beta-Cell-Specific Deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase Causes Overt Diabetes due to Reduction of beta-Cell Mass and Impaired Insulin Secretion

Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes. To investigate the role of HMGCR in the development of beta-cells and glucose homeostasis, we deletedHmgcrin a beta-cell-specific manner by using the Cre-loxP technique. Mice lackingHmgcrin beta-cells (beta-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both beta-cell mass and insulin secretion. Ki67-positive cells were reduced in beta-KO mice at P9; thus, beta-cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (Ngn3), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of beta-cell-associated genes, such as insulin, pancreatic and duodenal homeobox 1 (Pdx1), and MAF BZIP transcription factor A (Mafa) in the islets from beta-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of beta-cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of beta-cells in mice.