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- Title
MEK/ERK Signaling in β-Cells Bifunctionally Regulates β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis.
- Authors
Ikushima, Yoshiko Matsumoto; Awazawa, Motoharu; Kobayashi, Naoki; Osonoi, Sho; Takemiya, Seiichi; Kobayashi, Hiroshi; Suwanai, Hirotsugu; Morimoto, Yuichi; Soeda, Kotaro; Adachi, Jun; Muratani, Masafumi; Charron, Jean; Mizukami, Hiroki; Takahashi, Noriko; Ueki, Kohjiro
- Abstract
In diabetic pathology, insufficiency in β-cell mass, unable to meet peripheral insulin demand, and functional defects of individual β-cells in production of 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-feeding 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.
- Subjects
INSULIN; SECRETION; DRUG development; TYPE 2 diabetes; GLUCOSE intolerance; HOMEOSTASIS; RESEARCH; ANIMAL experimentation; RESEARCH methodology; BLOOD sugar; CELL physiology; ANIMAL nutrition; MEDICAL cooperation; EVALUATION research; ISLANDS of Langerhans; CELLULAR signal transduction; COMPARATIVE studies; TRANSFERASES; CELL lines; MICE; PHOSPHORYLATION
- Publication
Diabetes, 2021, Vol 70, Issue 7, p1519
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db20-1295