TY - JOUR
T1 - Glucokinase and IRS-2 are required for compensatory β cell hyperplasia in response to high-fat diet-induced insulin resistance
AU - Terauchi, Yasuo
AU - Takamoto, Iseki
AU - Kubota, Naoto
AU - Matsui, Junji
AU - Suzuki, Ryo
AU - Komeda, Kajuro
AU - Hara, Akemi
AU - Toyoda, Yukiyasu
AU - Miwa, Ichitomo
AU - Aizawa, Shinichi
AU - Tsutsumi, Shuichi
AU - Tsubamoto, Yoshiharu
AU - Hashimoto, Shinji
AU - Eto, Kazuhiro
AU - Nakamura, Akinobu
AU - Noda, Mitsuhiko
AU - Tobe, Kazuyuki
AU - Aburatani, Hiroyuki
AU - Nagai, Ryozo
AU - Kadowaki, Takashi
PY - 2007/1/4
Y1 - 2007/1/4
N2 - Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of β cell-specific Gck (Gck+/-) causes impaired insulin secretion to glucose, although the animals have a normal β cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked β cell hyperplasia, whereas Gck+/- mice demonstrated decreased β cell replication and insufficient β 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 Irs+/- mice failed to show a sufficient increase in β cell mass, and overexpression of Irs2 in β cells of HF diet-fed Gck+/- mice partially prevented diabetes by increasing β cell mass. These results suggest that Gck and Irs2 are critical requirements for β cell hyperplasia to occur in response to HF diet-induced insulin resistance.
AB - Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of β cell-specific Gck (Gck+/-) causes impaired insulin secretion to glucose, although the animals have a normal β cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked β cell hyperplasia, whereas Gck+/- mice demonstrated decreased β cell replication and insufficient β 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 Irs+/- mice failed to show a sufficient increase in β cell mass, and overexpression of Irs2 in β cells of HF diet-fed Gck+/- mice partially prevented diabetes by increasing β cell mass. These results suggest that Gck and Irs2 are critical requirements for β cell hyperplasia to occur in response to HF diet-induced insulin resistance.
UR - http://www.scopus.com/inward/record.url?scp=33846024011&partnerID=8YFLogxK
U2 - 10.1172/JCI17645
DO - 10.1172/JCI17645
M3 - 学術論文
C2 - 17200721
AN - SCOPUS:33846024011
SN - 0021-9738
VL - 117
SP - 246
EP - 257
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -