|
1
|
Tabaeian SP, Mahmoudi T, Rezamand G, Nobakht H, Dabiri R, Farahani H, Asadi A, Zali MR. RESISTIN GENE POLYMORPHISM AND NONALCOHOLIC FATTY LIVER DISEASE RISK. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:483-487. [PMID: 36515343 DOI: 10.1590/s0004-2803.202204000-86] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/01/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and one of the main global health issues in which liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Owing to the link between NAFLD and insulin resistance (IR) and obesity and the role of resistin in theses metabolic disorders, we explored the possible association between resistin gene (RETN) variant and NAFLD. METHODS A total of 308 unrelated subjects, including 152 patients with biopsy-proven NAFLD and 156 controls were enrolled and genotyped for the RETN gene rs3745367 variant using PCR-RFLP method. RESULTS NAFLD patients had higher liver enzymes, systolic blood pressure (SBP), and diastolic blood pressure (DBP) than the controls (P<0.001). However, we observed no significant difference in genotype and allele frequencies between the cases with NAFLD and the controls for the RETN rs3745367 polymorphism either before or after adjustment for confounding factors including age, BMI, sex, smoking status, SBP, and DBP. CONCLUSION To our knowledge, this study is the first one that investigated the association between RETN gene rs3745367 variant and biopsy-proven NAFLD. Our findings do not support a role for this gene polymorphism in NAFLD risk in Iranian population; nonetheless, they need to be further investigated in other populations.
Collapse
Affiliation(s)
- Seidamir Pasha Tabaeian
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Touraj Mahmoudi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gholamreza Rezamand
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Nobakht
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Reza Dabiri
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Hamid Farahani
- Department of Physiology and Pharmacology, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Asadollah Asadi
- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
2
|
Wang X, Zhao B, Sun H, You H, Qu S. Effects of sitagliptin on intrahepatic lipid content in patients with non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2022; 13:866189. [PMID: 36072931 PMCID: PMC9441565 DOI: 10.3389/fendo.2022.866189] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients. METHODS A prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks. RESULTS 1) WC and BMI were decreased significantly in all groups except control group (all P<0.05). 2) There was no statistically significant difference in IHL among the sitagliptin, metformin, and sitagliptin plus metformin groups before and after treatment(all P>0.05). Only the metformin group showed a statistically significant difference in IHL before and after treatment(P<0.05). 3) Sitagliptin treatment led to a significant decrease in FBG and HbA1c when compared with the control group (all P<0.01). Additionally, HhA1c was significant decreased in the sitagliptin group when compared with the metformin group (P< 0.05). 4) HbA1c and FBG were decreased by 0.8% and 0.7 mmol/l respectively and the percentage of patients with HbA1c less than 7% was 65% with sitagliptin treatment. CONCLUSION Sitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.
Collapse
Affiliation(s)
- Xingchun Wang
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bangfeng Zhao
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Hang Sun
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Hui You
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Shen Qu,
| |
Collapse
|
|
3
|
Gutierrez AD, Flores CA, Naik S, Lee M, Asgarisabet P, Resman M, Lee M, McCormick JB, Fisher-Hoch SP. Resistin levels decrease as insulin resistance increases in a Mexican-American cohort. Cytokine 2021; 148:155687. [PMID: 34509726 PMCID: PMC10960335 DOI: 10.1016/j.cyto.2021.155687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 06/30/2021] [Accepted: 08/15/2021] [Indexed: 10/20/2022]
Abstract
AIMS Links between resistin, insulin resistance (IR), and resistin-stimulated cytokine signaling remain unknown in Mexican-Americans. A Mexican-American cohort was examined to determine (1) relationships between circulating resistin and IR, (2) resistin's associations with cytokines and demographic and anthropometric variables, and (3) similar measurements with other adipokines. METHODS For cross sectional analyses, 953 adults (367 males and 586 females) in the Cameron County Hispanic Cohort (CCHC) were stratified into three groups: normal glucose tolerance, prediabetes, and diabetes mellitus. Differences in resistin and other adipokine levels were examined using linear regression via unadjusted model (Model 1), model adjusted for cytokines (Model 2), and model further adjusted for demographic and anthropometric variables (Model 3). RESULTS HOMA-IR increased with worsening glucose tolerance (p < 0.0001). In all models, resistin significantly decreased as glucose tolerance deteriorated. Model 3 resistin was positively associated with IL-1β (p = 0.0252) and IL-8 (p < 0.0001), inversely associated with TNF-α (p = 0.0352), but nonsignificantly associated with IL-6 (p = 0.8671). Model 3 leptin was significantly lower in diabetes mellitus compared to other groups (p < 0.005) and positively associated with female sex (p < 0.0001), age (p = 0.024), and BMI (p < 0.0001), without significant cytokine associations. Adiponectin displayed no significant associations with glucose tolerance, but was significantly associated with sex, BMI, and lipids (Model 3). CONCLUSIONS Resistin unexpectedly decreased as IR increased while supporting evidence of a resistin-stimulated cytokine pathway in this Mexican-American cohort. Leptin fell with elevated IR after adjusting for cytokines, demographic and anthropometric variables. Adiponectin nonsignificantly decreased as IR increased while showing significant associations with sex, BMI, and lipids.
Collapse
Affiliation(s)
- Absalon D Gutierrez
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.
| | - Carlos A Flores
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Sapna Naik
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - MinJae Lee
- Division of Biostatistics, Department of Population Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Parisa Asgarisabet
- Department of Management, Policy and Community Health, the University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Masha Resman
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Miryoung Lee
- Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston School of Public Health, Brownsville Regional Campus, Brownsville, TX, USA
| | - Joseph B McCormick
- Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston School of Public Health, Brownsville Regional Campus, Brownsville, TX, USA
| | - Susan P Fisher-Hoch
- Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston School of Public Health, Brownsville Regional Campus, Brownsville, TX, USA
| |
Collapse
|
|
4
|
Wen F, Shi Z, Liu X, Tan Y, Wei L, Zhu X, Zhang H, Zhu X, Meng X, Ji W, Yang M, Lu Z. Acute Elevated Resistin Exacerbates Mitochondrial Damage and Aggravates Liver Steatosis Through AMPK/PGC-1α Signaling Pathway in Male NAFLD Mice. Horm Metab Res 2021; 53:132-144. [PMID: 33302316 DOI: 10.1055/a-1293-8250] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Resistin was identified as a link between obesity and insulin resistance and is associated with many diseases in mice. Deciphering the related development and molecular mechanism is necessary for the treatment of these diseases. Previous studies have revealed that increased resistin levels are correlated with lipid accumulation and play a role in non-alcoholic fatty liver disease (NAFLD) development. However, the exact mechanisms underlying these processes remain unclear. To further clarify whether acute elevated resistin level exacerbated liver steatosis, a high-fat diet-induced NAFLD animal model was used and treated with or without resistin for 6 days. We discovered that resistin altered mitochondrial morphology, decreased mitochondrial content, and increased lipid accumulation in HFD mice. qRT-PCR and western blot analysis showed that acute elevated resistin significantly altered the gene expression of mitochondrial biogenesis and liver lipid metabolism molecules in HFD mice. Consequently, in vitro experiments verified that resistin reduced the mitochondrial content, impaired the mitochondrial function and increased the lipid accumulation of palmitate-treated HepG2 cells. Additionally, we demonstrated that resistin upregulated proinflammatory factors, which confirmed that resistin promoted the development of inflammation in NAFLD mice and palmitate-treated HepG2 cells. Signaling-transduction analysis demonstrated that acute elevated resistin aggravated liver steatosis through AMPK/PGC-1α pathway in male mice. This reveals a novel pathway through which lipogenesis is induced by resistin and suggests that maintaining mitochondrial homeostasis may be key to treatments for preventing resistin-induced NAFLD aggravation.
