title: Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.
abstract: Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of beta cell-specific Gck (Gck(+/-)) causes impaired insulin secretion to glucose, although the animals have a normal beta cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked beta cell hyperplasia, whereas Gck(+/-) mice demonstrated decreased beta cell replication and insufficient beta cell hyperplasia despite showing a similar degree of insulin resistance. DNA chip analysis revealed decreased insulin receptor substrate 2 (Irs2) expression in HF diet-fed Gck(+/-) mouse islets compared with wild-type islets. Western blot analyses confirmed upregulated Irs2 expression in the islets of HF diet-fed wild-type mice compared with those fed standard chow and reduced expression in HF diet-fed Gck(+/-) mice compared with those of HF diet-fed wild-type mice. HF diet-fed Irs2(+/-) mice failed to show a sufficient increase in beta cell mass, and overexpression of Irs2 in beta cells of HF diet-fed Gck(+/-) mice partially prevented diabetes by increasing beta cell mass. These results suggest that Gck and Irs2 are critical requirements for beta cell hyperplasia to occur in response to HF diet-induced insulin resistance.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Kajuro
authors.initials: K
authors.lastname: Komeda
authors.forename: Akemi
authors.initials: A
authors.lastname: Hara
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Ichitomo
authors.initials: I
authors.lastname: Miwa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aizawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Tsubamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Akinobu
authors.initials: A
authors.lastname: Nakamura
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology*; D005941:Glucokinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D004041:Dietary Fats; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D005941:Glucokinase