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

Diabetes. 2020 Nov;69(11):2352-2363. doi: 10.2337/db19-0996. Epub 2020 Aug 13.

Abstract

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 β-cells and glucose homeostasis, we deleted Hmgcr in a β-cell-specific manner by using the Cre-loxP technique. Mice lacking Hmgcr in β-cells (β-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both β-cell mass and insulin secretion. Ki67-positive cells were reduced in β-KO mice at P9; thus, β-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 β-cell-associated genes, such as insulin, pancreatic and duodenal homeobox 1 (Pdx1), and MAF BZIP transcription factor A (Mafa) in the islets from β-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of β-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 β-cells in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blood Glucose
  • Diabetes Mellitus
  • Feeding Behavior
  • Gene Expression Regulation, Enzymologic / physiology*
  • Glucose Tolerance Test
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hyperglycemia
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / metabolism
  • Maf Transcription Factors, Large / genetics
  • Maf Transcription Factors, Large / metabolism
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Blood Glucose
  • Homeodomain Proteins
  • Insulin
  • Maf Transcription Factors, Large
  • Mafa protein, mouse
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Hydroxymethylglutaryl CoA Reductases
  • Hmgcr protein, mouse

Associated data

  • figshare/10.2337/figshare.12771422