Endocrine Abstracts

Background and aims: Understanding the mechanisms that lead to remission of type 2 diabetes (T2D) after weight loss is critical to develop novel therapies. We hypothesized that weight loss decreases hepatic de novo lipogenesis (DNL), a primary mechanism expected to modulate T2D remission.

Methods: 24 mice (NONcNZO10/ltJ) at age 5-6 weeks were placed for 12 weeks on high sucrose diet (HSD: 60% sucrose/20% fat). After 12 weeks, 6 mice were placed on calorie restriction (CR) (30% of total calorie intake), and another group (n = 6) continued the HSD for up to 24weeks. Deuterated water (²H2O) and 13 ^C -labelled palmitic acid were used for tracing DNL and dietary fatty acids, respectively. Fat and lean mass were assessed and OGTT was performed at baseline, 12, and 24 weeks. Stable isotopes were analysed by high resolution LC–MS.

Results: HSD increased body weight and total fat mass but decreased lean mass (P < 0.0001 for all). CR had the opposite (P < 0.05). After 12 weeks, mice on HSD developed impaired glucose tolerance which exacerbated further at 24 weeks. However, CR brought about significant improvement in glucose tolerance (P < 0.001), and insulin sensitivity (P < 0.01) as assessed by OGTT. There was major decrease in hepatic lipid deposition after CR. The pro-lipogenic effect of HSD is supported by expression of DNL related genes. This was translated by higher incorporation of deuterium in the plasma and liver tissues. At 24 weeks, deuterium-labelled palmitic acid/octadecanoic acid had decreased in CR group (P < 0.05, P < 0.0001, respectively). Finally, HSD was associated with high leptin and low adiponectin levels.

Conclusion: Our data suggest an important role of DNL on restoration of normal glucose tolerance and resolution of T2D. In addition, the NONcNZO10/ltJ exhibits a unique metabolic phenotype similar to that of human, making it the ideal model to study T2D remission with specific emphasis on DNL pathway.