312-OR: Gender-Specific Effects on Hepatic Fat Metabolism in Type 2 Diabetes before and after Remission

Men are more susceptible to type 2 diabetes and NAFLD than women, possibly secondary to differences in hepatic lipoprotein metabolism. The Tyneside cohort of Diabetes Remission Clinical Trial (34M/30F, 52.3±8.0 years, BMI 35.1±4.5kg/m²) were studied at baseline and to 24 months after weight loss. 3-point Dixon MRI was used for intra-organ fat. Hepatic VLDL-TG production was measured using a competitive blocking method. In the nondiabetic group, both liver and pancreas fat differed markedly in men and women (5.4± 1.1 vs. 3.4±0.1%, p=0.005, and 7.6±0.5 vs. 4.7±0.4%, p=0.0006, respectively). In diabetes, both liver and pancreas fat were similar in men and women at baseline (15.4±1.9 vs. 16.9±1.9%, p=0.57; and 8.5±0.4 vs. 8.4±0.5%, p=0.66, respectively). They decreased similarly after weight loss in both men and women (liver fat: 2.6±0.6% and 3.6±0.7%; pancreas fat: 7.6 ±0.4% and 7.5±0.5%, p<0.0001 vs. baseline for both). VLDL-TG production was also similar at baseline (554±39 vs. 559±33mg/kg/day, p=0.96) and after weight loss (418±28 vs. 448±37mg/kg/day, p=0.29). Women had a lower VLDL-TG pool size (p=0.002), lower plasma VLDL-TG (p<0.0001), lower fasting glucagon (p<0.05), higher adiponectin (p<0.001), and lower visceral adipose tissue (p<0.0001) volumes than men regardless of diabetes status. However, diabetic women had higher: subcutaneous fat (p<0.0001), leptin (p<0.0001), fasting NEFA (p=0.004), GDF-15 (p=0.044), and FGF-21 (p=0.008). After 24 months of intervention, men and women remained significantly different in VLDL-TG pool, NEFA, SAT, VAT, leptin, and adiponectin (p<0.05 for all). Women are likely to process lipoproteins more rapidly and safely store VLDL-TG. This minimizes delivery of toxic lipid metabolites from VLDL-TG to pancreatic islets. These data demonstrate important gender differences in hepatic fat handling, and underscore the importance of considering this when designing metabolic studies.