Collapse
Affiliation(s)
- Fengyun Wen
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Zhuoyan Shi
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Xiaoping Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Yuguang Tan
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Lan Wei
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Xuemin Zhu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Hui Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Xiaohuan Zhu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Xiangmiao Meng
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Weixia Ji
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Mengting Yang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| | - Zhaoxuan Lu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, P. R. China
| |
Collapse
|
|
5
|
Jiang X, Hao J, Liu Z, Ma X, Feng Y, Teng L, Li Y, Wang D. Anti-obesity effects of Grifola frondosa through the modulation of lipid metabolism via ceramide in mice fed a high-fat diet. Food Funct 2021; 12:6725-6739. [PMID: 34160500 DOI: 10.1039/d1fo00666e] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Obesity is characterized by massive fat deposition and is related to a series of metabolic complications, such as insulin resistance (IR) and steatohepatitis. Grifola frondosa (GF) is a basidiomycete fungus and a source of various nutritional ingredients related to human health. In this study, after a systematic analysis of its nutritional ingredients, GF was administered to mice fed a high-fat diet (HFD) to investigate its effects on lipid metabolism. In HFD-fed mice, GF significantly controlled the body weight, blood glucose and related organ indices, and effectively counteracted hyperlipidemia and IR triggered by the HFD. GF administration efficiently alleviated hepatic steatosis and adipocyte hypertrophy, and regulated alanine aminotransferase and aspartate aminotransferase in the liver. An analysis of the intestinal microflora showed that GF reversed obesity-induced dysbiosis by affecting the relative abundance of certain bacteria, reducing lipopolysaccharide production and regulating the superpathway of heme biosynthesis associated with inflammation. According to the results of lipidomics, ceramide, a metabolite related to inflammation and IR, was found to be dysregulated in HFD-fed mice. However, GF regulated the ceramide levels and restored lipid metabolism via the suppression of Toll-like receptor 4/nuclear factor kappa-B signaling, which is involved in inflammation and IR. This study provides the experimental basis for the application of GF as an agent for obesity.
Collapse
Affiliation(s)
- Xue Jiang
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Acierno C, Caturano A, Pafundi PC, Nevola R, Adinolfi LE, Sasso FC. Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.
Collapse
Affiliation(s)
- Carlo Acierno
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Ital
| |
Collapse
|
|
7
|
Zuo L, Wang J, Zhang N, Wang J. Pioglitazone Therapy Decreases Bone Mass Density and Increases Fat Mass: A Meta-Analysis. Curr Pharm Des 2019; 25:3590-3596. [PMID: 31538886 DOI: 10.2174/1381612825666190920123129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/12/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Pioglitazone is mainly used for the management of type 2 diabetes and other insulinassociated diseases. However, the molecular mechanism of pioglitazone can lead to an imbalance in bone metabolism, thus decreasing bone mass density (BMD) and increasing the risk for fractures. OBJECTIVE To demonstrate the effect of pioglitazone therapy on bone metabolism and fat mass. METHODS A comprehensive search of the PubMed, EMBASE, Web of Science and Cochrane Central databases for randomized controlled trials (RCTs) on the effect of pioglitazone therapy on BMD and fat mass was performed. The primary outcome measures were the measured values of BMD, percentage changes in BMD, measured values of bone turnover markers and bone metabolic hormones, changes in BMI, body and leg fat mass, and fracture rates. The final search was performed in May 2019. RESULTS Six RCTs were included. A total of 749 patients met the inclusion criteria. Pioglitazone therapy was shown to significantly reduce the BMD of the whole body, lumbar spine, and total hip and serum PTH levels and increase BMI, total body fat mass and leg fat mass. In addition, 30 mg/d and 30 mg/d initially for one month followed by 45 mg/d pioglitazone could reduce the BMD of the lumbar spine. Pioglitazone therapy exerted no significant influence on the BMD of the femoral neck, serum BSAP or 25-OHD levels, or fracture rates. CONCLUSION Compared with placebo, pioglitazone therapy reduced BMD and serum PTH levels and increased fat mass and BMI with no difference in serum BSAP or 25-OHD levels or fracture rates; 30 mg/d pioglitazone was sufficient to reduce the BMD of the lumbar spine.
Collapse
Affiliation(s)
- Liyun Zuo
- Medical College of Shanxi Datong University, Shanxi, 037009, China
| | - Jianbin Wang
- Medical College of Shanxi Datong University, Shanxi, 037009, China
| | - Nianping Zhang
- Medical College of Shanxi Datong University, Shanxi, 037009, China
| | - Junjie Wang
- Changzhi Medical College, Changzhi, Shanxi, China
| |
Collapse
|
|
8
|
Singh R, Moreno P, Hajjar RJ, Lebeche D. A role for calcium in resistin transcriptional activation in diabetic hearts. Sci Rep 2018; 8:15633. [PMID: 30353146 PMCID: PMC6199245 DOI: 10.1038/s41598-018-34112-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/06/2018] [Indexed: 12/12/2022] Open
Abstract
The adipokine resistin has been proposed to link obesity, insulin resistance and diabetes. We have previously reported that diabetic hearts express high levels of resistin while overexpression of resistin in adult rat hearts gives rise to a phenotype resembling diabetic cardiomyopathy. The transcriptional regulation of resistin in diabetic cardiac tissue is currently unknown. This study investigated the mechanism of resistin upregulation and the role of Serca2a in its transcriptional suppression. We demonstrate that restoration of Ca2+ homeostasis in diabetic hearts, through normalization of Serca2a function genetically and pharmacologically, suppressed resistin expression via inhibition of NFATc. H9c2 myocytes stimulated with high-glucose concentration or Ca2+ time-dependently increased NFATc and resistin expression while addition of the Ca2+ chelator BAPTA-AM attenuated this effect. NFATc expression was enhanced in hearts from ob/ob diabetic and from cardiac-specific Serca2a−/− mice. Similarly, NFATc increased resistin expression in myocytes cultured in low glucose while the NFATc inhibitor VIVIT blocked glucose-induced resistin expression, suggesting that hyperglycemia/diabetes induces resistin expression possibly through NFATc activation. Interestingly, overexpression of Serca2a or VIVIT mitigated glucose-stimulated resistin and NFATc expression and enhanced AMPK activity, a downstream target of resistin signaling. NFATc direct activation of resistin was verified by resistin promoter luciferase activity and chromatin-immunoprecipitation analysis. Interestingly, activation of Serca2a by a novel agonist, CDN1163, mirrored the effects of AAV9-Serca2a gene transfer on resistin expression and its promoter activity and AMPK signaling in diabetic mice. These findings parse a role for Ca2+ in resistin transactivation and provide support that manipulation of Serca2a-NFATc-Resistin axis might be useful in hyper-resistinemic conditions.
Collapse
Affiliation(s)
- Rajvir Singh
- Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA
| | - Pedro Moreno
- Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA
| | - Roger J Hajjar
- Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA
| | - Djamel Lebeche
- Cardiovascular Research Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA. .,Diabetes, Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA. .,Graduate School of Biological Sciences, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA.
| |
Collapse
|
|
9
|
Al-Muzafar HM, Amin KA. Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl-CoA desaturase-1, lipase activity, leptin and resistin. Exp Ther Med 2018; 16:2938-2948. [PMID: 30214514 PMCID: PMC6125847 DOI: 10.3892/etm.2018.6563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 04/06/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatosteatosis is a disease present worldwide, which presents a number of health problems. Recently, thiazolidinedione (TZD) has been used as a therapy for lipid disorders. The present study demonstrates the potential of TZD as a treatment for hepatosteatosis and its mechanism of action, particularly focusing on its role in lipid metabolism. A total of 60 (80-90 g) rats were divided into three groups: A normal group with a standard diet, a high-fat, high-carbohydrate diet (HFCD) group or a HFCD+TZD group (n=20/group). The HFCD induced hepatosteatosis over a period of 12 weeks and the HFCD+TZD group were administered TZD in weeks 13-16. Blood and tissue samples were collected to measure hepatic function, the lipid profile, metabolism and hormone biomarkers, including serum triglyceride (TG), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD-1), leptin and resistin. The HFCD-fed rats exhibited a significant increase in serum TG, total cholesterol, low-density lipoproteins, alanine transaminase and bilirubin compared with the normal group as well as a significant decrease in high-density lipoprotein. In addition, serum leptin and resistin were significantly elevated in the HFCD group compared with the normal group. The administration of TZD significantly increased SCD-1 activity and significantly inhibited LPL activity. It also attenuated the changes in the lipid profiles and normalized serum leptin and resistin levels. The results of the present study indicated that HFCD induced lipid abnormalities associated with hypertriglyceridemia, hypercholesterolemia and hepatosteatosis. These changes resulted from disruption to leptin and resistin, which may be due to alterations in LPL and SCD-1 activity. TZD mitigated the effects of HFCD-induced hepatosteatosis, indicating a possible regulatory effect of TZD in the development of hepatosteatosis. The authors suggest that the manipulation of SCD-1 and lipase by TZD may be useful as a treatment for hepatosteatosis.
