Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy
A. Dutour
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
These authors contributed equally to the work.Search for more papers by this authorI. Abdesselam
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
These authors contributed equally to the work.Search for more papers by this authorP. Ancel
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Search for more papers by this authorF. Kober
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Search for more papers by this authorG. Mrad
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Search for more papers by this authorP. Darmon
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
Search for more papers by this authorO. Ronsin
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
Search for more papers by this authorV. Pradel
Aix Marseille Université, Marseille, France
Statistics Department, Assistance Publique Hôpitaux Marseille, CHU Sainte Marguerite, Marseille, France
Search for more papers by this authorN. Lesavre
Aix Marseille Université, Marseille, France
Centre d'investigation Clinique, 1409, Assistance Publique Hôpitaux de Marseille, CHU Nord, Marseille, France
Search for more papers by this authorJ. C. Martin
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Search for more papers by this authorA. Jacquier
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Radiology Department, CHU La Timone, Marseille, France
Search for more papers by this authorY. Lefur
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Search for more papers by this authorM. Bernard
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Search for more papers by this authorCorresponding Author
B. Gaborit
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
Correspondence to: Bénédicte Gaborit, Inserm U1062, Inra U1260, Aix Marseille Université, Faculté de Médecine, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France.
E-mail: benedicte.gaborit@ap-hm.fr
Search for more papers by this authorA. Dutour
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
These authors contributed equally to the work.Search for more papers by this authorI. Abdesselam
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
These authors contributed equally to the work.Search for more papers by this authorP. Ancel
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Search for more papers by this authorF. Kober
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Search for more papers by this authorG. Mrad
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Search for more papers by this authorP. Darmon
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
Search for more papers by this authorO. Ronsin
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
Search for more papers by this authorV. Pradel
Aix Marseille Université, Marseille, France
Statistics Department, Assistance Publique Hôpitaux Marseille, CHU Sainte Marguerite, Marseille, France
Search for more papers by this authorN. Lesavre
Aix Marseille Université, Marseille, France
Centre d'investigation Clinique, 1409, Assistance Publique Hôpitaux de Marseille, CHU Nord, Marseille, France
Search for more papers by this authorJ. C. Martin
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Search for more papers by this authorA. Jacquier
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Radiology Department, CHU La Timone, Marseille, France
Search for more papers by this authorY. Lefur
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Search for more papers by this authorM. Bernard
Aix Marseille Université, Marseille, France
Centre de Résonance Magnétique Biologique et Médicale, CNRS UMR 7339, Marseille, France
Search for more papers by this authorCorresponding Author
B. Gaborit
Inserm U1062, Inra U1260, Faculté de Médecine, 13385 Marseille, France
Aix Marseille Université, Marseille, France
Department of Endocrinology, Metabolic Diseases and Nutrition, Pole Endo, Marseille, France
Correspondence to: Bénédicte Gaborit, Inserm U1062, Inra U1260, Aix Marseille Université, Faculté de Médecine, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France.
E-mail: benedicte.gaborit@ap-hm.fr
Search for more papers by this authorAbstract
Aim
To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores.
Methods
A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment.
Results
The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m2. Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (−0.7 ± 0.3% vs. −0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (−5.5 ± 1.2 kg vs. −0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (−8.8 ± 2.1%) and HTGC (−23.8 ± 9.5%), compared with the reference treatment (EAT: −1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively).
Conclusion
Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.
Supporting Information
| Filename | Description |
|---|---|
| dom12680-sup-0001-FigureS1.tiffTIFF image, 8 MB | Figure S1. Discriminant multivariate analysis showing the distribution of patients according to the change of clinical and biological variables between baseline and 26 weeks. |
| dom12680-sup-0002-FigureS2.tiffTIFF image, 2.3 MB | Figure S2. Heat map of patients regarding the change of their metabolic data between baseline and 26 weeks. |
| dom12680-sup-0003-TableS1.docWord document, 37.5 KB | Table S1. Left ventricular function parameters evolution between groups. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Britton KA, Fox CS. Ectopic fat depots and cardiovascular disease. Circulation 2011; 124: e837–e841.
- 2Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881–887.
- 3Neeland IJ, Turer AT, Ayers CR et al. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA 2012; 308: 1150–1159.
- 4Fabbrini E, Yoshino J, Yoshino M et al. Metabolically normal obese people are protected from adverse effects following weight gain. J Clin Invest 2015; 125: 787–795.
- 5Mahabadi AA, Berg MH, Lehmann N et al. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf Recall Study. J Am Coll Cardiol 2013; 61: 1388–1395.
- 6Gaborit B, Kober F, Jacquier A et al. Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat. Int J Obes (Lond) 2012; 36: 422–430.
- 7Rijzewijk LJ, van der Meer RW, Smit JW et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 2008; 52: 1793–1799.
- 8Williamson RM, Price JF, Glancy S et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care 2011; 34: 1139–1144.
- 9Romeo S, Kozlitina J, Xing C et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461–1465.
- 10Gaborit B, Abdesselam I, Kober F et al. Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int J Obes (Lond) 2015; 39: 480–487.
- 11Tushuizen ME, Bunck MC, Pouwels PJ et al. Pancreatic fat content and beta-cell function in men with and without type 2 diabetes. Diabetes Care 2007; 30: 2916–2921.
- 12Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17: 819–837.
- 13Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care 2010; 33: 1028–1030.
