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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
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posted on 2020-08-13, 20:06 authored by Ada AdminAda Admin, Shoko Takei, Shuichi Nagashima, Akihito Takei, Daisuke Yamamuro, Tetsuji Wakabayashi, Akiko Murakami, Masayo Isoda, Hisataka Yamazaki, Chihiro Ebihara, Manabu Takahashi, Ken Ebihara, Katsuya Dezaki, Yuki Takayanagi, Tatsushi Onaka, Ken Fujiwara, Takashi Yashiro, Shun IshibashiInhibitors of
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins, which are used to prevent cardiovascular
diseases, are associated with a modest increase in the risk of new-onset
diabetes mellitus. 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.