Collapse
Affiliation(s)
- Hessah Mohammed Al-Muzafar
- Department of Chemistry and Biochemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Kamal Adel Amin
- Department of Chemistry and Biochemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| |
Collapse
|
|
10
|
Song BM, Kim HC, Kim DJ, Ahn SV, Kim KM, Lee JM, Koh SB, Suh I. Aminotransferase levels, body mass index, and the risk of diabetes: a prospective cohort study. Ann Epidemiol 2018; 28:675-680.e6. [PMID: 30075987 DOI: 10.1016/j.annepidem.2018.07.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 05/26/2018] [Accepted: 07/11/2018] [Indexed: 01/17/2023]
Abstract
PURPOSE To investigate whether the relationship between body mass index (BMI) and incident diabetes is modified by different alanine or aspartate aminotransferases (ALT or AST) levels. METHODS We carried out an analysis of 6484 participants aged 40 years or older using data from the Korean Genome Epidemiology Study. The serum aminotransferase levels were stratified into low and high groups according to the median values and classified into three groups: both low, either high, and both high. To assess the association between BMI and incident diabetes according to the serum aminotransferase levels, multiple logistic regression models were used. RESULTS In participants with high levels of both ALT and AST, compared with the first BMI quartile, the adjusted odds ratios for incident diabetes of the second, third, and fourth BMI quartiles were 1.72 (95% confidence interval, 0.84-3.55), 2.19 (1.11-4.33), and 3.08 (1.60-5.90), respectively (P trend < .001). In participants with either high ALT or AST, the adjusted odds ratios were 3.58 (1.23-10.41), 2.65 (0.90-7.76), and 5.28 (1.86-15.02), respectively (P trend = .005). However, in participants with both low ALT and AST levels, high BMI was not independently associated with the risk of incident diabetes. CONCLUSIONS There was a strong association between BMI and incident diabetes among individuals with high aminotransferase levels, whereas no association was observed among those with low aminotransferase levels.
Collapse
Affiliation(s)
- Bo Mi Song
- Cardiovascular and Metabolic Disease Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Hyeon Chang Kim
- Cardiovascular and Metabolic Disease Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea; Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea.
| | - Dae Jung Kim
- Cardiovascular and Metabolic Disease Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea; Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea
| | - Song Vogue Ahn
- Cardiovascular and Metabolic Disease Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea; Department of Preventive Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyoung Min Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ju-Mi Lee
- Cardiovascular and Metabolic Disease Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea; Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang-Baek Koh
- Department of Occupational and Environmental Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Il Suh
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
11
|
Pop LM, Lingvay I, Yuan Q, Li X, Adams-Huet B, Maalouf NM. Impact of pioglitazone on bone mineral density and bone marrow fat content. Osteoporos Int 2017; 28:3261-3269. [PMID: 28735463 DOI: 10.1007/s00198-017-4164-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 07/17/2017] [Indexed: 12/20/2022]
Abstract
UNLABELLED Pioglitazone use is associated with an increased risk of fractures. In this randomized, placebo-controlled study, pioglitazone use for 12 months was associated with a significant increase in bone marrow fat content at the femoral neck, accompanied by a significant decrease in total hip bone mineral density. The change in bone marrow fat with pioglitazone use was predominantly observed in female vs. male participants. INTRODUCTION Use of the insulin sensitizer pioglitazone is associated with greater fracture incidence, although the underlying mechanisms are incompletely understood. This study aimed to assess the effect of pioglitazone treatment on femoral neck bone marrow (BM) fat content and on bone mineral density (BMD), and to establish if any correlation exists between the changes in these parameters. METHODS In this double-blind placebo-controlled clinical trial, 42 obese volunteers with metabolic syndrome were randomized to pioglitazone (45 mg/day) or matching placebo for 1 year. The following measurements were conducted at baseline and during the treatment: liver, pancreas, and femoral neck BM fat content (by magnetic resonance spectroscopy), BMD by DXA, abdominal subcutaneous and visceral fat, and beta-cell function and insulin sensitivity. RESULTS Results were available for 37 subjects who completed the baseline and 1-year evaluations. At 12 months, BM fat increased with pioglitazone (absolute change, +4.1%, p = 0.03), whereas BM fat content in the placebo group decreased non-significantly (-3.1%, p = 0.08) (p = 0.007 for the pioglitazone-placebo response difference). Total hip BMD declined in the pioglitazone group (-1.4%) and increased by 0.8% in the placebo group (p = 0.03 between groups). The change in total hip BMD was inversely and significantly correlated with the change in BM fat content (Spearman rho = -0.56, p = 0.01) in the pioglitazone group, but not within the placebo group (rho = -0.29, p = 0.24). Changes in BM fat with pioglitazone were predominantly observed in female vs. male subjects. CONCLUSIONS Pioglitazone use for 12 months compared with placebo is associated with significant increase in BM fat content at the femoral neck, accompanied by a small but significant decrease in total hip BMD.
Collapse
Affiliation(s)
- L M Pop
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - I Lingvay
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - Q Yuan
- Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - X Li
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - B Adams-Huet
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
- Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8885, USA
- Department of Internal Medicine, Division of Mineral Metabolism, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8885, USA
| | - N M Maalouf
- Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8885, USA.
- Department of Internal Medicine, Division of Mineral Metabolism, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8885, USA.
| |
Collapse
|
|
12
|
Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism 2016; 65:1062-79. [PMID: 26725002 DOI: 10.1016/j.metabol.2015.11.006] [Citation(s) in RCA: 252] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 11/19/2015] [Accepted: 11/20/2015] [Indexed: 12/13/2022]
Abstract
Since the discovery of adipose tissue as a higly active endocrine tissue, adipokines, peptides produced by adipose tissue and exerting autocrine, paracrine and endocrine function, have gained increasing interest in various obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD). Data regarding the association between NAFLD and circulating leptin and adiponectin levels are generally well documented: leptin levels increase, whereas adiponectin levels decrease, by increasing the severity of NAFLD. Data regarding other adipokines in histologically confirmed NAFLD populations are inconclusive (e.g., resistin, visfatin, retinol-binding protein-4, chemerin) or limited (e.g., adipsin, obestatin, omentin, vaspin etc.). This review summarizes evidence on the association between adipokines and NAFLD. The first part of the review provides general consideration on the interplay between adipokines and NAFLD, and the second part provides evidence on specific adipokines possibly involved in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines with NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD.
Collapse
Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.
| | - Jannis Kountouras
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
13
|
Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives. Int J Mol Sci 2016; 17:ijms17070999. [PMID: 27347932 PMCID: PMC4964375 DOI: 10.3390/ijms17070999] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 06/13/2016] [Accepted: 06/21/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; METHODS Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; RESULTS PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; CONCLUSION PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM) and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer.
