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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
figure
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 UekiIn 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.