1. MEK/ERK Signaling in β-Cells Bifunctionally Regulates β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis
- Author
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Hiroshi Kobayashi, Jean Charron, Hiroki Mizukami, Hirotsugu Suwanai, Sho Osonoi, Naoki Kobayashi, Masafumi Muratani, Yoshiko Matsumoto Ikushima, Kohjiro Ueki, Yuichi Morimoto, Jun Adachi, Seiichi Takemiya, Motoharu Awazawa, Noriko Takahashi, and Kotaro Soeda
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Type 2 diabetes ,Diet, High-Fat ,Exocytosis ,Cell Line ,Mice ,Insulin-Secreting Cells ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,Internal Medicine ,medicine ,Animals ,Homeostasis ,Humans ,Glucose homeostasis ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Mitogen-Activated Protein Kinase Kinases ,geography ,geography.geographical_feature_category ,Chemistry ,Insulin ,medicine.disease ,Islet ,Pathophysiology ,Mice, Inbred C57BL ,Endocrinology ,Signal Transduction - 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.
- Published
- 2021
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