Collapse
|
|
14
|
Tang W, Xu Q, Hong T, Tong G, Feng W, Shen S, Bi Y, Zhu D. Comparative efficacy of anti-diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized and non-randomized studies. Diabetes Metab Res Rev 2016; 32:200-16. [PMID: 26381272 DOI: 10.1002/dmrr.2713] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 07/10/2015] [Accepted: 07/23/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has a high prevalence in patients with type 2 diabetes mellitus (T2DM). In this study, we sought to provide a comprehensive assessment regarding the effects of anti-diabetic agents on NAFLD in patients with T2DM. METHODS MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) with different anti-diabetic agents in T2DM. Observational trials were also recruited to expand our population. Hepatic fat content and liver histology were evaluated as primary outcomes. Pooled estimates were calculated using a fixed effect model. RESULTS One thousand one hundred ninety-six participants in 19 RCTs and 14 non-randomized studies were included. Evidence from RCTs and observational studies suggested that greater hepatic fat content reduction and improved liver histology were seen in thiazolidinediones for 12-72 weeks; glucagon-like peptide-1 receptor agonists had beneficial effects on hepatic fat content after 26-50 weeks intervention, and insulin/metformin combination with 3-7 months improved hepatic fat content. Initiating metformin or dapagliflozin showed no benefit on hepatic fat content or liver histology in 16-48 weeks. Besides, nateglinide for 18 months was reported in a small sample-size RCT to improve hepatic fat content and liver histology. Sitagliptin therapy of 1 year also provided benefit on nonalcoholic steatohepatitis score in an observational study. CONCLUSIONS For T2DM with NAFLD, administrating thiazolidinediones and glucagon-like peptide-1 receptor agonists seems to provide more identified advances in attenuating hepatic fat content. Further RCTs are warranted to assess the efficacy of various hypoglycemic agents on clinical outcomes associated with NAFLD in T2DM. Copyright © 2015 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Wenjuan Tang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Qianyue Xu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Ting Hong
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Guoyu Tong
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Wenhuan Feng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Shanmei Shen
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
- Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
15
|
Abstract
Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.
Collapse
Affiliation(s)
- E Rosenthal
- Service de Médecine Interne, Hôpital de l'Archet, CHU de Nice, Nice; Université de Nice-Sophia Antipolis, Nice, France COREVIH PACA EST, CHU de Nice, France
| | - P Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France INSERM, UMR_S 959, Paris, France CNRS, FRE3632, Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| |
Collapse
|
|
16
|
Abstract
Cardiovascular disease, including heart failure (HF), is the major cause of death in patients with diabetes. A contributing factor to the occurrence of HF in such patients is the development of diabetic cardiomyopathy. Recent evidence demonstrates that perturbations associated with adipokines secretion and signaling result in lusitropic and inotropic defects in diabetic cardiomyopathy. This perspective editorial will discuss the central role of resistin, a recently discovered adipokine, in the maladaptive cardiac phenotype seen in diabetic hearts. Given the pleiotropic effects of resistin, strategies targeting the control of resistin levels may constitute a potentially viable therapeutic utility in patients with diabetes and diabetes-induced cardiovascular diseases.
Collapse
Affiliation(s)
- Djamel Lebeche
- Cardiovascular Research Institute, Graduate School of Biological Sciences, Department of Medicine, Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| |
Collapse
|
|
17
|
DeFronzo RA, Tripathy D, Abdul-Ghani M, Musi N, Gastaldelli A. The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone. J Clin Endocrinol Metab 2014; 99:3774-81. [PMID: 24937535 DOI: 10.1210/jc.2014-1515] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
AIMS AND HYPOTHESIS The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity. METHODS A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years. RESULTS Pioglitazone reduced IGT conversion to diabetes by 72% (P < .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia. CONCLUSIONS These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.
Collapse
Affiliation(s)
- Ralph A DeFronzo
- Texas Diabetes Institute and University of Texas Health Science Center at San Antonio (R.A.D., D.T., M.A.-G., N.M., A.G.), South Texas Veterans Health Care System Audie Murphy Division (R.A.D., D.T.), San Antonio, Texas 78229; and Cardiometabolic Risk Unit, Institute of Clinical Physiology (A.G.), 56124 Pisa, Italy
| | | | | | | | | |
Collapse
|
|
18
|
Murad A, Hassan H, Husein H, Ayad A. Serum resistin levels in nonalcoholic fatty liver disease and their relationship to severity of liver disease. JOURNAL OF ENDOCRINOLOGY, METABOLISM AND DIABETES OF SOUTH AFRICA 2014. [DOI: 10.1080/22201009.2010.10872225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
|
|
19
|
Ferreira DMS, Simão AL, Rodrigues CMP, Castro RE. Revisiting the metabolic syndrome and paving the way for microRNAs in non-alcoholic fatty liver disease. FEBS J 2014; 281:2503-24. [PMID: 24702768 DOI: 10.1111/febs.12806] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Revised: 03/16/2014] [Accepted: 04/03/2014] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma. Despite being one of the most common chronic liver diseases, NAFLD pathogenesis remains largely unknown. In this review, we discuss the key molecular mechanisms involved in NAFLD development and progression, focusing on the emerging role of microRNAs. NAFLD is intrinsically related to obesity and the metabolic syndrome. Changes in lipid metabolism increase free fatty acids in blood, which in turn induces peripheral insulin resistance and increases oxidative and endoplasmic reticulum stress. Although not yet considered in the diagnosis of NAFLD, recent reports also reinforce the crucial role of apoptosis in disease progression via activation of either death receptor or mitochondrial pathways and p53. In addition, the role of gut microbiota and the gut-liver axis has been recently associated with NAFLD. Finally, there is an accumulating and growing body of evidence supporting the role of microRNAs in NAFLD pathogenesis and progression, as well as hinting at their use as biomarkers or therapeutic tools. The ultimate goal is to review different molecular pathways that may underlie NAFLD pathogenesis in the hope of finding targets for new and efficient therapeutic interventions.
Collapse
Affiliation(s)
- Duarte M S Ferreira
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
| | | | | | | |
Collapse
|
|
20
|
Resistin: a potential biomarker for periodontitis influenced diabetes mellitus and diabetes induced periodontitis. DISEASE MARKERS 2014; 2014:930206. [PMID: 24692844 PMCID: PMC3944905 DOI: 10.1155/2014/930206] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 07/01/2013] [Accepted: 11/12/2013] [Indexed: 11/28/2022]
Abstract
Biomarkers are highly specific and sensitive indicators of disease activity. Resistin is a recently discovered adipocytokine, having a potent biomarker quality. Initially resistin was thought to be produced by adipocytes alone; however, emerging evidence suggests that it is also produced in abundance by various cells of the immunoinflammatory system, indicating its role in various chronic inflammatory diseases. Data suggests that resistin plays a role in obesity, insulin resistance, cardiovascular diseases, and periodontitis. Resistin derived its name from the original observation that it induced insulin resistance (resist-in: resist insulin) in mice and is downregulated in mature murine adipocytes cultured in the presence of insulin sensitizing drugs like thiazolidinediones. It is well recognized that obesity, is associated with insulin resistance and diabetes. A three-way relationship has been established between diabetes, obesity and periodontitis. Recent evidence also suggests an association between obesity and increased risk for periodontitis. Our previous research showed incremental elevation of resistin with periodontal disease activity and a reduced level of resistin, after periodontal therapy. Thus resistin would be one of the molecular links connecting obesity, periodontitis, and diabetes and may serve as a marker that links periodontal disease with other systemic diseases. A Medline/PubMed search was carried out for keywords “Diabetes Mellitus,” “Periodontitis,” and “Resistin,” and all relevant research papers from 1990 in English were shortlisted and finalized based on their importance. This review provides an insight into the biological action of resistin and its possible role in periodontitis influenced diabetes mellitus and diabetes induced periodontitis.
