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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 13.08.2020 by Ada 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 Ishibashi
Inhibitors 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.

Funding

This study was supported by JSPS KAKENHI Grant Numbers JP16K09789, JP19H03712, JP17390266 and Program for the Strategic Research Foundation at Private Universities (2011-2015) Cooperative Basic and Clinical Research on Circadian Medicine and Non-communicable diseases from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and unrestricted grants from Astellas Pharma, Daiichi Sankyo Co, Shionogi Co, Boehriger Ingelheim Japan, Ono Pharma, Mitsubishi Tanabe Pharma, Takeda Pharma Co, Toyama Chemical Co, Teijin, Sumitomo Dainippon Pharma, Sanofi K.K., Novo Nordisk Pharma, MSD K.K., Pfizer Japan, Novartis Pharma, and Eli Lilly Co.

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