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

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.

Divalent Metal Transporter 1 Knock-Down Modulates IL-1β Mediated Pancreatic Beta-Cell Pro-Apoptotic Signaling Pathways through the Autophagic Machinery

“…In our results ( Figure 5 B and Table S6 ), eleven (phospho)proteins (HMGCR, IRS2-T517, T524, PCLO-S4823, SYTL4-S217, BAIAP3-S215, RAB3B, ABCA1-S2234, CLASP1-S1220, CADM1, SCG2-S534, and CHGB-S79,S397,T400,S405) were involved in insulin secretion, and they were restored towards normal in DMT1 -silenced β-cells against IL-1β exposure. For instance, β-cell-specific silencing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) acutely triggered the reduction of β-cell mass and insulin secretion after postnatal day 9 in mice and eventually leading to the development of diabetes [ 97 ]. Knock-down of cell adhesion molecule 1 (CADM1) promotes GSIS in rat and human islet β-cells whereas the induction of CADM1 inhibits GSIS [ 98 ].…”

Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome

“…Statin-induced reduction in insulin secretion from β-cells happens because statins disrupt the production of endogenous cholesterol in β-cells, which is important to maintain the functionality of CaV channels and insulin secretion [ 17 ]. Additionally, pancreatic β-cell-specific ablation of HMGCR gene in mice resulted in a phenotype with severe hypoinsulinemia and hyperglycemia [ 43 ]. This study revealed the importance of HMGCR and mevalonate pathway for pancreatic β-cell development [ 43 ].…”

“…Additionally, pancreatic β-cell-specific ablation of HMGCR gene in mice resulted in a phenotype with severe hypoinsulinemia and hyperglycemia [ 43 ]. This study revealed the importance of HMGCR and mevalonate pathway for pancreatic β-cell development [ 43 ].…”

“…One of the limitations is the short incubation time compared to the duration of the treatment in the patients. HMG-CoA reductase is highly important for adipose tissue and pancreas functions [ 22 , 43 ]. Although 24 h incubation of MIN6 cells with atorvastatin (10 µM) has shown a reduction in cholesterol content in the cells [ 44 ], measuring the cholesterol content or HMGCR activity in human islets and adipose tissue is warranted.…”

Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice

“…After female mice were acclimated in an individual metabolic cage for 3 days, VO2 and VCO2 were measured using ARCO-2000 (ARCO System) for 4 days as described previously (49). Locomotor activity was measured using the ACTIMO-100 activity monitoring system (Shinfactory).…”