davila”, 020022 Bucharest, Romania
| | - Irina Albadi
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (I.A.); (E.V.I.); (C.O.)
- Teaching Emergency County Hospital “Sf. Apostol Andrei”, 900591 Constanta, Romania
| | - Gabriela Dogaru
- Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Clinical Rehabilitation Hospital, 400437 Cluj-Napoca, Romania
| | - Sînziana Calina Silișteanu
- Faculty of Medicine and Biological Sciences, “Stefan cel Mare” University of Suceava, 720229 Suceava, Romania;
| | - Elena Valentina Ionescu
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (I.A.); (E.V.I.); (C.O.)
- Balneal and Rehabilitation Sanatorium of Techirghiol, 906100 Techirghiol, Romania
| | | | - Anca Mirela Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020022 Bucharest, Romania;
| | - Carmen Oprea
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (I.A.); (E.V.I.); (C.O.)
- Balneal and Rehabilitation Sanatorium of Techirghiol, 906100 Techirghiol, Romania
| | - Gelu Onose
- Neuromuscular Rehabilitation Division, Teaching Emergency Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania;
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020022 Bucharest, Romania;
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Shibasaki I, Nakajima T, Fukuda T, Hasegawa T, Ogawa H, Tsuchiya G, Takei Y, Tezuka M, Kato T, Kanazawa Y, Kano Y, Kuwata T, Ouchi M, Toyoda S, Aso Y, Fukuda H. Serum and Adipose Dipeptidyl Peptidase 4 in Cardiovascular Surgery Patients: Influence of Dipeptidyl Peptidase 4 Inhibitors. J Clin Med 2022; 11:jcm11154333. [PMID: 35893426 PMCID: PMC9331841 DOI: 10.3390/jcm11154333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/18/2022] [Accepted: 07/22/2022] [Indexed: 12/25/2022] Open
Abstract
Dipeptidyl peptidase 4 (DPP-4) is a novel adipokine and may be involved in the association between adipose tissue and metabolic syndrome. We investigated DPP-4 and adiponectin levels in the serum, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), and their relationship with preoperative factors, as well as comparing the DPP-4 levels in SAT and EAT with and without DPP-4 inhibitors. This study included 40 patients (25 men, age 67.5 ± 13.8 years). The serum adipokine, DPP-4, and adiponectin levels in SAT and EAT were measured using ELISA and Western blotting. The DPP-4 and adiponectin levels were significantly higher in the SAT than in the EAT. The serum DPP-4 and DPP-4 activity levels had no correlation with the DPP-4 levels in the SAT and EAT, but the DPP-4 levels in the SAT and EAT had a positive correlation. The DPP-4 levels in the SAT were positively correlated with atherosclerosis, diabetes mellitus, DPP-4-inhibitor use, and fasting blood glucose. The DPP-4 levels in the EAT showed a negative correlation with eGFR and a positive correlation with atrial fibrillation. The DPP-4 activity in the serum had a lower tendency in the group taking DPP-4 inhibitors than in the group not taking them. DPP-4 inhibitors may suppress angiogenesis and adipose-tissue hypertrophy.
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Affiliation(s)
- Ikuko Shibasaki
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
- Correspondence:
| | - Toshiaki Nakajima
- Department of Medical KAATSU Training, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (T.N.); (T.H.)
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan;
| | - Taira Fukuda
- Department of Liberal Arts and Human Development, Kanagawa University of Human Services, Yokosuka 238-8522, Kanagawa, Japan;
| | - Takaaki Hasegawa
- Department of Medical KAATSU Training, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (T.N.); (T.H.)
| | - Hironaga Ogawa
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
| | - Go Tsuchiya
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
| | - Yusuke Takei
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
| | - Masahiro Tezuka
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
| | - Takashi Kato
- Department of Cardiovascular Surgery, Maebashi Red Cross Hospital, Maebashi 371-0811, Gunma, Japan; (T.K.); (T.K.)
| | - Yuta Kanazawa
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
| | - Yasuyuki Kano
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
| | - Toshiyuki Kuwata
- Department of Cardiovascular Surgery, Maebashi Red Cross Hospital, Maebashi 371-0811, Gunma, Japan; (T.K.); (T.K.)
| | - Motoshi Ouchi
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan;
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan;
| | - Yoshimasa Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan;
| | - Hirotsugu Fukuda
- Department of Cardiac and Vascular Surgery, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan; (H.O.); (G.T.); (Y.T.); (M.T.); (Y.K.); (Y.K.); (H.F.)
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Fadimu GJ, Le TT, Gill H, Farahnaky A, Olatunde OO, Truong T. Enhancing the Biological Activities of Food Protein-Derived Peptides Using Non-Thermal Technologies: A Review. Foods 2022; 11:1823. [PMID: 35804638 PMCID: PMC9265340 DOI: 10.3390/foods11131823] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/14/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
Bioactive peptides (BPs) derived from animal and plant proteins are important food functional ingredients with many promising health-promoting properties. In the food industry, enzymatic hydrolysis is the most common technique employed for the liberation of BPs from proteins in which conventional heat treatment is used as pre-treatment to enhance hydrolytic action. In recent years, application of non-thermal food processing technologies such as ultrasound (US), high-pressure processing (HPP), and pulsed electric field (PEF) as pre-treatment methods has gained considerable research attention owing to the enhancement in yield and bioactivity of resulting peptides. This review provides an overview of bioactivities of peptides obtained from animal and plant proteins and an insight into the impact of US, HPP, and PEF as non-thermal treatment prior to enzymolysis on the generation of food-derived BPs and resulting bioactivities. US, HPP, and PEF were reported to improve antioxidant, angiotensin-converting enzyme (ACE)-inhibitory, antimicrobial, and antidiabetic properties of the food-derived BPs. The primary modes of action are due to conformational changes of food proteins caused by US, HPP, and PEF, improving the susceptibility of proteins to protease cleavage and subsequent proteolysis. However, the use of other non-thermal techniques such as cold plasma, radiofrequency electric field, dense phase carbon dioxide, and oscillating magnetic fields has not been examined in the generation of BPs from food proteins.
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Affiliation(s)
- Gbemisola J. Fadimu
- School of Science, RMIT University, Melbourne, VIC 3083, Australia; (G.J.F.); (H.G.); (A.F.)
| | - Thao T. Le
- Department of Food and Microbiology, Auckland University of Technology, Private Bag 92006, Auckland 1142, New Zealand;
| | - Harsharn Gill
- School of Science, RMIT University, Melbourne, VIC 3083, Australia; (G.J.F.); (H.G.); (A.F.)
| | - Asgar Farahnaky
- School of Science, RMIT University, Melbourne, VIC 3083, Australia; (G.J.F.); (H.G.); (A.F.)
| | - Oladipupo Odunayo Olatunde
- Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada;
| | - Tuyen Truong
- School of Science, RMIT University, Melbourne, VIC 3083, Australia; (G.J.F.); (H.G.); (A.F.)
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13
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A Treatment to Cure Diabetes Using Plant-Based Drug Discovery. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8621665. [PMID: 35586686 PMCID: PMC9110154 DOI: 10.1155/2022/8621665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/14/2022] [Accepted: 03/04/2022] [Indexed: 01/11/2023]
Abstract
The field of peptides and proteins has opened up new doors for plant-based medication development because of analytical breakthroughs. Enzymatic breakdown of plant-specific proteins yields bioactive peptides. These plant-based proteins and peptides, in addition to their in vitro and vivo outcomes for diabetes treatment, are discussed in this study. The secondary metabolites of vegetation can interfere with the extraction, separation, characterization, and commercialization of plant proteins through the pharmaceutical industry. Glucose-lowering diabetic peptides are a hot commodity. For a wide range of illnesses, bioactive peptides from flora can offer up new avenues for the development of cost-effective therapy options.
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14
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Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules 2022; 27:3055. [PMID: 35630534 PMCID: PMC9147686 DOI: 10.3390/molecules27103055] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/02/2022] [Accepted: 05/07/2022] [Indexed: 02/07/2023] Open
Abstract
In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.
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Affiliation(s)
| | | | | | | | - Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China; (R.Y.); (Y.X.); (X.W.); (L.Y.)
