Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.
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.
Terauchi
Yasuo
Y
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan.
Takamoto
Iseki
I
Kubota
Naoto
N
Matsui
Junji
J
Suzuki
Ryo
R
Komeda
Kajuro
K
Hara
Akemi
A
Toyoda
Yukiyasu
Y
Miwa
Ichitomo
I
Aizawa
Shinichi
S
Tsutsumi
Shuichi
S
Tsubamoto
Yoshiharu
Y
Hashimoto
Shinji
S
Eto
Kazuhiro
K
Nakamura
Akinobu
A
Noda
Mitsuhiko
M
Tobe
Kazuyuki
K
Aburatani
Hiroyuki
H
Nagai
Ryozo
R
Kadowaki
Takashi
T
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
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