- •DMT2 with concomitant NAFLD is associated with a greater decrease in adiponectin.
- •Adiponectin concentration was found to correlate negatively with the degree of ALT.
- •Exenatide was effective in inducing weight loss and non-inferior in lowering HbA1c.
- •Exenatide proved equally effective in increasing adiponectin levels.
- •Increases of adiponectin were attributable to weight loss, glucose control and CRP.
Diabetes mellitus type 2 (DMT2) and non-alcoholic fatty liver disease (NAFLD) are both characterized by decreased circulating adiponectin. Recently, glucagon-like peptide-1 receptor agonists have been shown to induce adiponectin's expression. However, their interaction on clinical grounds needs to be further elucidated.
DMT2 patients with abnormal aminotransferases were screened for NAFLD and subjected to liver biopsy (group A, n = 17). A subgroup of patients (n = 110), after assessed for eligibility criteria, was blindly randomized to receive either 6-month exenatide supplementation on glargine insulin (group B) or intense, self-regulated, insulin therapy alone (group C).
Baseline patient characteristics: 49(38.6%) males, aged 63.1 ± 7.5 years-old, BMI 32.9 ± 4.9 kg/m2, HbA1c 8.1 ± 1.2% (65 ± 14 mmol/mol), median ALT 23 U/L (range 5–126), AST 20 U/L (7–72). Group A had biopsy-proven NAFLD with a median Activity Score of 5 and fibrosis stage 3. Presence of NAFLD was accompanied by a significant decline in adiponectin (p < 0.001), which was negatively correlated with the degree of ALT in all groups (Spearman's correlation, rs = −0.644, p < 0.001). In the subgroup intervention trial, adiponectin was significantly raised in both groups B and C (t-Student for paired samples, p = 0.001) by Δ= +24.2% (interquartile range 14.8–53.2%). This elevation was not associated with the type of intervention but with weight loss, glycemic control and reduction of C-reactive protein (one-way ANCOVA).
Supplementation of exenatide to glargine insulin compared to standard insulin was: (i) effective in inducing weight loss, (ii) non-inferior in lowering HbA1c and (iii) non-inferior in increasing circulating adiponectin. Higher adiponectin was associated with lower ALT, suggesting a hepato-protective role for this cytokine.
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- Global estimates of diabetes prevalence in adults for 2013 and projections for 2035.Diabetes Res Clin Pract. 2014; 103: 137-149
- Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials.Clin Ther. 2007; 29: 139-153
- Effects of exenatide on diabetes, obesity, cardiovascular risk factors, and hepatic biomarkers in patients with type 2 diabetes.J Diabetes Sci Technol. 2008; 2: 255-260
- Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients.Diabetes Care. 2007; 30: 1212-1218
- The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.Gastroenterology. 2012; 142: 1592-1609
- Biomarkers for diabetes prediction, pathogenesis or pharmacotherapy guidance? Past, present and future possibilities.Diabet Med. 2012; 29: 5-13
- The role of adipokines in β-cell failure of type 2 diabetes.J Endocrinol. 2013; 216: T37-T45
- Hypoadiponectinaemia in diabetes mellitus type 2: molecular mechanisms and clinical significance.Clin Exp Pharmacol Physiol. 2011; 38: 897-904
- Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause?.Hepatology. 2013; 57: 2180-2188
- Signaling mechanisms underlying the insulin-sensitizing effects of adiponectin.Best Pract Res Clin Endocrinol Metab. 2014; 28: 3-13
- GLP-1 and adiponectin: effect of weight loss after dietary restriction and gastric bypass in morbidly obese patients with normal and abnormal glucose metabolism.Obes Surg. 2009; 19: 313-320
- GLP-1 receptor agonists.Br J Cardiol. 2011; 18: 167-169
- Liraglutide, a glucagon-like peptide-1 analog, increased insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus.J Diabetes Res. 2015; 2015: 706416
- Exendin-4 increases insulin sensitivity via a PI-3-kinase-dependent mechanism: contrasting effects of GLP-1.Biochem Pharmacol. 2002; 63: 993-996
- Effects of liraglutide, a human glucagon-like peptide-1 analogue, on body weight, body fat area and body fat-related markers in patients with type 2 diabetes mellitus.Intern Med. 2013; 52: 1029-1034
- Exenatide plus metformin compared with metformin alone on β-cell function in patients with type 2 diabetes.Diabet Med. 2012; 29: 1515-1523
- Weight loss effect of glucagon-like peptide-1 mimetics on obese/overweight adults without diabetes: a systematic review and meta-analysis of randomized controlled trials.J Diabetes. 2015; 7: 329-339
- Glucagon-like peptide 1 receptor and the liver.Liver Int. 2011; 31: 1243-1245
- Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice.Hepatology. 2006; 43: 173-181
- Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway.Hepatology. 2010; 51: 1584-1592
- Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial.Diabetologia. 2011; 54: 3093-3100
- The glucagon-like peptide-1 analogue liraglutide inhibits oxidative stress and inflammatory response in the liver of rats with diet-induced non-alcoholic fatty liver disease.Biol Pharm Bull. 2015; 38: 694-702
- Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.Curr Med Res Opin. 2008; 24: 275-286
- Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis.Liver Int. 2011; 31: 1285-1297
- Incretin mimetics as a novel therapeutic option for hepatic steatosis.Liver Int. 2006; 26: 1015-1017
- Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes.Obesity (Silver Spring). 2011; 19: 2310-2315
- Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease.Arq Bras Endocrinol Metabol. 2013; 57: 702-708
- Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists.PLOS ONE. 2012; 7: e50117
- Exenatide prevents fat-induced insulin resistance and raises adiponectin expression and plasma levels.Diabetes Obes Metab. 2008; 10: 921-930
- GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK.Liver Int. 2013; 33: 794-804
- Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression.Biochem Biophys Res Commun. 2009; 390: 613-618
- CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials.BMJ. 2010; 340: c332
- The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FER(HDL)).Clin Biochem. 2001; 34: 583-588
Quantikine. Human Adiponectin/Acrp30 Immunoassay. [R&D Systems Website]. Available at: http://www.rndsystems.com/pdf/drp300.pdf.
- Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474
- Nonalcoholic steatohepatitis clinical research network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321
- Clinical and histological spectrum of non-alcoholic fatty liver disease associated with normal ALT values.Hepatology. 2003; 37: 1286-1292
- Non-alcoholic fatty liver disease.N Eng J Med. 2002; 346: 1221-1231
- Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): diagnosis and clinical course.Best Pract Res Clin Gastrenterol. 2004; 18: 1089-1104
- Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.Diabetologia. 2003; 46: 459-469
- Low circulating levels of dehydroepiandrosterone in histologically advanced NAFLD.Hepatology. 2008; 47: 484-492
- Does the hormone of eternal youth protect against NASH?.Hepatology. 2008; 48: 1351
- Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes.Diabetes Care. 2012; 35: 955-958
- Six-month exenatide improves HOMA hyperbolic product in type 2 diabetic patients mostly by enhancing beta-cell function rather than insulin sensitivity.Diabetes Metab. 2010; 36: 293-298
- Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition.Diabetes Care. 2010; 33: 1734-1737
- Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with type 2 diabetes: a prospective study.Diabetes Res Clin Pract. 2014; 104: 92-96
Published online: January 08, 2016
Accepted: December 27, 2015
Received in revised form: October 19, 2015
Received: July 10, 2015
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