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15
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Saeedi M, Mehranfar F, Ghorbani F, Eskandari M, Ghorbani M, Babaeizad A. Review of pharmaceutical and therapeutic approaches for type 2 diabetes and related disorders. Recent Pat Biotechnol 2022; 16:188-213. [PMID: 35088682 DOI: 10.2174/1872208316666220128102934] [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: 09/12/2021] [Revised: 11/05/2021] [Accepted: 11/30/2021] [Indexed: 11/22/2022]
Abstract
One of the essential diseases that are increasing in the world is type 2 diabetes (T2D), which many people around the world live with this disease. Various studies have revealed that insulin resistance, lessened insulin production has been associated with T2D, and they also show that this disease can have a genetic origin and is associated with different genes such as KCNQ1, PPAR-γ, calpain-10, ADIPOR2, TCF7L2 that can be utilized as a therapeutic target. Different therapeutic approaches and strategies such as exercise and diet, pharmacological approaches, and utilization of nanoparticles in drug delivery and gene therapy can be effective in the treatment and control of T2D. Glucagon-like peptide 1 (GLP-1) and sodium glucose cotransporter-2 (SGLT2) have both been considered as drug classes in the treatment of T2D and T2D-related diseases such as cardiovascular disease and renal disease, and have considerable influences such as diminished cardiovascular mortality in individuals with T2D, ameliorate postprandial glycaemia, ameliorate fasting glycaemia, and diminish body weight on disease treatment and improvement process. In the present review article, we have made an attempt to explore the risk factors, Genes, and diseases associated with T2D, therapeutic approaches in T2D, the influences of drugs such as Dapagliflozin, Metformin, Acarbose, Januvia (Sitagliptin), and Ertugliflozin on T2D in clinical trials and animal model studies. Research in clinical trials has promising results that support the role of these drug approaches in T2D prophylaxis and ameliorate safety even though additional clinical research is still obligatory.
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Affiliation(s)
- Mohammad Saeedi
- Department of Hematology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mehranfar
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fateme Ghorbani
- Department of immunology, Semnan university of Medical sciences, Semnan, Iran
| | - Mohammadali Eskandari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Majid Ghorbani
- Department of Hematology, Mashhad University of Medical sciences, Mashhad, Iran
| | - Ali Babaeizad
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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16
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Ren J, Wang X, Yee C, Gorrell MD, McLennan SV, Twigg SM. Sitagliptin Is More Effective Than Gliclazide in Preventing Pro-Fibrotic and Pro-Inflammatory Changes in a Rodent Model of Diet-Induced Non-Alcoholic Fatty Liver Disease. Molecules 2022; 27:727. [PMID: 35163991 PMCID: PMC8838637 DOI: 10.3390/molecules27030727] [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] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED A diet-induced non-alcoholic fatty liver disease (NAFLD) model causing obesity in rodents was used to examine whether sitagliptin and gliclazide therapies have similar protective effects on pathological liver change. METHODS Male mice were fed a high-fat diet (HFD) or standard chow (Chow) ad libitum for 25 weeks and randomly allocated to oral sitagliptin or gliclazide treatment for the final 10 weeks. Fasting blood glucose and circulating insulin were measured. Inflammatory and fibrotic liver markers were assessed by qPCR. The second messenger ERK and autophagy markers were examined by Western immunoblot. F4/80, collagens and CCN2 were assessed by immunohistochemistry (IHC). RESULTS At termination, HFD mice were obese, hyperinsulinemic and insulin-resistant but non-diabetic. The DPP4 inhibitor sitagliptin prevented intrahepatic induction of pro-fibrotic markers collagen-IV, collagen-VI, CCN2 and TGF-β1 and pro-inflammatory markers TNF-α and IL-1β more effectively than sulfonylurea gliclazide. By IHC, liver collagen-VI and CCN2 induction by HFD were inhibited only by sitagliptin. Sitagliptin had a greater ability than gliclazide to normalise ERK-protein liver dysregulation. CONCLUSION These data indicate that sitagliptin, compared with gliclazide, exhibits greater inhibition of pro-fibrotic and pro-inflammatory changes in an HFD-induced NAFLD model. Sitagliptin therapy, even in the absence of diabetes, may have specific benefits in diet-induced NAFLD.
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Affiliation(s)
- Jing Ren
- Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; (J.R.); (X.W.); (C.Y.); (S.V.M.)
| | - Xiaoyu Wang
- Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; (J.R.); (X.W.); (C.Y.); (S.V.M.)
| | - Christine Yee
- Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; (J.R.); (X.W.); (C.Y.); (S.V.M.)
| | - Mark D. Gorrell
- Liver Enzymes in Metabolism and Inflammation Program, Centenary Institute, The University of Sydney, Newtown, NSW 2042, Australia;
- A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
| | - Susan V. McLennan
- Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; (J.R.); (X.W.); (C.Y.); (S.V.M.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
- New South Wales Health Pathology (Eastern), Camperdown, NSW 2050, Australia
| | - Stephen M. Twigg
- Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; (J.R.); (X.W.); (C.Y.); (S.V.M.)
- Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
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Dawwas GK, Hennessy S, Brensinger CM, Deo R, Bilker WB, Soprano SE, Dhopeshwarkar N, Flory JH, Bloomgarden ZT, Aquilante CL, Kimmel SE, Leonard CE. Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors and Sudden Cardiac Arrest and Ventricular Arrhythmia: Population-Based Cohort Studies. Clin Pharmacol Ther 2022; 111:227-242. [PMID: 34331322 PMCID: PMC9450482 DOI: 10.1002/cpt.2381] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/21/2021] [Indexed: 12/18/2022]
Abstract
In vivo studies suggest that arrhythmia risk may be greater with less selective dipeptidyl peptidase-4 inhibitors, but evidence from population-based studies is missing. We aimed to compare saxagliptin, sitagliptin, and linagliptin with regard to risk of sudden cardiac arrest (SCA)/ventricular arrhythmia (VA). We conducted high-dimensional propensity score (hdPS) matched, new-user cohort studies. We analyzed Medicaid and Optum Clinformatics separately. We identified new users of saxagliptin, sitagliptin (both databases), and linagliptin (Optum only). We defined SCA/VA outcomes using emergency department and inpatient diagnoses. We identified and then controlled for confounders via a data-adaptive, hdPS approach. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar year. We identified the following matched comparisons: saxagliptin vs. sitagliptin (23,895 vs. 96,972) in Medicaid, saxagliptin vs. sitagliptin (48,388 vs. 117,383) in Optum, and linagliptin vs. sitagliptin (36,820 vs. 78,701) in Optum. In Medicaid, use of saxagliptin (vs. sitagliptin) was associated with an increased rate of SCA/VA (adjusted HR (aHR), 2.01, 95% confidence interval (CI) 1.24-3.25). However, in Optum data, this finding was not present (aHR, 0.79, 95% CI 0.41-1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65, 95% CI 0.36-1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared with sitagliptin in two independent datasets. It remains unclear whether these findings are due to heterogeneity of treatment effect in the different populations, chance, or unmeasured confounding.
