Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor.
It was the aim of this study to further explore the functional role of vitamin D in the endocrine pancreas. By gene targeting, we have recently generated mice in which a lacZ reporter gene is driven by the endogenous vitamin D receptor (VDR) promoter. These mice express a functionally inactive mutant VDR. Pancreatic islets but not exocrine pancreas cells showed strong lacZ reporter gene expression in mutant mice. To rule out possible influences of hypocalcemia on pancreatic endocrine function, a rescue diet enriched with calcium, phosphorus, and lactose was fed to wild-type (WT) and VDR mutant mice. The rescue diet normalized body weight and mineral homeostasis in VDR mutants. In glucose tolerance tests, baseline blood glucose levels were unchanged in fasting VDR mutants. However, blood glucose was elevated after oral or subcutaneous glucose loading, and maximum serum insulin levels were reduced by approximately 60% in VDR mutants vs. WT mice on either diet. In addition, insulin mRNA levels were decreased in VDR mutant mice on both diets, whereas pancreatic beta cell mass, islet architecture, and islet neogenesis were normal. These findings clearly establish a molecular role of the vitamin D-responsive elements in pancreatic insulin synthesis and secretion in vivo.
Zeitz
Ute
U
Institute of Animal Physiology, Ludwig Maximilians University, 80539 Munich, Germany.
Weber
Karin
K
Soegiarto
Desi W
DW
Wolf
Eckhard
E
Balling
Rudi
R
Erben
Reinhold G
RG
D000818:Animals; D002117:Calcitriol / Q000502:physiology*; D017930:Genes, Reporter; D005951:Glucose Tolerance Test; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics*
D007328:Insulin; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002117:Calcitriol