86-OR: High-Fat Diet Prevents Autoimmune Diabetes in NOD Mice

Abstract

Type 1 diabetes (T1D) has a strong genetic predisposition and requires an environmental trigger to initiate autoimmune destruction of beta cells. The rate of childhood obesity has risen in parallel to the rate of T1D, suggesting high fat diet (HFD) may be an environmental trigger in the development of autoimmune diabetes. Supporting this hypothesis, HFD can induce insulin resistance, beta cell stress, dysfunctional insulin production, and beta cell death. To explore the role of HFD in the development of T1D, 4 week-old non-obese diabetic (NOD) female mice were placed on HFD or chow diet (CD). At 10 weeks of age NOD mice fed with HFD demonstrated a significant increase in body weight and non-fasting blood glucose along with mild glucose intolerance compared with NOD CD fed mice. Histological analysis at 10 weeks of age revealed significantly less pancreatic immune cell infiltration and increased beta cell mass in HFD fed mice compared to CD fed mice. By 15 weeks of age, HFD fed NOD animals demonstrated impaired glucose tolerance similar to CD fed mice, increased glucose-stimulated insulin secretion and total insulin content, and insulin resistance. Surprisingly, at 25 weeks of age the HFD fed NOD mice were completely protected from the development of diabetes, while as expected 70% of NOD CD fed mice had developed diabetes. In summary, this study demonstrates that in the NOD model of T1D HFD reduced islet immune cell infiltration, increased beta cell mass, insulin content and insulin secretion protecting the mice from development of diabetes. The mechanism underlying this protection seems to be two-fold: expansion of beta cell mass and prevention of autoimmune-mediated beta cell death. Our data correlate with other recent studies indicating that early stimulation of beta cell replication can induce immune tolerance in NOD animals preventing T1D. Identification of the mechanisms by which HFD leads to prevention of diabetes in NOD animals may lead to the development of novel therapeutic interventions to prevent T1D in humans. Disclosure A.L. Clark: None. Z. Yan: None. S.X. Chen: None. M. Fuess: None. G. McGinn: None. M.S. Remedi: None. Funding National Institutes of Health (P30DK020579, K12HD076224-04)