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Affiliation(s)
- Ghadeer K. Dawwas
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sean Hennessy
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Systems Pharmacology Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Colleen M. Brensinger
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rajat Deo
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Warren B. Bilker
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Samantha E. Soprano
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Neil Dhopeshwarkar
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James H. Flory
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Endocrinology Service, Department of Subspecialty Medicine, Department of Subspecialty Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Zachary T. Bloomgarden
- Division of Endocrinology Metabolism, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christina L. Aquilante
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy Pharmaceutical Sciences, Anschutz Medical Campus, University of Colorado, Aurora, Colorado, USA
| | - Stephen E. Kimmel
- Department of Epidemiology, College of Public Health Health Professions & College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Charles E. Leonard
- Center for Pharmacoepidemiology Research Training, Center for Clinical Epidemiology Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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18
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Rokszin G, Kiss Z, Sütő G, Kempler P, Jermendy G, Fábián I, Szekanecz Z, Poór G, Wittmann I, Molnár GA. Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study. Front Oncol 2021; 11:725465. [PMID: 34778040 PMCID: PMC8581296 DOI: 10.3389/fonc.2021.725465] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/30/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND In diabetes mellitus, during the last years, cancer became of equivalent importance as a cardiovascular disease in terms of mortality. In an earlier study, we have analyzed data of the National Health Insurance Fund (NHIF) of Hungary with regards all patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) vs. those treated with dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4is) in a given timeframe. In propensity score-matched groups of SGLT2i- vs. DPP-4i-treated patients, we found a lower incidence of cancer in general. In this post-hoc analysis, we aimed to obtain data on the incidence of site-specific cancer. PATIENTS AND METHODS All patients starting an SGLT2i or a DPP-4i between 2014 and 2017 in Hungary were included; the two groups (SGLT2i vs. DPP-4i) were matched for 54 clinical and demographical parameters. The follow-up period was 639 vs. 696 days, respectively. Patients with a letter "C" International Classification of Diseases, 10th Revision (ICD-10) code have been chosen, and those with a known malignancy within a year before the onset of the study have been excluded from the analysis. RESULTS We found a lower risk of urinary tract [HR 0.50 (95% CI: 0.32-0.79) p = 0.0027] and hematological malignancies [HR 0.50 (95% CI: 0.28-0.88) p = 0.0174] in patients treated with SGLT2i vs. those on DPP-4i. Risk of other types of cancer (including lung and larynx, lower gastrointestinal (GI) tract, rectum, pancreas, non-melanoma skin cancers, breast, or prostate) did not differ significantly between the two groups. When plotting absolute risk difference against follow-up time, an early divergence of curves was found in case of prostate, urinary tract, and hematological malignancies, whereas late divergence can be seen in case of cancers of the lung and larynx, the lower GI tract, and the breast. CONCLUSIONS Urinary tract and hematological malignancies were less frequent in patients treated with SGLT2i vs. DPP-4i. An early vs. late divergence could be observed for different cancer types, which deserves further studies.
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Affiliation(s)
| | - Zoltán Kiss
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Gábor Sütő
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Péter Kempler
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | | | - Ibolya Fábián
- RxTarget Ltd, Szolnok, Hungary
- Faculty of Mathematics, University of Veterinary Medicine, Budapest, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gyula Poór
- National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
| | - István Wittmann
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Gergő Attila Molnár
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
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19
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Phillips J, Chen JHC, Ooi E, Prunster J, Lim WH. Global Epidemiology, Health Outcomes, and Treatment Options for Patients With Type 2 Diabetes and Kidney Failure. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2021; 2:731574. [PMID: 36994340 PMCID: PMC10012134 DOI: 10.3389/fcdhc.2021.731574] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
The burden of type 2 diabetes and related complications has steadily increased over the last few decades and is one of the foremost global public health threats in the 21st century. Diabetes is one of the leading causes of chronic kidney disease and kidney failure and is an important contributor to the cardiovascular morbidity and mortality in this population. In addition, up to one in three patients who have received kidney transplants develop post-transplant diabetes, but the management of this common complication continues to pose a significant challenge for clinicians. In this review, we will describe the global prevalence and temporal trend of kidney failure attributed to diabetes mellitus in both developing and developed countries. We will examine the survival differences between treated kidney failure patients with and without type 2 diabetes, focusing on the survival differences in those on maintenance dialysis or have received kidney transplants. With the increased availability of novel hypoglycemic agents, we will address the potential impacts of these novel agents in patients with diabetes and kidney failure and in those who have developed post-transplant diabetes.
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Affiliation(s)
- Jessica Phillips
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- *Correspondence: Jessica Phillips,
| | - Jenny H. C. Chen
- School of Medicine, University of Wollongong, Wollongong, NSW, Australia
- Depatment of Nephrology, Wollongong Hospital, Wollongong, NSW, Australia
| | - Esther Ooi
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns, QLD, Australia
| | - Wai H. Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Medical School, University of Western Australia, Perth, WA, Australia
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20
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Blahova J, Martiniakova M, Babikova M, Kovacova V, Mondockova V, Omelka R. Pharmaceutical Drugs and Natural Therapeutic Products for the Treatment of Type 2 Diabetes Mellitus. Pharmaceuticals (Basel) 2021; 14:806. [PMID: 34451903 PMCID: PMC8398612 DOI: 10.3390/ph14080806] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas, meglinides), alpha-glucosidase inhibitors, and the newest incretin-based therapies and sodium-glucose co-transporter 2 inhibitors. However, their long-term application can cause many harmful side effects, emphasising the importance of the using natural therapeutic products. Natural health substances including non-flavonoid polyphenols (e.g., resveratrol, curcumin, tannins, and lignans), flavonoids (e.g., anthocyanins, epigallocatechin gallate, quercetin, naringin, rutin, and kaempferol), plant fruits, vegetables and other products (e.g., garlic, green tea, blackcurrant, rowanberry, bilberry, strawberry, cornelian cherry, olive oil, sesame oil, and carrot) may be a safer alternative to primary pharmacological therapy. They are recommended as food supplements to prevent and/or ameliorate T2DM-related complications. In the advanced stage of T2DM, the combination therapy of synthetic agents and natural compounds with synergistic interactions makes the treatment more efficient. In this review, both pharmaceutical drugs and selected natural products, as well as combination therapies, are characterized. Mechanisms of their action and possible negative side effects are also provided.
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Affiliation(s)
- Jana Blahova
- Department of Botany and Genetics, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia; (J.B.); (M.B.); (V.M.)
| | - Monika Martiniakova
- Department of Zoology and Anthropology, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia;
| | - Martina Babikova
- Department of Botany and Genetics, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia; (J.B.); (M.B.); (V.M.)
| | - Veronika Kovacova
- Department of Zoology and Anthropology, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia;
| | - Vladimira Mondockova
- Department of Botany and Genetics, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia; (J.B.); (M.B.); (V.M.)
| | - Radoslav Omelka
- Department of Botany and Genetics, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia; (J.B.); (M.B.); (V.M.)
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Paul RK, Nath V, Kumar V. Structure based virtual screening of natural compounds and molecular dynamics simulation: Butirosin as Dipeptidyl peptidase (DPP-IV) inhibitor. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2021. [DOI: 10.1016/j.bcab.2021.102042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Ahrén B. Glucose-lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase-4 inhibition. J Diabetes Investig 2021; 12:1128-1135. [PMID: 33949781 PMCID: PMC8264410 DOI: 10.1111/jdi.13564] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/13/2021] [Accepted: 04/18/2021] [Indexed: 12/28/2022] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibition is a glucose-lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose-dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP-4 inhibition represents a therapy that targets the underlying mechanisms of the disease. If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium-glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms. In individuals of East Asian origin, islet dysfunction is of particular importance for the development of type 2 diabetes. Consequently, it has been shown in several studies that DPP-4 is efficient in these populations. This mini-review highlights the islet mechanisms of DPP-4 inhibition, islet dysfunction as a key factor for hyperglycemia in type 2 diabetes and that, consequently, DPP-4 is of particular value in populations where islet dysfunction is central, such as in individuals of East Asian origin.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Kang SM, Jung HS, Kwon MJ, Lee SH, Park JH. Effects of anagliptin on the stress induced accelerated senescence of human umbilical vein endothelial cells. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:750. [PMID: 34268363 PMCID: PMC8246235 DOI: 10.21037/atm-21-393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/14/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Dipeptidyl peptidase 4 (DPP-4) inhibitors have been used to treat type 2 diabetes mellitus (T2DM) via inhibition of the enzymatic activity of DPP-4 in degrading active circulating glucagon-like peptide-1. In addition to their glucose-lowering effect, DPP-4 inhibitors have pleiotropic effects. Cellular senescence regarded as important pathophysiological mechanism underlying many degenerative diseases, including atherosclerosis. This study was performed to examine whether the DPP-4 inhibitor, anagliptin, can directly protect against stress-induced accelerated senescence (SIAS) of vascular endothelial cells, regardless of changes in ambient glucose level. METHODS Cultured human umbilical vein endothelial cells (HUVECs) were exposed to various concentrations of H2O2, and a fixed high concentration of glucose (25 mM) with varying concentrations of palmitate. Changes in cell viability, senescence-associated beta-galactosidase (SA-β-Gal), p16 protein, markers of endoplasmic reticulum (ER) stress, NOX4, NLRP inflammasome, lactate dehydrogenase (LDH) release and interleukin (IL) 1β levels were measured by Cell Counting Kit-8 assay, immunofluorescent staining, Western blotting, and enzyme-linked immunosorbent assay, respectively before and after application of anagliptin. RESULTS The application of oxidative and glucolipotoxic stresses markedly increased the degree of SIAS of HUVECs, represented by increased SA-β-Gal immunopositivity and p16 protein expression. Aggravation of ER stress and inflammatory response were also observed through increased levels of ATF4, CHOP, peIF2α, NOX4, NLRP inflammasome, LDH, and IL1β. These changes were markedly reversed by the administration of anagliptin. CONCLUSIONS The DPP-4 inhibitor anagliptin effectively protects HUVECs against SIAS, suggesting its potential use in the development of new treatment strategies for aging.
