1844-P: Long-Term Remission of Type 2 Diabetes after Weight Loss Requires Effective Clearance of Hepatic VLDL-TG and Maintenance of Low Intrapancreatic Fat

Abstract

The Diabetes Remission Clinical Trial (DiRECT) demonstrated initial remission of type 2 diabetes in about half of a large primary care population, and this was associated with decrease in intrapancreatic fat content and return of beta cell function. We have carried out detailed metabolic studies on a subgroup at 2 years, comparing those who remained in remission (HbA1c <6.5%; n=20, 7F/13M, 54.6±7.3 years, BMI 34.5±4.9kg/m2), and those who failed to maintain the initial remission (n=13, 6F/7M, 52.6±8.3 years, BMI 34.9±3.7kg/m2). Pancreas and liver fat were quantified by 3-point Dixon MRI. Hepatic VLDL-triglyceride (VLDL1-TG) production was measured in vivo using a non-isotopic competitive blocking method. Remission of diabetes was associated with major decreases in liver fat, pancreas fat, and hepatic VLDL-TG production during the weight loss phase between baseline to 5 months in both groups. However, those who failed to maintain remission were characterized by more weight regain (11. 3±1.9 vs. 6.6±1.0 kg, p=0.036), and greater increases in both liver (6.2±1.1 vs. 3.6±0.9%, p=0.05), and pancreas fat (+1.0±0.39 vs. -0.48±0.25%, p=0.005) between 5 months and 24 months. Hepatic VLDL-TG pool level remained stable under remission conditions (1046.4± 204.6 to 1638.6± 372.11 mg, p=0.35), whereas there was a significant increase when remission was lost (1328.0± 271.8 to 2865.6±692.4mg, p=0.04). In those who failed to maintain remission, fasting VLDL-TG increased (0.46±0.10 to 0.84±0.17 mmol/l, p<0.05), and there was a positive correlation between the rise in liver fat and intrapancreatic fat (r=0.64, p=0.018). These data emphasize the link between hepatic VLDL-TG-metabolism and accumulation of fat within the liver and pancreas in the pathogenesis of type 2 diabetes, provide further evidence for the role of fat in its pathophysiology, and show that longer term remission of type 2 diabetes is dependent upon avoidance of weight regain. Disclosure A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. M.E. Lean: Consultant; Self; Counterweight Ltd., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. R. Taylor: Advisory Panel; Self; Wilmington Healthcare. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG. Funding Diabetes UK