Collapse
|
|
21
|
Baranova A, Randhawa M, Jarrar M, Younossi ZM. Adipokines and melanocortins in the hepatic manifestation of metabolic syndrome: nonalcoholic fatty liver disease. Expert Rev Mol Diagn 2014; 7:195-205. [PMID: 17331066 DOI: 10.1586/14737159.7.2.195] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Metabolic syndrome is associated with nonalcoholic fatty liver disease and its more aggressive form, nonalcoholic steatohepatitis. Adipokines produced by white adipose tissue possess broad physiological activity and play an important autocrine role in obesity-associated complications, including metabolic syndrome, nonalcoholic fatty liver disease and cardiovascular disease. Various adipokines may have beneficial or harmful effects. Other tissues, particularly stomach and intestine, produce active molecules that can influence the function of adipocytes and, possibly, the levels of adipokine secretion. In some cases, the production sites of these molecules remain unknown. The review focuses on our current understanding of the disease-related effects of the adipokines and the melanocortins on various peripheral tissues, and discusses some of their potential interactions with each other. Potential therapeutic applications are also considered.
Collapse
Affiliation(s)
- Ancha Baranova
- Center for Liver Diseases, Inova Fairfax Hospital, VA, USA.
| | | | | | | |
Collapse
|
|
22
|
Bray GA, Smith SR, Banerji MA, Tripathy D, Clement SC, Buchanan TA, Henry RR, Kitabchi AE, Mudaliar S, Musi N, Ratner RE, Schwenke DC, Stentz FB, Reaven PD, DeFronzo RA. Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial. Diabetes Obes Metab 2013; 15:931-7. [PMID: 23551856 DOI: 10.1111/dom.12099] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 01/26/2013] [Accepted: 03/14/2013] [Indexed: 01/08/2023]
Abstract
AIMS This study examined the effects of pioglitazone on body weight and bone mineral density (BMD) prospectively in patients with impaired glucose tolerance as pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures. METHODS A total of 71 men and 163 women aged 49.3 (10.7) years [mean (s.d.)]; body mass index (BMI), 34.5 (5.9) kg/m(2) were recruited at five sites for measurements of body composition by dual energy X-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted. RESULTS Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63 ± 0.60 (m ± s.e.) kg in the pioglitazone group compared to 0.98 ± 0.62 kg in the PIO group (p < 0.0001). Body fat rose 4.89 ± 0.42 kg in the pioglitazone group compared to 1.41 ± 0.44 kg, (p < 0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. BMD was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk and in the total body. CONCLUSIONS Pioglitazone increased peripheral fat more than truncal fat and decreased BMD in several regions of the body.
Collapse
Affiliation(s)
- G A Bray
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care 2013; 36 Suppl 2:S127-38. [PMID: 23882037 PMCID: PMC3920797 DOI: 10.2337/dcs13-2011] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center, San Antonio, Texas, USA.
| | | | | |
Collapse
|
|
24
|
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, encompasses a spectrum of abnormal liver histology ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Population studies show that NAFLD is strongly associated with insulin resistance, obesity, type 2 diabetes mellitus, and lipid abnormalities. In the context of hepatic steatosis, factors that promote cell injury, inflammation, and fibrosis include oxidative stress, early mitochondrial dysfunction, endoplasmic reticulum stress, iron accumulation, apoptosis, adipocytokines, and stellate cell activation. The exact NASH prevalence is unknown because of the absence of simple noninvasive diagnostic tests. Although liver biopsy is the "gold standard" for the diagnosis of NASH, other tests are needed to facilitate the diagnosis and greatly reduce the requirement for invasive liver biopsy. In addition, the development of new fibrosis markers in NASH is needed to facilitate the assessment of its progression and the effectiveness of new therapies. The aim of this chapter, which is overview of biomarkers in NASH, is to establish a systematic approach to laboratory findings of the disease.
Collapse
|
|
25
|
Edwards CR, Hindle AK, Latham PS, Fu SW, Brody FJ. Resistin expression correlates with steatohepatitis in morbidly obese patients. Surg Endosc 2012; 27:1310-4. [PMID: 23233000 DOI: 10.1007/s00464-012-2603-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Accepted: 09/17/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Morbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients. METHODS Blood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student's t test. RESULTS Resistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (>4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, p = 0.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (p < 0.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (p = 0.051). CONCLUSIONS In morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis.
Collapse
Affiliation(s)
- Claire R Edwards
- Department of Surgery, The George Washington University Medical Center, 2150 Pennsylvania Ave., NW, Suite 6B, Washington, DC 20037, USA.
| | | | | | | | | |
Collapse
|
|
26
|
Kawamoto R, Tabara Y, Kohara K, Kusunoki T, Abe M, Miki T. Plasma Resistin Levels Are Associated with Insulin Resistance in Older Japanese Men from a Rural Village. Metab Syndr Relat Disord 2012; 10:380-6. [DOI: 10.1089/met.2012.0032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Ryuichi Kawamoto
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yasuharu Tabara
- Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Katsuhiko Kohara
- Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tomo Kusunoki
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masanori Abe
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tetsuro Miki
- Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| |
Collapse
|
|
27
|
Gómez-Díaz RA, Talavera JO, Pool EC, Ortiz-Navarrete FV, Solórzano-Santos F, Mondragón-González R, Valladares-Salgado A, Cruz M, Aguilar-Salinas CA, Wacher NH. Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. Metabolism 2012; 61:1247-55. [PMID: 22424822 DOI: 10.1016/j.metabol.2012.02.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Revised: 02/06/2012] [Accepted: 02/06/2012] [Indexed: 01/15/2023]
Abstract
The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation (C-reactive protein, cytokines, body weight, HbA1c, among others) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were randomized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty-two patients were included, 11.9±2.6 years old; 28 (12 males/16 females) received metformin and 24 placebo (11 males/13 females). Baseline characteristics were similar between groups (except for body mass index, which in the metformin group was slightly higher). Percentage weight loss was greater in the metformin group (-5.86% vs 2.75%, P<.05). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables (F=7.714; P<.006). Also, metformin was associated with a significant decrease in HOMA-IR index (P=.032) and HbA1c levels (P=.001), but no change was observed in the concentration of other markers of inflammation. Metformin resulted in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers.
Collapse
Affiliation(s)
- Rita A Gómez-Díaz
- Unidad de Investigación Médica en Epidemiología Clínica, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico Ciy, Mexico
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Falcão-Pires I, Castro-Chaves P, Miranda-Silva D, Lourenço AP, Leite-Moreira AF. Physiological, pathological and potential therapeutic roles of adipokines. Drug Discov Today 2012; 17:880-9. [PMID: 22561894 DOI: 10.1016/j.drudis.2012.04.007] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 03/19/2012] [Accepted: 04/19/2012] [Indexed: 02/06/2023]
Abstract
Formerly regarded purely as passive energy storage, adipose tissue is now recognized as a vital endocrine organ. Adipocytes secrete diverse peptide hormones named adipokines, which act in a autocrine, paracrine or endocrine way to influence several biological functions. Adipokines comprise diverse bioactive substances, including cytokines, growth, and complement factors, which perform essential regulatory functions related to energy balance, satiety and immunity. Presently adipokines have been widely implicated in obesity, diabetes, hypertension and cardiovascular diseases. In this article we aim to present a brief description of the roles and potential therapeutic modulation of adipokines, such as leptin, resistin, adiponectin, apelin, visfatin, FABP-4, tumor necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1).