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Affiliation(s)
- Seon Mee Kang
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, South Korea
- Paik Institute for Clinical Research, Inje University, Busan, South Korea
| | - Hye Sook Jung
- Paik Institute for Clinical Research, Inje University, Busan, South Korea
| | - Min Jeong Kwon
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, South Korea
| | - Soon Hee Lee
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, South Korea
| | - Jeong Hyun Park
- Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, South Korea
- Paik Institute for Clinical Research, Inje University, Busan, South Korea
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Gupta A, Behl T, Sehgal A, Bhardwaj S, Singh S, Sharma N, Hafeez A. Exploring the recent molecular targets for diabetes and associated complications. Mol Biol Rep 2021; 48:2863-2879. [PMID: 33763776 DOI: 10.1007/s11033-021-06294-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 03/16/2021] [Indexed: 12/19/2022]
Abstract
Diabetes is likely one of the centenarian diseases which is apprehended with certainty to humans. According to established protocols of the World Health Organisation (WHO) and numerous investigated studies diabetes is analyzed as a stellar and leading health issue worldwide. Although, the implicit costs of this pathology are increasing every year, thus, there is a need to find a novel method which can provide promising results in the management of diabetes and can overcome the side effects associated with the conventional medication. Comprehensive review of this topic was undertaken through various research and review papers which were conducted using MEDLINE, BIOSIS and EMBASE database. Using various keywords, we retrieve the most relevant content for the thorough review on recent targets and novel molecular pathways for targeting diabetes and associated complications. From the detailed analysis, we have highlighted some molecular pathways and novel targets which had shown promising results in both in-vitro and in-vivo studies and may be considered as pipeline target for clinical trials. Furthermore, these targets not only abetted amelioration of diabetes but also helped in mitigation of diabetes associated complications as well. Thus, based on the available information and literature on these potential molecules, conclusive evidence can be drawn which confirms targeting these novel pathways may unleash an array of benefits that have the potential to overpower the benefits obtained from conventional therapy in the management of diabetes thereby decreasing morbidity and mortality associated with diabetic complications.
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Affiliation(s)
- Amit Gupta
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Shaveta Bhardwaj
- GHG Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Abdul Hafeez
- Glocal School of Pharmacy, Glocal University, Mirzapur Pole, Uttar Pradesh, India
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Katsuno T, Shiraiwa T, Iwasaki S, Park H, Watanabe N, Kaneko S, Terasaki J, Hanafusa T, Imagawa A, Shimomura I, Ikegami H, Koyama H, Namba M, Miyagawa JI. Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2). Adv Ther 2021; 38:1514-1535. [PMID: 33507500 DOI: 10.1007/s12325-021-01631-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/15/2021] [Indexed: 12/22/2022]
Abstract
INTRODUCTION This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM). METHODS This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events. RESULTS HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups. CONCLUSIONS Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.
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Affiliation(s)
- Tomoyuki Katsuno
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
- Department of Occupational Therapy, School of Rehabilitation, Hyogo University of Health Sciences, Hyogo, Japan.
| | | | | | | | | | | | - Jungo Terasaki
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Osaka, Japan
| | | | - Akihisa Imagawa
- Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroshi Ikegami
- Department of Endocrinology, Metabolism and Diabetes, Kindai University, Osaka, Japan
| | - Hidenori Koyama
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Mitsuyoshi Namba
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
- Takarazuka City Hospital, Hyogo, Japan
| | - Jun-Ichiro Miyagawa
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
- Keiseikai Medical Corporation, Osaka, Japan
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Man AWC, Xia N, Li H. Circadian Rhythm in Adipose Tissue: Novel Antioxidant Target for Metabolic and Cardiovascular Diseases. Antioxidants (Basel) 2020; 9:E968. [PMID: 33050331 PMCID: PMC7601443 DOI: 10.3390/antiox9100968] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity is a major risk factor for most metabolic and cardiovascular disorders. Adipose tissue is an important endocrine organ that modulates metabolic and cardiovascular health by secreting signaling molecules. Oxidative stress is a common mechanism associated with metabolic and cardiovascular complications including obesity, type 2 diabetes, and hypertension. Oxidative stress can cause adipose tissue dysfunction. Accumulating data from both humans and experimental animal models suggest that adipose tissue function and oxidative stress have an innate connection with the intrinsic biological clock. Circadian clock orchestrates biological processes in adjusting to daily environmental changes according to internal or external cues. Recent studies have identified the genes and molecular pathways exhibiting circadian expression patterns in adipose tissue. Disruption of the circadian rhythmicity has been suggested to augment oxidative stress and aberrate adipose tissue function and metabolism. Therefore, circadian machinery in the adipose tissue may be a novel therapeutic target for the prevention and treatment of metabolic and cardiovascular diseases. In this review, we summarize recent findings on circadian rhythm and oxidative stress in adipose tissue, dissect the key components that play a role in regulating the clock rhythm, oxidative stress and adipose tissue function, and discuss the potential use of antioxidant treatment on metabolic and cardiovascular diseases by targeting the adipose clock.
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Affiliation(s)
| | | | - Huige Li
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Langenbeckstr, 1, 55131 Mainz, Germany; (A.W.C.M.); (N.X.)
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Abstract
In spite of developments with novel insulin preparations, novel modes of insulin delivery with insulin infusion pumps, and the facility of continuous glucose monitoring, only 20% of patients with type 1 diabetes are under adequate control. The need for innovation is clear, and, therefore, the use of adjunct therapies with other pharmacological agents currently in use for type 2 diabetes, has been tried. Currently, pramlintide is the only agent licensed for use in this condition in addition to insulin. Global trials have been conducted with liraglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and sotagliflozin, an inhibitor of both SGLT1 and SGLT2 transporters. While dapagliflozin and sotagliflozin have now been licensed for clinical use in this condition in Europe and Japan, they have hitherto not been licensed in the United States due to a small increase in the risk of diabetic ketoacidosis. However, these agents reduce glycosylated hemoglobin (HbA1c) by 0.4%, reduce glycemic oscillations, and do not increase the risk of hypoglycemia. Liraglutide, on the other hand, induced a smaller reduction in HbA1c and thus was not considered for a license. However, further trials are currently being conducted with a combination of semaglutide, the most potent GLP-1RA, and dapagliflozin to determine whether this approach would yield better outcomes.
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Affiliation(s)
- Itivrita Goyal
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
| | - Alamgir Sattar
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
| | - Megan Johnson
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
| | - Paresh Dandona
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
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Anderson S, Cotiguala L, Tischer S, Park JM, McMurry K. Review of Newer Antidiabetic Agents for Diabetes Management in Kidney Transplant Recipients. Ann Pharmacother 2020; 55:496-508. [PMID: 32795145 DOI: 10.1177/1060028020951955] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE This systematic review describes the efficacy, safety, and drug interactions of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose transport protein 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs). DATA SOURCES Articles were identified by English-language MEDLINE search, published prior to May 2020, using the terms kidney transplant, OR PTDM, OR NODAT, AND metformin, OR DPP4, OR GLP1, OR SGLT2. STUDY SELECTION AND DATA EXTRACTION All selected studies were included if the study population was composed of adult KTRs who were diagnosed with either impaired glucose tolerance, diabetes mellitus (DM), new-onset diabetes after transplant (NODAT), or posttransplantation diabetes mellitus (PTDM). DATA SYNTHESIS In KTRs, there is evidence for safety with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors. However, urinary tract infections and a slight initial decrease in renal function may limit use of SGLT2 inhibitors. As compared with the nontransplant type 2 DM population, SGLT2 inhibitors are not as efficacious in KTRs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE This review provides an overview of the current literature on newer antidiabetic agents, addressing efficacy, safety, and drug interactions to help guide clinical decision-making for their use in KTRs. CONCLUSION Newer antidiabetic agents have been recommended by the American Diabetes Association for potential cardiovascular, renal, and hypoglycemic benefits. Particular agents, such as DPP-4 inhibitors and GLP-1 RAs may play a role in correcting PTDM-related defects. Clinicians need to take into account both patient-specific and drug-specific characteristics when initiating these agents in KTRs.
