Islet Dysfunction Induced by Niemann-Pick C1 (NPC1) Heterozygous Mutation Combined with High-fat Diet in C57BL/6C Mice

Male patients with NPC1 heterozygous mutation (Npc1+/-) are prone to obesity and diabetes, yet the mechanism remains unclear. In this study, male Npc1+/- mice (C57BL/6C-Npc1) were used to evaluate the effects of NPC1 heterozygous mutation combined with 60% high-fat diet (HFD) on glucolipid metabolism, cholesterol accumulation, islet dysfunction and β-cell dedifferentiation. Compared with male HFD-Npc1+/+ or Npc1+/- mice fed with low-fat diet (LFD), body weight of male HFD-Npc1+/- mice gradually increased with elevated levels of fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG), showing hyperinsulinemia and typical characteristics of diabetes. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) indicated that HFD-Npc1+/- mice developed marked oral glucose intolerance and severe systemic insulin resistance after 4 months. TC and TG were accumulated in both liver and pancreas. The HE results confirmed the large diameter of epididymal adipocytes in HFD-Npc1+/- mice. Furthermore, protein levels of insulin, 4E-BP1, p-S6 and PDX1 were suppressed obviously in β cells of HFD-Npc1+/- mice, while expression of glucagon and precursor marker ALDH1A3 increased, indicating the typical dedifferentiation occurred in β cells. This study partly reveals the underlying mechanism of susceptibility of obesity and diabetes in Npc1+/- male mice induced by 60% HFD. High metabolic stress and abnormal cholesterol metabolism in islets more directly lead to the dedifferentiation and dysfunction of β cells, to aggravate the process from obesity to diabetes.