Endocrine Abstracts

Background and Aims: Obesity is a major risk factor for type 2 diabetes (T2D). Remission of diabetes can be achieved by dietary weight loss although the underlying molecular mechanism(s) are unknown. These beneficial effects could be related to decreasing hepatic fat delivery to the pancreas and eventually restoring β-cell function. We hypothesised that hepatic de novo lipogenesis (DNL) is the primary driver of pancreas “lipotoxicity” and the process can be reversed during weight loss. We therefore aimed to mimic the process of T2D development and remission in human using this model and assess the change in DNL rates.

Methods: The first stage of the study was designed to optimise nutritional and stable isotopes conditions to induce T2D in this model (NONcNZO10/LtJ). 12 male mice were imported from the Jackson Laboratory at 5-6 weeks of age and were placed for 12 weeks on either high sucrose or corn starch diet with moderate fat content (Research Diet). The diet was also enriched with ¹³C-labelled palmitic acid and deuterated water (²H2O) for tracking of dietary and endogenous sources of fatty acids, respectively. Fat and lean mass were determined by TD NMR, and Glucose Tolerance Testing (GTT) was carried out by oral gavage at baseline and 12 weeks. Stable isotopes were analysed by high resolution LC-MS.

Results: At 12 weeks, mice on the high sucrose diet gained more body weight and total fat mass accompanied with higher liver fat and impaired glucose tolerance. Sucrose diet also promoted high rate of DNL as measured by deuterium incorporation into plasma palmitic and stearic acids. Analysis of liver tissues confirmed high DNL and expression of lipogenic genes.

Conclusion: Our findings suggest that this high sucrose model is useful to study DNL in T2D. Work is underway to mimic the remission process by calorie restriction.