Collapse
Affiliation(s)
- Inês Falcão-Pires
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Universidade do Porto, Porto, Portugal
| | | | | | | | | |
Collapse
|
|
29
|
Rienstra M, Sun JX, Lubitz SA, Frankel DS, Vasan RS, Levy D, Magnani JW, Sullivan LM, Meigs JB, Ellinor PT, Benjamin EJ. Plasma resistin, adiponectin, and risk of incident atrial fibrillation: the Framingham Offspring Study. Am Heart J 2012; 163:119-124.e1. [PMID: 22172445 DOI: 10.1016/j.ahj.2011.09.029] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 09/26/2011] [Indexed: 01/01/2023]
Abstract
BACKGROUND We sought to investigate whether higher concentrations of resistin and lower concentrations of adiponectin relate to incident atrial fibrillation (AF) and whether this association is mediated by AF risk factors and inflammation. Resistin and adiponectin are adipokines that have been associated with multiple known risk factors for AF including diabetes, obesity, inflammation, and heart failure. METHODS We studied the relations between circulating concentrations of both adipokines and incident AF in participants of the Framingham Offspring Study. RESULTS Participants (n = 2,487) had a mean age of 61 ± 10 years, and 54% were women. During a mean follow-up of 7.6 ± 2.0 years, 206 (8.3%) individuals (96 women) developed incident AF. Plasma resistin concentration was significantly associated with incident AF (multivariable-adjusted hazard ratio [HR] 1.17 per SD [0.41 ng/mL] of natural logarithmically transformed resistin, 95% CI 1.02-1.34, P = .028). The resistin-AF association was attenuated after further adjustment for C-reactive protein (HR per SD increase resistin 1.14, 95% CI 0.99-1.31, P = .073). Adiponectin concentrations were not significantly associated with incident AF (multivariable-adjusted HR of 0.95 per SD [0.62 μg/mL] of logarithmically transformed adiponectin, 95% CI 0.81-1.10, P = .478). CONCLUSION In our community-based longitudinal study, higher mean concentrations of resistin were associated with incident AF, but the relation was attenuated by adjustment for C-reactive protein. We did not detect a statistically significant association between adiponectin and incident AF. Additional studies are needed to clarify the potential role of adipokines in AF and mechanisms linking adiposity to AF.
Collapse
|
|
30
|
Pioglitazone versus Rosiglitazone: Effects on Lipids, Lipoproteins, and Apolipoproteins in Head-to-Head Randomized Clinical Studies. PPAR Res 2011; 2008:520465. [PMID: 18769492 PMCID: PMC2519139 DOI: 10.1155/2008/520465] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Accepted: 06/08/2008] [Indexed: 12/13/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating both glucose and lipid metabolism. Agonists for both PPARγ and PPARγ have been used to treat dyslipidemia and hyperglycemia, respectively. In addition to affecting glucose metabolism, PPARγ agonists also regulate lipid metabolism. In this review, we will focus on the randomized clinical trials that directly compared the lipid effects of the thiazolidinedione class of PPARγ agonists, pioglitazone and rosiglitazone, head-to-head either as monotherapy or in combination with other lipid-altering or glucose-lowering agents
Collapse
|
|
31
|
Kontrogianni-Konstantopoulos A. Resisting resistin; it's good for the heart. J Mol Cell Cardiol 2011; 51:141-3. [PMID: 21635896 DOI: 10.1016/j.yjmcc.2011.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Accepted: 05/16/2011] [Indexed: 11/30/2022]
|
|
32
|
Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010; 8:1017-29. [PMID: 20870037 DOI: 10.1016/j.cgh.2010.08.026] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 08/20/2010] [Accepted: 08/24/2010] [Indexed: 02/06/2023]
Abstract
In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to anti-HCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients.
Collapse
Affiliation(s)
- Ira M Jacobson
- Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
| | | | | | | | | |
Collapse
|
|
33
|
Gupta V, Singh A, Pant A. Could resistin be a noble marker for metabolic syndrome? Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2010. [DOI: 10.1016/j.dsx.2010.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
34
|
Triplitt C, Cersosimo E, DeFronzo RA. Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound treatment. Vasc Health Risk Manag 2010; 6:671-90. [PMID: 20859539 PMCID: PMC2941781 DOI: 10.2147/vhrm.s4852] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Indexed: 01/11/2023] Open
Abstract
Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in type 2 diabetes mellitus (T2DM). Pioglitazone is a potent insulin sensitizer, improves pancreatic beta cell function and has been shown in several outcome trials to lower the risk of atherosclerotic and cardiovascular events. Glucagon-like peptide-1 deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Alogliptin is a new DPP-4 inhibitor that reduces glycosylated hemoglobin (HbA1c), is weight neutral, has an excellent safety profile, and can be used in combination with oral agents and insulin. Alogliptin has a low risk of hypoglycemia, and serious adverse events are uncommon. An alogliptin–pioglitazone combination is advantageous because it addresses both insulin resistance and islet dysfunction in T2DM. HbA1c reductions are significantly greater than with either monotherapy. This once-daily oral combination medication does not increase the risk of hypoglycemia, and tolerability and discontinuation rates do not differ significantly from either monotherapy. Importantly, measures of beta cell function and health are improved beyond that observed with either monotherapy, potentially improving durability of HbA1c reduction. The alogliptin–pioglitazone combination represents a pathophysiologically sound treatment of T2DM.
Collapse
Affiliation(s)
- Curtis Triplitt
- Diabetes Division, Department of Medicine, University of Texas, Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA
| | | | | |
Collapse
|
|
35
|
Dobrin JS, Lebeche D. Diabetic cardiomyopathy: signaling defects and therapeutic approaches. Expert Rev Cardiovasc Ther 2010; 8:373-91. [PMID: 20222816 DOI: 10.1586/erc.10.17] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus is the world's fastest growing disease with high morbidity and mortality rates, predominantly as a result of heart failure. A significant number of diabetic patients exhibit diabetic cardiomyopathy; that is, left ventricular dysfunction independent of coronary artery disease or hypertension. The pathogenesis of diabetic cardiomyopathy is complex, and is characterized by dysregulated lipid metabolism, insulin resistance, mitochondrial dysfunction and disturbances in adipokine secretion and signaling. These abnormalities lead to impaired calcium homeostasis, ultimately resulting in lusitropic and inotropic defects. This article discusses the impact of these hallmark factors in diabetic cardiomyopathy, and concludes with a survey of available and emerging therapeutic modalities.
Collapse
Affiliation(s)
- Joseph S Dobrin
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
| | | |
Collapse
|
|
36
|
Insulin resistance, adipose depots and gut: interactions and pathological implications. Dig Liver Dis 2010; 42:310-9. [PMID: 20194050 DOI: 10.1016/j.dld.2010.01.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Accepted: 01/17/2010] [Indexed: 12/11/2022]
Abstract
This review article focuses on the many metabolic actions of insulin at the level of muscle, liver and adipose tissue. In terms of pathogenetic mechanisms, the condition of insulin resistance is complex, as multiple genetic and environmental factors, among which an increasingly sedentary lifestyle associated with high-fat diet, mutually interact according to variable patterns in time in any given individual. It is well recognized that obesity (in particular abdominal obesity) favours the development of insulin resistance. Here we evaluate the impact of obesity and ectopic fat accumulation (visceral and hepatic) on insulin resistance at the level of different target organs, i.e., muscle, liver and adipose tissue. The roles of the gut and the liver, in particular of bile acids and gut microflora, are also discussed as possible determinants of energy balance and glucose metabolism.
Collapse
|
|
37
|
Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis 2010; 42:320-30. [PMID: 20207596 DOI: 10.1016/j.dld.2010.01.016] [Citation(s) in RCA: 371] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Accepted: 01/17/2010] [Indexed: 02/07/2023]
Abstract
The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.
Collapse
Affiliation(s)
- Ester Vanni
- Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, C. so Bramante 88, 10126 Turin, Italy
| | | | | | | | | | | |
Collapse
|
|
38
|
Metabolic syndrome: A review of emerging markers and management. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2009. [DOI: 10.1016/j.dsx.2009.04.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
39
|
Filková M, Haluzík M, Gay S, Senolt L. The role of resistin as a regulator of inflammation: Implications for various human pathologies. Clin Immunol 2009; 133:157-70. [PMID: 19740705 DOI: 10.1016/j.clim.2009.07.013] [Citation(s) in RCA: 311] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 07/24/2009] [Accepted: 07/29/2009] [Indexed: 12/28/2022]
Abstract
Resistin was originally described as an adipocyte-secreted peptide that induced insulin resistance in rodents. Increasing evidence indicates its important regulatory roles in various biological processes, including several inflammatory diseases. Further studies have shown that resistin in humans, in contrast to its production by adipocytes in mice, is synthesized predominantly by mononuclear cells both within and outside adipose tissue. Possible roles for resistin in obesity-related subclinical inflammation, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, rheumatic diseases, malignant tumors, asthma, inflammatory bowel disease, and chronic kidney disease have already been demonstrated. In addition, resistin can modulate several molecular pathways involved in metabolic, inflammatory, and autoimmune diseases. In this review, current knowledge about the functions and pathophysiological implications of resistin in different human pathologies is summarized, although there is a significant lack of firm evidence regarding the specific role resistin plays in the "orchestra" of the numerous mediators of inflammation.