- 14Abdesselam I, Pepino P, Troalen T et al. Time course of cardiometabolic alterations in a high fat high sucrose diet mice model and improvement after GLP-1 analog treatment using multimodal cardiovascular magnetic resonance. J Cardiovasc Mag Reson 2015; 17: 95.
- 15Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006; 43: 173–181.
- 16Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T. Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart Circ Physiol 2013; 305: H295–H304.
- 17Liu Y, Wei R, Hong TP. Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20: 9090–9097.
- 18Armstrong MJ, Hull D, Guo K et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis. J Hepatol 2015; 64: 399–408.
- 19Cuthbertson DJ, Irwin A, Gardner CJ et al. 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.
- 20Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring) 2011; 19: 2310–2315.
- 21Banerjee R, Pavlides M, Tunnicliffe EM et al. Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease. J Hepat0ol 2014; 60: 69–77.
- 22Lingvay I, Esser V, Legendre JL et al. Noninvasive quantification of pancreatic fat in humans. J Clin Endocrinol Metab 2009; 94: 4070–4076.
- 23Lamb HJ, Smit JW, van der Meer RW et al. Metabolic MRI of myocardial and hepatic triglyceride content in response to nutritional interventions. Curr Opin Clin Nutr Metab Care 2008; 11: 573–579.
- 24Gaborit B, Jacquier A, Kober F et al. Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. J Am Coll Cardiol 2012; 60: 1381–1389.
- 25Vanhamme L, van den Boogaart A, Van Huffel S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson 1997; 129: 35–43.
- 26Szczepaniak LS, Nurenberg P, Leonard D et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462–E468.
- 27Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956; 4: 20–34.
- 28Jonker JT, Lamb HJ, van der Meer RW et al. Pioglitazone compared with metformin increases pericardial fat volume in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010; 95: 456–460.
- 29Shimabukuro M, Hirata Y, Tabata M et al. Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2013; 33: 1077–1084.
- 30Eroglu S, Sade LE, Yildirir A et al. Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease. Nutr Metab Cardiovasc Dis 2009; 19: 211–217.
- 31Sade LE, Eroglu S, Bozbas H et al. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis 2009; 204: 580–585.
- 32Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res 2014; 114: 1788–1803.
- 33Wallner M, Kolesnik E, Ablasser K et al. Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium. J Mol Cell Cardiol 2015; 89 (Pt B): 365–375.
- 34Abdesselam I, Dutour A, Kober F et al. Time course of change in ectopic fat stores after bariatric surgery. J Am Coll Cardiol 2016; 67: 117–119.
- 35Morano S, Romagnoli E, Filardi T et al. Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonists on fat distribution in patients with type 2 diabetes mellitus: an ultrasonography study. Acta Diabetol 2015; 52: 727–732.
- 36Iacobellis G, Singh N, Wharton S, Sharma AM. Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity (Silver Spring) 2008; 16: 1693–1697.
- 37Kim MK, Tanaka K, Kim MJ et al. Comparison of epicardial, abdominal and regional fat compartments in response to weight loss. Nutr Metab Cardiovasc Dis 2009; 19: 760–766.
- 38Kim MK, Tomita T, Kim MJ, Sasai H, Maeda S, Tanaka K. Aerobic exercise training reduces epicardial fat in obese men. J Appl Physiol 2009; 106: 5–11.
- 39Jonker JT, de Mol P, de Vries ST et al. Exercise and type 2 diabetes mellitus: changes in tissue-specific fat distribution and cardiac function. Radiology 2013; 269: 434–442.
- 40McKenney ML, Schultz KA, Boyd JH et al. Epicardial adipose excision slows the progression of porcine coronary atherosclerosis. J Cardiothorac Surg 2014; 9: 2.
- 41McGavock JM, Lingvay I, Zib I et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 2007; 116: 1170–1175.
- 42Levelt E, Mahmod M, Piechnik SK et al. Relationship between Left ventricular structural and metabolic remodelling in type 2 diabetes mellitus. Diabetes 2016; 65: 44–52.
- 43Kotronen A, Juurinen L, Hakkarainen A et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care 2008; 31: 165–169.
- 44Samson SL, Gonzalez EV, Yechoor V, Bajaj M, Oka K, Chan L. Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model. Mol Ther 2008; 16: 1805–1812.
- 45Verges B, Bouillet B, Guiu B et al. Treatment with liraglutide leads to an important reduction in liver fat content, assessed by mangnetic resonance spectroscopy, in pepole with type 2 diabetes. Oral presentation abstract. European Association for the Study of Diabetes, Stockholm, Sweden, 2015, 15 September 2015.
- 46Armstrong MJ, Gaunt P, Aithal GP et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387: 679–690.
- 47Samson SL, Sathyanarayana P, Jogi M et al. 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.
- 48Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab 2013; 24: 537–545.
- 49Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 2011; 6: e25269.
- 50Vanderheiden A, Harrison LB, Warshauer JT et al. Mechanisms of action of liraglutide in patients with type 2 diabetes treated with high-dose insulin. J Clin Endocrinol Metab 2016; 101: 1798–1806.
- 51Hu HH, Kim HW, Nayak KS, Goran MI. Comparison of fat-water MRI and single-voxel MRS in the assessment of hepatic and pancreatic fat fractions in humans. Obesity (Silver Spring) 2010; 18: 841–847.
- 52Livingstone RS, Begovatz P, Kahl S et al. Initial clinical application of modified Dixon with flexible echo times: hepatic and pancreatic fat assessments in comparison with (1)H MRS. MAGMA 2014; 27: 397–405.