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Fernandes G, Matos JE, Jaffe DH, Beyer G, Yang L, Iglay K, Gantz I, Rajpathak S. Factors associated with the discontinuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) after initiation of insulin. Curr Med Res Opin 2020; 36:377-386. [PMID: 31771370 DOI: 10.1080/03007995.2019.1698416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Objective: Type 2 diabetes (T2D) is a prevalent health problem. Oral agents, with the exception of metformin, are often discontinued with the initiation of insulin. The objective was to understand the proportion of patients discontinuing dipeptidyl peptidase-4 inhibitors (DPP-4is) and the reasons for the decision to discontinue.Methods: A retrospective study using a health claims database investigated discontinuation of DPP-4i in adult patients on a dual therapy of metformin and DPP-4i who initiated insulin (n = 3391). An online survey administered to 406 physicians in the US examined reasons for discontinuation. Physicians surveyed included endocrinologists (34.5%), general practitioners (32.5%), internal medicine specialists (30.5%), and diabetologists (2.5%), treating a monthly average of 154 patients.Results: Among patients treated with metformin and DPP-4is who were newly prescribed insulin, 33.3 and 57.3% discontinued DPP-4i therapy within 3 and 12 months, respectively. Patients who discontinued DPP-4i therapy had higher out-of-pocket costs and a greater proportion of renal and liver disease. Top 3 responses for discontinuation included adverse events/tolerability issues (58.9%), lack of efficacy/treatment goals not being met (55.4%) and additional cost of DPP-4i with insulin (48.5%). Top 3 responses for continuing DPP-4i included meeting treatment goals (70.7%), using a lower dose of insulin (65.3%) and good tolerability (48.0%). Physician characteristics, such as physician specialty, age, gender and location impacted to some extent the reasons for treatment decisions.Conclusions: A large proportion of patients discontinue DPP-4is in the real world when initiating insulin. The impact of physician characteristics in treatment decisions highlights the need for enhanced physician training and support as new clinical data emerges and therapy options are available.
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Affiliation(s)
| | | | | | | | | | | | - Ira Gantz
- Merck & Co., Inc., Kenilworth, NJ, USA
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Nam DH, Park J, Park SH, Kim KS, Baek EB. Effect of gemigliptin on cardiac ischemia/reperfusion and spontaneous hypertensive rat models. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2019; 23:329-334. [PMID: 31496870 PMCID: PMC6717789 DOI: 10.4196/kjpp.2019.23.5.329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023]
Abstract
Diabetes is associated with an increased risk of cardiovascular complications. Dipeptidyl peptidase-4 (DPP-IV) inhibitors are used clinically to reduce high blood glucose levels as an antidiabetic agent. However, the effect of the DPP-IV inhibitor gemigliptin on ischemia/reperfusion (I/R)-induced myocardial injury and hypertension is unknown. In this study, we assessed the effects and mechanisms of gemigliptin in rat models of myocardial I/R injury and spontaneous hypertension. Gemigliptin (20 and 100 mg/kg/d) or vehicle was administered intragastrically to Sprague-Dawley rats for 4 weeks before induction of I/R injury. Gemigliptin exerted a preventive effect on I/R injury by improving hemodynamic function and reducing infarct size compared to the vehicle control group. Moreover, administration of gemigliptin (0.03% and 0.15%) powder in food for 4 weeks reversed hypertrophy and improved diastolic function in spontaneously hypertensive rats. We report here a novel effect of the gemigliptin on I/R injury and hypertension.
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Affiliation(s)
- Dae-Hwan Nam
- Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea.,Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
| | - Jinsook Park
- Corporate R&D, LG Chem, Ltd., Daejeon 34122, Korea
| | - Sun-Hyun Park
- Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea
| | - Ki-Suk Kim
- Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea.,Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, Korea
| | - Eun Bok Baek
- Corporate R&D, LG Chem, Ltd., Daejeon 34122, Korea
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An Integrated In Silico and In Vitro Assays of Dipeptidyl Peptidase-4 and α-Glucosidase Inhibition by Stellasterol from Ganoderma australe. Sci Pharm 2019. [DOI: 10.3390/scipharm87030021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Ganoderma fungus is rich in terpenoids. These compounds are known for their anti-hyperglycemic activities. However, the study of terpenoids as the secondary metabolite from Ganoderma as a dipeptidyl peptidase-4 (DPP-4) inhibitor remains unexplored. In addition, we examined the α-glucosidase inhibition activity. Objective: This study aimed to isolate the major terpenoid from non-laccate Ganoderma and examined its inhibitor activity on DPP-4 and α-glucosidase enzymes, and its interaction. Methods: The compound was isolated using column chromatography from Ganoderma australe. The structure of the isolated compound was confirmed by 1H and 13C nuclear magnetic resonance spectroscopy, while the inhibitory activity was evaluated using an enzymatic assay. The interaction of the isolated compound with DPP-4 and α-glucosidase enzymes was investigated using an in silico study. Results: The isolated compound was identified as stellasterol; IC50 values for DPP-4 and α-glucosidase inhibitor were 427.39 µM and 314.54 µM, respectively. This study revealed that the inhibitory effect of stellasterol on DPP-4 enzyme is through hydrophobic interaction, while the α-glucosidase enzyme is due to the interaction with six amino acids of the enzyme. Conclusion: Stellasterol is the major component of the steroid from G. australe. Enzyme inhibitory assay and in silico study suggest that stellasterol may contribute antidiabetic activity with a mechanism closer to acarbose rather than to sitagliptin.
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Patil SP, Goswami A, Kalia K, Kate AS. Plant-Derived Bioactive Peptides: A Treatment to Cure Diabetes. Int J Pept Res Ther 2019; 26:955-968. [PMID: 32435169 PMCID: PMC7223764 DOI: 10.1007/s10989-019-09899-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2019] [Indexed: 12/17/2022]
Abstract
ABSTRACT Recent advances in analytical techniques have opened new opportunities for plant-based drug discovery in the field of peptide and proteins. Enzymatic hydrolysis of plant parent proteins forms bioactive peptides which are explored in the treatment of various diseases. In this review, we will discuss the identified plant-based bioactive proteins and peptides and the in vitro, in vivo results for the treatment of diabetes. Extraction, isolation, characterization and commercial utilization of plant proteins is a challenge for the pharmaceutical industry as plants contain several interfering secondary metabolites. The market of peptide drugs for the treatment of diabetes is growing at a fast rate. Plant-based bioactive peptides might open up new opportunities to discover economic lead for the management of various diseases. GRAPHIC ABSTRACT
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Affiliation(s)
- Shital P. Patil
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat India
| | - Ashutosh Goswami
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat India
| | - Kiran Kalia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat India
| | - Abhijeet S. Kate
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat India
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Hussain H, Abbas G, Green IR, Ali I. Dipeptidyl peptidase IV inhibitors as a potential target for diabetes: patent review (2015-2018). Expert Opin Ther Pat 2019; 29:535-553. [PMID: 31203700 DOI: 10.1080/13543776.2019.1632290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs. AREAS COVERE This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018. EXPERT OPINION A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.
