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