Collapse
Affiliation(s)
- Mária Filková
- Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Prague 2, 128 50, Czech Republic
| | | | | | | |
Collapse
|
|
40
|
Xue J, Ding W, Liu Y. Anti-diabetic effects of emodin involved in the activation of PPARgamma on high-fat diet-fed and low dose of streptozotocin-induced diabetic mice. Fitoterapia 2009; 81:173-7. [PMID: 19699280 DOI: 10.1016/j.fitote.2009.08.020] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2009] [Revised: 08/11/2009] [Accepted: 08/12/2009] [Indexed: 01/30/2023]
Abstract
Rheum palmatum Linn has been widely applied in the clinical treatment of diabetes mellitus. It has been found that emodin as the major bioactive component of R. palmatum L exhibits the competency to activate peroxisomal proliferator-activated receptor-gamma (PPARgamma) in vitro. So the aim of this study was to evaluate the anti-diabetic effects of emodin through the activation of PPARgamma on high-fat diet-fed and low dose of streptozotocin (STZ)-induced diabetic mice. The diabetic mice were intraperitoneally injected with emodin for three weeks. No changes of food consumption and the body weight in emodin-treated mice were monitored daily during the entire experiment. At the end of experiment, the levels of blood glucose, triglyceride and total cholesterol in serum were significantly decreased after emodin treatment. However, serum high-density lipoprotein cholesterol (HDLc) concentration was significantly elevated. The glucose tolerance and insulin sensitivity in emodin-treated group were significantly improved. Furthermore, the results of quantitative RT-PCR analysis showed that emodin significantly elevated the mRNA expression level of PPARgamma and regulated the mRNA expressions of LPL, FAT/CD36, resistin and FABPs (ap2) in liver and adipocyte tissues. No effects on the mRNA expressions of PPARalpha and PPARalpha-target genes were observed. Taken together, the results suggested that the activation of PPARgamma and the modulation of metabolism-related genes were likely involved in the anti-diabetic effects of emodin.
Collapse
Affiliation(s)
- Jianfeng Xue
- College of Life Sciences, Graduate University of Chinese Academy of Sciences, No. 19 A Yu Quan Road, Beijing, China
| | | | | |
Collapse
|
|
41
|
Clarson CL, Mahmud FH, Baker JE, Clark HE, McKay WM, Schauteet VD, Hill DJ. Metformin in combination with structured lifestyle intervention improved body mass index in obese adolescents, but did not improve insulin resistance. Endocrine 2009; 36:141-6. [PMID: 19387874 DOI: 10.1007/s12020-009-9196-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Revised: 03/23/2009] [Accepted: 04/07/2009] [Indexed: 11/29/2022]
Abstract
This study assessed the efficacy of adding metformin to a structured lifestyle intervention in reducing BMI in obese adolescents with insulin resistance. Obese adolescents (25) aged 10-16 years with a body mass index (BMI) > 95th percentile and insulin resistance (Homeostasis Model Assessment-HOMA) > 3.0 were assessed in a community clinic. A structured lifestyle intervention comprising nutritional and exercise education and motivational support in both individual and group sessions was delivered over 6 months. Subjects were randomized to lifestyle intervention alone or with metformin (1500 g daily). The primary outcome measures were a change in BMI and modification of metabolic risk factors, including insulin resistance, plasma lipids and adipocytokines. Eleven adolescents receiving lifestyle and metformin intervention and 14 receiving lifestyle alone completed the study. BMI decreased by 1.8 kg/m(2) with lifestyle and metformin but did not change with lifestyle alone. HOMA was significantly decreased in the lifestyle intervention group, but not following metformin, while the adiponectin/leptin ratio improved significantly in both groups. Dyslipidemic profiles improved most significantly with metformin. We conclude that metformin in combination with a 6-month structured lifestyle intervention is effective in reducing BMI in obese adolescents but did not improve insulin resistance. Lifestyle intervention, with or without metformin, improved metabolic risk factors such as plasma lipids and adipocytokines.
Collapse
Affiliation(s)
- Cheril L Clarson
- Children's Hospital, London Health Sciences Centre, London, ON, N6A 5W9, Canada.
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58:773-95. [PMID: 19336687 PMCID: PMC2661582 DOI: 10.2337/db09-9028] [Citation(s) in RCA: 1919] [Impact Index Per Article: 119.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Ralph A Defronzo
- Diabetes Division, University of Texas Health Science Center, San Antonio, Texas, USA.
| |
Collapse
|
|
43
|
Chen BH, Song Y, Ding EL, Roberts CK, Manson JE, Rifai N, Buring JE, Gaziano JM, Liu S. Circulating levels of resistin and risk of type 2 diabetes in men and women: results from two prospective cohorts. Diabetes Care 2009; 32:329-34. [PMID: 18957529 PMCID: PMC2628703 DOI: 10.2337/dc08-1625] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate the role of circulating resistin levels in the development of type 2 diabetes using two prospective cohorts of well-characterized men and women. RESEARCH DESIGN AND METHODS We conducted two prospective case-control studies nested in the Women's Health Study (WHS) and Physicians' Health Study II (PHS II). In the WHS, during a median of 10-years of follow-up, 359 postmenopausal women, who were apparently healthy at baseline and later developed type 2 diabetes, were prospectively matched with 359 healthy control subjects. In the PHS II, with 8 years of total follow-up, 170 men, who were apparently healthy at baseline and later developed type 2 diabetes, were matched with 170 healthy control subjects. Control subjects were matched by age, race, and time of blood draw. RESULTS Resistin levels at baseline were significantly higher in women than in men (P = 0.003) and in case patients than in control subjects for both women (P < 0.001) and men (P = 0.07). After adjustment for matching factors, physical activity, alcohol intake, smoking, and family history of diabetes, the relative risk of type 2 diabetes comparing the highest to the lowest quartile of resistin in women was 2.22 ([95% CI 1.32-3.73]; Ptrend = 0.002). This association was attenuated after further adjustment for BMI (1.51 [0.86-2.65]; Ptrend = 0.20) or C-reactive protein (1.18 [0.68-2.07]; Ptrend = 0.60). A similar but weaker pattern was observed in men. CONCLUSIONS Elevated levels of circulating resistin were significantly related to increased risk of type 2 diabetes, which appears to be partially accounted for by adiposity and the inflammatory process.
Collapse
Affiliation(s)
- Brian H Chen
- Program on Genomics and Nutrition, Department of Epidemiology, UCLA School of Public Health, Los Angeles, California, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Rijkelijkhuizen JM, Doesburg T, Girman CJ, Mari A, Rhodes T, Gastaldelli A, Nijpels G, Dekker JM. Hepatic fat is not associated with beta-cell function or postprandial free fatty acid response. Metabolism 2009; 58:196-203. [PMID: 19154952 DOI: 10.1016/j.metabol.2008.09.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2008] [Accepted: 09/23/2008] [Indexed: 10/21/2022]
Abstract
We evaluated the association of hepatic fat with beta-cell function estimated from the oral glucose tolerance test. In addition, we tested the hypothesis that postprandial free fatty acid (FFA) suppression after a meal tolerance test (MTT) is linked to hepatic fat. Individuals with normal glucose metabolism (NGM; n = 10 with low and n = 10 with high insulin secretion, matched for insulin sensitivity and sex), impaired glucose metabolism (IGM; n = 14), and type 2 diabetes mellitus (DM; n = 14) underwent a 75-g oral glucose tolerance test and MTT. beta-Cell function estimates were calculated from C-peptide using a mathematical model. Liver fat was quantified by proton magnetic resonance ((1)H-MR) spectroscopy. Area under the curve (AUC) of triglycerides (TG) and FFA responses during MTT represented postprandial lipid responses. Linear regression models were adjusted for age, sex, and additionally for insulin sensitivity for IGM/DM subjects. Liver fat content was equal for the NGM groups with low and high insulin secretion: 4.5% (2.6-6.0) (median, interquartile range) and 4.9% (2.3-7.8), respectively; liver fat percentages of IGM and diabetic subjects were significantly higher: 11.2 (6.7-21.1) and 10.0 (7.8-24.5). Liver fat showed a fairly strong, significant negative association with insulin sensitivity, but was not associated with beta-cell function. Significant associations of liver fat with fasting TG and AUC(TG) were shown in the total study population and in IGM/DM subjects separately. No relationship existed between fasting FFA or AUC(FFA) and liver fat. We conclude that fat accumulation in the liver is tightly linked to insulin sensitivity but not to beta-cell function. Furthermore, liver fat is associated with circulating TG levels, but not with FFA concentrations.