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Affiliation(s)
- Hidayat Hussain
- a Department of Bioorganic Chemistry , Leibniz Institute of Plant Biochemistry , Halle (Saale) , Germany
| | - Ghulam Abbas
- b Department of Biological Sciences and Chemistry , College of Arts and Sciences, University of Nizwa , Nizwa , Sultanate of Oman
| | - Ivan R Green
- c Department of Chemistry and Polymer Science , University of Stellenbosch , Matieland, Stellenbosch , South Africa
| | - Iftikhar Ali
- d Department of Chemistry , Karakoram International University , Gilgit, Gilgit-Baltistan , Pakistan
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Abstract
In the 1990s it was discovered that the enzyme dipeptidyl peptidase-4 (DPP-4) inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibition results in raised levels of the two incretin hormones which in turn result in lowering of circulating glucose through stimulation of insulin secretion and inhibition of glucagon secretion. Since then, several small orally available molecules have been developed with DPP-4 inhibitory action. Early studies in the 1990s showed that the DPP-4 inhibitors improve glycemia in animals. Subsequent clinical studies during the 2000s showed a glucose-lowering action of DPP-4 inhibitors also in human subjects with type 2 diabetes. This action was seen when DPP-4 inhibitors were used both as monotherapy and as add-on to other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. The DPP-4 inhibitors were also found to have a low risk of adverse events, including hypoglycemia. Five of the DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities and entered the market between 2006 and 2013. DPP-4 inhibitors have thereafter undergone long-term cardiovascular outcome trials, showing non-inferiority for risk of major acute cardiovascular endpoints. Also the risk of other potential adverse events is low in these long-term studies. DPP-4 inhibitors are at present included in guidelines as a glucose-lowering concept both as monotherapy and in combination therapies. This article summarizes the development of the DPP-4 inhibition concept from its early stages in the 1990s. The article underscores that the development has its basis in scientific studies on pathophysiology of type 2 diabetes and the importance of targeting the islet dysfunction, that the development has been made possible through academic science in collaboration with the research-oriented pharmaceutical industry, and that the development of a novel concept takes time and requires focused efforts, persistence and long-term perserverance.
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Kim HJ, Baek EB, Kim SJ. Potentiation of endothelium-dependent vasorelaxation of mesenteric arteries from spontaneously hypertensive rats by gemigliptin, a dipeptidyl peptidase-4 inhibitor class of anti-diabetic drug. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 22:713-719. [PMID: 30402032 PMCID: PMC6205934 DOI: 10.4196/kjpp.2018.22.6.713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/09/2018] [Accepted: 08/10/2018] [Indexed: 12/11/2022]
Abstract
Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are anti-diabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by 1 µM gemigliptin while not by saxagliptin and sitagliptin up to 10 µM. The ACh-EDR of SHR MA was also improved by 1 µM gemigliptin while similar recovery was observed with higher concentration (10 µM) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endotheliumdenuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with 30 µM pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.
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Affiliation(s)
- Hae Jin Kim
- Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.,Hypoxic/Ischemic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Eun Bok Baek
- Department of Regulatory Toxicology, Life Science R&D, LG Chem Ltd., LG Science Park, Seoul 07796, Korea
| | - Sung Joon Kim
- Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.,Hypoxic/Ischemic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
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Frandsen CS, Dejgaard TF, Madsbad S, Holst JJ. Non-insulin pharmacological therapies for treating type 1 diabetes. Expert Opin Pharmacother 2018; 19:947-960. [PMID: 29991320 DOI: 10.1080/14656566.2018.1483339] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Despite intensified insulin treatment, many persons with type 1 diabetes (T1D) do not achieve glycemic and metabolic targets. Consequently, non-insulin chemical therapies that improve glycemic control and metabolic parameters without increasing the risk of adverse events (including hypoglycemia) are of interest as adjunct therapies to insulin. AREAS COVERED In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D. EXPERT OPINION The current evidence shows that the efficacy of non-insulin therapies as add-on therapies to insulin is minimal or modest with an average HbA1c reduction of 0.2-0.5% (2-6 mmol/mol). Indeed, the current focus is on the development of SGLT inhibitors as adjuncts to insulin in type 1 diabetes. Studies of subgroups with obesity, residual beta-cell function (including newly diagnosed patients) and patients prone to hypoglycemia could be areas of future research.
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Affiliation(s)
| | - Thomas Fremming Dejgaard
- a Department of Endocrinology , Hvidovre Hospital, University of Copenhagen , Hvidovre , Denmark.,b Steno Diabetes Center Copenhagen , Gentofte , Denmark
| | - Sten Madsbad
- a Department of Endocrinology , Hvidovre Hospital, University of Copenhagen , Hvidovre , Denmark
| | - Jens Juul Holst
- c Department of Biomedical Sciences and NNF Center for Basic Metabolic Research , University of Copenhagen , Copenhagen , Denmark
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Moriwaki K, Takeuchi T, Fujimoto N, Sawai T, Sato Y, Kumagai N, Masuda J, Nakamori S, Ishida M, Yamada N, Nakamura M, Sakuma H, Ito M, Dohi K. Effect of Sitagliptin on Coronary Flow Reserve Assessed by Magnetic Resonance Imaging in Type 2 Diabetic Patients With Coronary Artery Disease. Circ J 2018; 82:2119-2127. [PMID: 29760346 DOI: 10.1253/circj.cj-18-0083] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND The present study was conducted to assess the cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) on coronary flow reserve (CFR), left ventricular (LV) function and endothelial function of the peripheral artery by comparison with those of α-glucosidase inhibitors (αGI) in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). METHODS AND RESULTS We randomly assigned 30 patients with T2DM and CAD to receive either sitagliptin or voglibose, and 28 patients (age 69±9 years, 75% male, hemoglobin A1c [HbA1c] 6.62±0.48%) completed the study (14 in each group). CFR and LV function, assessed by cardiac magnetic resonance imaging, and endothelial function, assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT), were measured at baseline and 24 weeks after treatment. Clinical and laboratory parameters, including HbA1c level, plasma active glucagon-like peptide-1 concentrations, and biomarkers of inflammation, were unchanged in both groups after 24 weeks of treatment. CFR were unchanged in both the αGI group (3.01±0.98 at baseline and 3.06±0.8 after treatment, P=NS) and the DPP4i group (4.29±2.04 at baseline and 3.63±1.31 after treatment, P=NS), with no interaction effect. LV functional parameters and the reactive hyperemia index also remained unchanged after the 24-week treatment. CONCLUSIONS DPP4i did not improve CFR, LV function or endothelial function of the peripheral artery in patients with relatively well-controlled T2DM and CAD.
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Affiliation(s)
- Keishi Moriwaki
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Tetsushiro Takeuchi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Naoki Fujimoto
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Toshiki Sawai
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Yuichi Sato
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Naoto Kumagai
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Jun Masuda
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Shiro Nakamori
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Masaki Ishida
- Department of Radiology, Mie University Graduate School of Medicine
| | - Norikazu Yamada
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Mashio Nakamura
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Hajime Sakuma
- Department of Radiology, Mie University Graduate School of Medicine
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
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Sloop KW, Emmerson PJ, Statnick MA, Willard FS. The current state of GPCR-based drug discovery to treat metabolic disease. Br J Pharmacol 2018; 175:4060-4071. [PMID: 29394497 DOI: 10.1111/bph.14157] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 10/14/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023] Open
Abstract
One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. LINKED ARTICLES This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.
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Affiliation(s)
- Kyle W Sloop
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
| | - Paul J Emmerson
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
| | - Michael A Statnick
- Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
| | - Francis S Willard
- Quantitative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
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Reynolds L, Genuth SM. The Role of Diabetes Care and Its Contributions to the Field of Diabetes: A Profile in Progress. Diabetes Care 2018; 41:241-249. [PMID: 29358468 DOI: 10.2337/dci17-0021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Abstract
PURPOSE OF REVIEW Guidelines for a standard second diabetes medication for the treatment of type 2 diabetes (T2DM) have yet to be established. The rapid increase in the number of newer therapies available makes the choice more difficult. Thus, we reviewed clinical trial evidence evaluating newer therapies available for treatment intensification beyond monotherapy. RECENT FINDINGS Head-to-head studies comparing newer therapies versus traditional (i.e., sulfonylurea) approaches consistently find lower incidence of hypoglycemia and weight gain with newer therapies. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors demonstrate high glycemic efficacy, while merits of dipeptidyl peptidase-4 (DPP-4) inhibitors include their tolerability. Secondary effects (weight loss, cardiovascular outcomes, renal function) are of growing interest with newer therapies. Choices for treatment intensification in T2DM diabetes are numerous. Understanding the comparative evidence of newer treatment choices, as provided in this review, may help guide clinical decision making.
