American Diabetes Association
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MEK/ERK Signaling in β Cells Bifunctionally Regulates β-cell Mass and Glucose-stimulated Insulin-secretion Response to Maintain Glucose Homeostasis

Version 2 2021-06-25, 21:51
Version 1 2021-04-27, 16:31
posted on 2021-06-25, 21:51 authored by Yoshiko Matsumoto Ikushima, Motoharu Awazawa, Naoki Kobayashi, Sho Osonoi, Seiichi Takemiya, Hiroshi Kobayashi, Hirotsugu Suwanai, Yuichi Morimoto, Kotaro Soeda, Jun Adachi, Masafumi Muratani, Jean Charron, Hiroki Mizukami, Noriko Takahashi, Kohjiro Ueki
In diabetic pathology, insufficiency in β-cell mass unable to meet peripheral insulin demand and functional defects of individual β cells to produce insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet-fed conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.


This work was supported by JSPS KAKENHI Grant number JP16K19067 (granted to YMI) and JP19K16547 (granted to YMI); National Center for Global Health and Medicine Grant number 29-1021 (granted to YMI) and 20A1011 (granted to YMI).


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