title: Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats.
abstract: Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD-low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down-regulation of the mRNA expressions of sterol regulatory element binding protein-1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-α and carnitine palmitoyltransferase-1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-γ expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-γ expression and treatment with a PPAR-γ antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased β-cell mass by decreasing β-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin resistance by decreasing adipose PPAR-γ expression and deteriorating β-cell function and mass.
authors.affiliation: Dept. of Food & Nutrition, Obesity/Diabetes Research Institutes, College of Natural Science, Hoseo University, Asan, Korea. Electronic address: smpark@hoseo.edu.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Park
authors.affiliation: Dept. of Food & Nutrition, Obesity/Diabetes Research Institutes, College of Natural Science, Hoseo University, Asan, Korea.
authors.forename: Da Sol
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Dept. of Food & Nutrition, Obesity/Diabetes Research Institutes, College of Natural Science, Hoseo University, Asan, Korea.
authors.forename: Suna
authors.initials: S
authors.lastname: Kang
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001823:Body Composition; D004734:Energy Metabolism; D005947:Glucose / Q000008:administration & dosage*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009765:Obesity / Q000503:physiopathology; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D014280:Triglycerides / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000503:physiopathology*
chemical_list: D007328:Insulin; D047495:PPAR gamma; D014280:Triglycerides; D005947:Glucose
keywords: Energy expenditure; Insulin resistance; Insulin secretion; Lean body mass; PPAR-γ; Vitamin D