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Mega C, Teixeira-de-Lemos E, Fernandes R, Reis F. Renoprotective Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin: A Review in Type 2 Diabetes. J Diabetes Res 2017; 2017:5164292. [PMID: 29098166 PMCID: PMC5643039 DOI: 10.1155/2017/5164292] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 07/12/2017] [Indexed: 12/13/2022] Open
Abstract
Diabetic nephropathy (DN) is now the single commonest cause of end-stage renal disease (ESRD) worldwide and one of the main causes of death in diabetic patients. It is also acknowledged as an independent risk factor for cardiovascular disease (CVD). Since sitagliptin was approved, many studies have been carried out revealing its ability to not only improve metabolic control but also ameliorate dysfunction in various diabetes-targeted organs, especially the kidney, due to putative underlying cytoprotective properties, namely, its antiapoptotic, antioxidant, anti-inflammatory, and antifibrotic properties. Despite overall recommendations, many patients spend a long time well outside the recommended glycaemic range and, therefore, have an increased risk for developing micro- and macrovascular complications. Currently, it is becoming clearer that type 2 diabetes mellitus (T2DM) management must envision not only the improvement in glycaemic control but also, and particularly, the prevention of pancreatic deterioration and the evolution of complications, such as DN. This review aims to provide an overview of the current knowledge in the field of renoprotective actions of sitagliptin, namely, improvement in diabetic dysmetabolism, hemodynamic factors, renal function, diabetic kidney lesions, and cytoprotective properties.
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Affiliation(s)
- Cristina Mega
- Agrarian School of Viseu (ESAV), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
- Centre for the Study of Education, Technologies and Health (CI&DETS), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
- Institute of Pharmacology and Experimental Therapeutics and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Edite Teixeira-de-Lemos
- Agrarian School of Viseu (ESAV), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
- Centre for the Study of Education, Technologies and Health (CI&DETS), Polytechnic Institute of Viseu (IPV), 3500-606 Viseu, Portugal
| | - Rosa Fernandes
- Institute of Pharmacology and Experimental Therapeutics and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC.IBILI Research Consortium, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Flávio Reis
- Institute of Pharmacology and Experimental Therapeutics and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC.IBILI Research Consortium, University of Coimbra, 3004-504 Coimbra, Portugal
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González-Heredia T, Hernández-Corona DM, González-Ortiz M, Martínez-Abundis E. Effect of Linagliptin Versus Metformin on Glycemic Variability in Patients with Impaired Glucose Tolerance. Diabetes Technol Ther 2017; 19:471-475. [PMID: 28581818 DOI: 10.1089/dia.2017.0020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Impaired glucose tolerance (IGT) and glycemic variability may be associated with increased risk of micro- and macrovascular complications. The aim of this study was to assess the effect of linagliptin versus metformin on glycemic variability in patients with IGT. MATERIAL AND METHODS A randomized, double-blind clinical trial with parallel groups was carried out in 16 adult patients with IGT, overweight or obesity. All patients signed an informed consent. The therapies were randomly assigned: (a) metformin 500 mg bid (n = 8) or (b) linagliptin 5 mg a.m. and placebo p.m. (n = 8), both for 90 days. At the beginning of the trial and 3 months later, fasting glucose, glycated hemoglobin A1c, oral glucose tolerance test (OGTT), and glycemic variability [area under the curve (AUC) of glucose, mean amplitude of glycemic excursion (MAGE), standard deviation (SD) of glucose, coefficient of variation (CV) of glucose, and mean blood glucose (MBG)] were measured. Mann-Whitney U, Wilcoxon, and Fisher exact tests were used for statistical analyses. RESULTS Both groups were similar in basal characteristics. After linagliptin administration, a significant decrease in glucose levels at 120 min of OGTT (9.0 ± 0.9 vs. 6.9 ± 2.2 mmol/L, P = 0.012) was observed. Glycemic variability showed a similar behavior and there were no significant differences in the AUC, MAGE, SD of glucose, CV of glucose, and MBG between groups. CONCLUSION Linagliptin administration resulted in better glycemic control according to the decrease of glucose levels by the OGTT at 120 min in patients with IGT. Meanwhile, glycemic variability was not modified in any of the study groups.
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Affiliation(s)
- Tonatiuh González-Heredia
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
| | - Diana M Hernández-Corona
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
| | - Manuel González-Ortiz
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
| | - Esperanza Martínez-Abundis
- Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara , Guadalajara, Mexico
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Zheng T, Chen B, Yang L, Hu X, Zhang X, Liu H, Qin L. Association of plasma dipeptidyl peptidase-4 activity with non-alcoholic fatty liver disease in nondiabetic Chinese population. Metabolism 2017. [PMID: 28637594 DOI: 10.1016/j.metabol.2017.04.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is attributed to a "multi-hits hypothesis" involving insulin resistance, oxidative stress and inflammation. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing the"multi-hits". Hence, we investigated the association between plasma DPP4 activity and NAFLD in nondiabetic Chinese population. DESIGN AND METHODS We performed a cross-sectional study using data from 1105 subjects (36-79years) in Guilin between 2015 and 2016. Plasma DPP4 activity, homeostatic model assessment of insulin resistance (HOMA-IR), oxidative stress parameters, and inflammatory markers were measured in all participants. NAFLD and its severity were diagnosed by ultrasound after the exclusion of alcohol abuse and other liver diseases. RESULTS Participants in the highest quartile of DPP4 activity had higher HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6, CRP, alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase compared with those in the lowest quartile (all P<0.05). Plasma DPP4 activity gradually increased across the groups according to the ultrasonographic severity of steatosis (P<0.001 for the trend). In the highest DPP4 quartile, NAFLD risk was higher (odds ratio 1.88; 95% CI 1.04-3.37) than in the lowest quartile after adjustment for confounders. The risk for NAFLD increased more with higher levels of DPP4 activity, HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6 and CRP. CONCLUSIONS Plasma DPP4 activity is significantly associated with NAFLD. The underlying mechanisms may be partly attributed to the interactions between insulin resistance, oxidative stress, inflammation, and DPP4.
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Affiliation(s)
- Tianpeng Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, PR China; Center of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, PR China.
| | - Bo Chen
- Department of Human Anatomy, Southwest Medical University, Luzhou, Sichuan, PR China
| | - Liuxue Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, PR China
| | - Xueping Hu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, PR China
| | - Xiaoxi Zhang
- Center of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, PR China
| | - Hongbo Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, PR China
| | - Linyuan Qin
- Department of Epidemiology and Health Statistics, Guilin Medical University, Guilin, Guangxi, China
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Mathieu C, Kozlovski P, Paldánius PM, Foley JE, Modgill V, Evans M, Serban C. Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance. EUROPEAN ENDOCRINOLOGY 2017; 13:68-72. [PMID: 29632610 PMCID: PMC5813467 DOI: 10.17925/ee.2017.13.02.68] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 07/25/2017] [Indexed: 12/30/2022]
Abstract
Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.
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Affiliation(s)
| | | | | | - James E Foley
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, US
| | | | - Marc Evans
- Diabetes Resource Centre, Llandough Hospital, Cardiff, UK
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Sokar SS, El-Sayad MES, Ghoneim MES, Shebl AM. Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats. Biomed Pharmacother 2017; 89:98-107. [DOI: 10.1016/j.biopha.2017.02.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 01/19/2017] [Accepted: 02/07/2017] [Indexed: 12/30/2022] Open
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VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins. Clin Sci (Lond) 2017; 131:673-687. [PMID: 28188238 DOI: 10.1042/cs20170010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/08/2017] [Accepted: 02/09/2017] [Indexed: 02/07/2023]
Abstract
The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.