Collapse
|
|
45
|
Makino H, Shimizu I, Murao S, Kondo S, Tabara Y, Fujiyama M, Fujii Y, Takada Y, Nakai K, Izumi K, Ohashi J, Kawamura R, Yamauchi J, Takata Y, Nishida W, Hashiramoto M, Onuma H, Osawa H. A pilot study suggests that the G/G genotype of resistin single nucleotide polymorphism at -420 may be an independent predictor of a reduction in fasting plasma glucose and insulin resistance by pioglitazone in type 2 diabetes. Endocr J 2009; 56:1049-58. [PMID: 19738363 DOI: 10.1507/endocrj.k08e-320] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P =0.012). When studies 1 and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.511, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.
Collapse
Affiliation(s)
- Hideichi Makino
- Institute of Diabetes Research Center, Takanoko Hospital, Ehime, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women. Mediators Inflamm 2008; 2008:892864. [PMID: 19125180 PMCID: PMC2606019 DOI: 10.1155/2008/892864] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2008] [Accepted: 10/09/2008] [Indexed: 01/18/2023] Open
Abstract
Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were all significantly higher in DM2 compared to control women (P < .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1β, TNF-α, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients.
Collapse
|
|
47
|
Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, Webb M, Zvibel I, Goldiner I, Blendis L, Halpern Z, Oren R. Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study. Hepatology 2008; 48:1791-8. [PMID: 18972405 DOI: 10.1002/hep.22525] [Citation(s) in RCA: 217] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
UNLABELLED Physical activity (PA) is commonly recommended for nonalchoholic fatty liver disease (NAFLD) patients. However, there is limited evidence on the independent role of PA in NAFLD. The aim of this study was to examine the association between PA and NAFLD. We conducted a cross-sectional study of a subsample (n = 375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for liver disease. Participants underwent an abdominal ultrasound examination; biochemical tests, including leptin, adiponectin, and resistin; and the noninvasive biomarker SteatoTest and anthropometric evaluations. A semiquantitative food frequency questionnaire and a detailed PA questionnaire were administered. Three hundred forty-nine patients (52.7% men, 30.9% primary NAFLD) were included. The NAFLD group engaged in less aerobic, resistance, or other kinds of PA (P </= 0.03). The SteatoTest was significantly lower among subjects engaging in any PA or resistance PA at least once a week (P </= 0.01). PA at least once a week in all categories was associated with a reduced risk for abdominal obesity. Adjusting for sex, engaging in any kind of sports (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.44-0.96 per 1 standard deviation increment in PA score) and resistance exercise (OR 0.61, 95% CI 0.38-0.85) were inversely associated with NAFLD. These associations remained unchanged after adjusting for homeostasis model assessment, most nutritional factors, adiponectin, and resistin. Only the association with resistance PA remained significant with further adjustment for body mass index (OR 0.61, 95% CI 0.44-0.85). Adding leptin or waist circumference to the model eliminated the statistical significance. CONCLUSION Habitual leisure-time PA, especially anaerobic, may play a protective role in NAFLD. This association appears to be mediated by a reduced rate of abdominal obesity.
Collapse
Affiliation(s)
- Shira Zelber-Sagi
- The Liver Unit, Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
Type 2 diabetes and cardiovascular disease represent a serious threat to the health of the population worldwide. Although overall adiposity and particularly visceral adiposity are established risk factors for these diseases, in the recent years fatty liver emerged as an additional and independent factor. However, the pathophysiology of fat accumulation in the liver and the cross-talk of fatty liver with other tissues involved in metabolism in humans are not fully understood. Here we discuss the mechanisms involved in the pathogenesis of hepatic fat accumulation, particularly the roles of body fat distribution, nutrition, exercise, genetics, and gene-environment interaction. Furthermore, the effects of fatty liver on glucose and lipid metabolism, specifically via induction of subclinical inflammation and secretion of humoral factors, are highlighted. Finally, new aspects regarding the dissociation of fatty liver and insulin resistance are addressed.
Collapse
Affiliation(s)
- Norbert Stefan
- Department of Internal Medicine, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany
| | | | | |
Collapse
|
|
49
|
Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008; 60:311-57. [PMID: 18922966 DOI: 10.1124/pr.108.00001] [Citation(s) in RCA: 295] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
Steatosis of the liver may arise from a variety of conditions, but the molecular basis for lipid droplet formation is poorly understood. Although a certain amount of lipid storage may even be hepatoprotective, prolonged lipid storage can result in an activation of inflammatory reactions and loss of metabolic competency. Apart from drug-induced steatosis, certain metabolic disorders associated with obesity, insulin resistance, and hyperlipidemia give also rise to nonalcoholic fatty liver diseases (NAFLD). It is noteworthy that advanced stages of nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis. In this regard, the lipid droplets (LDs) have been discovered to be metabolically highly active structures that play major roles in lipid transport, sorting, and signaling cascades. In particular, LDs maintain a dynamic communication with the endoplasmic reticulum (ER) and the plasma membrane via sphingolipid-enriched domains of the plasma membrane-the lipid rafts. These microdomains frequently harbor receptor tyrosine kinases and other signaling molecules and connect extracellular events with intracellular signaling cascades. Here, we review recent knowledge on the molecular mechanisms of drug and metabolically induced hepatic steatosis and its progression to steatohepatitis (NASH). The contribution of cytokines and other signaling molecules, as well as activity of nuclear receptors, lipids, transcription factors, and endocrine mediators toward cellular dysfunction and progression of steatotic liver disease to NASH is specifically addressed, as is the cross-talk of different cell types in the pathogenesis of NAFLD. Furthermore, we provide an overview of recent therapeutic approaches in NASH therapy and discuss new as well as putative targets for pharmacological interventions.
Collapse
Affiliation(s)
- Nora Anderson
- Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany
| | | |
Collapse
|
|
50
|
Krag MB, Nielsen S, Guo Z, Pedersen SB, Schmitz O, Christiansen JS, Jørgensen JOL. Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity. Clin Endocrinol (Oxf) 2008; 69:452-61. [PMID: 18331610 DOI: 10.1111/j.1365-2265.2008.03231.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
CONTEXT Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance. OBJECTIVE To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels. DESIGN A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks. INTERVENTION Patients received either pioglitazone 30 mg (N = 10) or placebo (N = 10) once daily for 12 weeks. RESULTS Adiponectin levels almost doubled during pioglitazone treatment (P = 0.0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels (P = 0.02) and lipid oxidation (P = 0.02). Basal glucose oxidation rate (P = 0.004) and insulin sensitivity (P = 0.03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal (R = 0.69, P = 0.04). CONCLUSION The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.
Collapse
Affiliation(s)
- Morten B Krag
- Medical Department M, Aarhus University Hospital, Aarhus Sygehus, Aarhus C, Denmark
| | | | | | | | | | | | | |
Collapse
|