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Kakara M, Nomura H, Ezaki M, Fukae M, Hirota T, Matsubayashi S, Hirakawa M, Ieiri I. Population pharmacodynamic analysis of hemoglobin A1c-lowering effects by adding treatment of DPP-4 inhibitors (sitagliptin) in type 2 diabetes mellitus patients based on electronic medical records. J Diabetes Complications 2016; 30:1282-6. [PMID: 27338508 DOI: 10.1016/j.jdiacomp.2016.06.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/19/2016] [Accepted: 06/07/2016] [Indexed: 10/21/2022]
Abstract
AIM To develop a population pharmacodynamic (PPD) model describing the time course for the hemoglobin A1c (HbA1c)-lowering effects of adding treatment of DPP-4 inhibitors and to assess the efficacy of combination therapy in type 2 diabetes mellitus patients based on electronic medical records. METHODS Information on patients was collected retrospectively from electronic medical records. Of the 4 DPP-4 inhibitors used, we focused on sitagliptin as it had the best time-response relationships. A physiological indirect response model was developed to describe changes in HbA1c levels. RESULTS An indirect response model, based on the 1300 HbA1c levels of 160 patients, described the time course for the HbA1c-lowering effects of adding sitagliptin. The combination with pioglitazone decreased the HbA1c synthesis rate by 7.74% relative to without pioglitazone. Bayesian forecasting based on the final PDD model using the first two HbA1c observations, before and within 30days after the addition of sitagliptin, gave a precise prediction of HbA1c-lowering effects individually. CONCLUSIONS Our PPD model quantitatively described the beneficial effects of combination therapy with pioglitazone and sitagliptin. The proposal methodology is also expected to be applicable to other medicines based on electronic medical records in clinical practice.
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Affiliation(s)
- Makoto Kakara
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hiroko Nomura
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Osaka Headquarters, Tokushukai General Incorporated Association, Osaka 530-0001, Japan; Hospital Pharmacy, Fukuoka Tokushukai Medical Center, Fukuoka 816-0864, Japan
| | - Mai Ezaki
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masato Fukae
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takeshi Hirota
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sunao Matsubayashi
- Department of Psychosomatic Medicine, Fukuoka Tokushukai Medical Center, Fukuoka 816-0864, Japan
| | - Masaaki Hirakawa
- Hospital Pharmacy, Fukuoka Tokushukai Medical Center, Fukuoka 816-0864, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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Frandsen CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol 2016; 4:766-780. [PMID: 26969516 DOI: 10.1016/s2213-8587(16)00039-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 12/10/2015] [Accepted: 01/26/2016] [Indexed: 02/06/2023]
Abstract
Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and different actions complementary to those of insulin-this Review reports the effects of these drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and bodyweight. Existing studies are of short duration with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese patients prone to hypoglycaemia and patients with residual β-cell function are populations of interest for future trials.
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Affiliation(s)
| | - Thomas Fremming Dejgaard
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Steno Diabetes Center, Gentofte, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
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Buonaiuto G, De Mori V, Braus A, Balini A, Berzi D, Carpinteri R, Forloni F, Meregalli G, Ronco GL, Bossi AC. PERS&O (PERsistent Sitagliptin treatment & Outcomes): observational retrospective study on cardiovascular risk evolution in patients with type 2 diabetes on persistent sitagliptin treatment. BMJ Open Diabetes Res Care 2016; 4:e000216. [PMID: 27486519 PMCID: PMC4947782 DOI: 10.1136/bmjdrc-2016-000216] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 05/15/2016] [Accepted: 05/31/2016] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES The UK Prospective Diabetes Study (UKPDS) Risk Engine (RE) provides the best risk estimates available for people with type 2 diabetes (T2D), so it was applied to patients on persistent sitagliptin treatment. DESIGN A 'real-world' retrospective, observational, single-center study. SETTING The study was performed in a general hospital in Northern Italy in order: (1) to validate UKPDS RE in a cohort of Italian participants with T2D without prespecified diabetes duration, with/without cardiovascular (CV) disease, treated with sitagliptin; (2) to confirm CV risk gender difference; (3) to evaluate the effect on metabolic control and on CV risk evolution obtained by 'add-on' persistent sitagliptin treatment. PARTICIPANTS Sitagliptin 100 mg once a day was taken by 462 participants with T2D: 170 of them (males: 106; age: 63.6±8.8; T2D duration: 11.58±7.33; females: 64; age: 65.6±7.95; T2D duration 13.5±7.9) were treated for 48 months with the same dosage. INTERVENTIONS An analysis of normality was performed both for continuous, and for groups variables on UKPDS RE percentage values, defining the requirement of a base log10 transformation to normalize risk factor values for analysis validation. RESULTS The evaluation of CV risk evolution by gender (t-test) confirmed the expected statistical difference (p<0.0001). Sitagliptin obtained significant results after 12 months, and at the end of the observation, both on metabolic control (expressed by glycated hemoglobin) and on UKPDS RE. Analysis of variance test revealed a significant effect on CV risk after 12 months (p=0.003), and after 48 months (p=0.04). A bivariate correlation analysis revealed a correlation index (r)=0.2 between the two variables (p<0.05). CONCLUSIONS These 'real-world' data obtained applying UKPDS RE may reflect patients' and clinicians' interest in realizing individual CV risk, and its evolution. Sitagliptin-persistent treatment for a medium-long period obtained an improvement on metabolic control, as well as a reduction on CV risk.
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Affiliation(s)
| | | | | | | | - Denise Berzi
- Endocrine Unit, Diabetes Regional Center, Treviglio, Italy
| | | | - Franco Forloni
- Endocrine Unit, Diabetes Regional Center, Treviglio, Italy
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Lind M, Matsson PO, Linder R, Svenningsson I, Jørgensen L, Ploug UJ, Gydesen H, Dorkhan M, Larsen S, Johansson G. Clinical Effectiveness of Liraglutide vs Sitagliptin on Glycemic Control and Body Weight in Patients with Type 2 Diabetes: A Retrospective Assessment in Sweden. Diabetes Ther 2016; 7:321-33. [PMID: 27216947 PMCID: PMC4900983 DOI: 10.1007/s13300-016-0173-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION The aim of the present study was to use real-world data from Swedish primary-care and national registries to understand clinical outcomes in patients with Type 2 diabetes (T2D) treated with liraglutide in clinical practice, and to compare with data from those treated with sitagliptin. METHODS This was a non-interventional, retrospective study conducted between February 2014 and September 2014 using T2D patient data from Swedish primary-care centers and national healthcare registries. The primary objective was to assess the effectiveness of liraglutide in control of glycemia and body weight in clinical practice (stage 1). The secondary objective was to compare the clinical effectiveness of liraglutide with sitagliptin on glycemic control and body weight in clinical practice in a propensity-score-matched population (stage 2). RESULTS In stage 1 (n = 402), 39.4% of patients treated with liraglutide achieved ≥1.0% (10.9 mmol/mol) reduction in glycated hemoglobin (HbA1c) after 180 days of treatment and 54.9% achieved the target HbA1c of <7.0% (53.0 mmol/mol). Moreover, compared with baseline, 22.5% of patients treated with liraglutide achieved both ≥1.0% reduction in HbA1c and ≥3.0% reduction in body weight. In stage 2, a significantly greater proportion of patients receiving liraglutide (n = 180) than sitagliptin (n = 208) achieved ≥1.0% reduction in HbA1c [52.9% vs 33.5%, respectively (P = 0.0002)]. Mean body-weight loss was also significantly greater in patients receiving liraglutide vs sitagliptin [-3.5 vs -1.3 kg, respectively (P < 0.0001)]. CONCLUSION This study provides real-world evidence from Sweden corroborating previous clinical trials that demonstrate greater efficacy of liraglutide over sitagliptin on glycemic control and body-weight reduction in patients with T2D. FUNDING Novo Nordisk A/S. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02077946.
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Affiliation(s)
- Marcus Lind
- Department of Medicine, NU-Hospital Group, Trollhättan/Uddevalla, Sweden.
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
| | | | | | - Irene Svenningsson
- Research and Development Unit, Primary Health Care, Närhälsan, Vänersborg, Sweden
| | | | | | | | | | | | - Gunnar Johansson
- Department of Caring Sciences and Family Medicine, Uppsala University, Uppsala, Sweden
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