PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells
Naoko Hashimoto, Yoshiaki Kido, Tohru Uchida, Tomokazu Matsuda, Kazuhisa Suzuki, Hiroshi Inoue, Michihiro Matsumoto, Wataru Ogawa, Sakan Maeda, Hiroaki Fujihara, Yoichi Ueta, Yasuo Uchiyama, Kazunori Akimoto, Shigeo Ohno, Tetsuo Noda, Masato Kasuga
Naoko Hashimoto, Yoshiaki Kido, Tohru Uchida, Tomokazu Matsuda, Kazuhisa Suzuki, Hiroshi Inoue, Michihiro Matsumoto, Wataru Ogawa, Sakan Maeda, Hiroaki Fujihara, Yoichi Ueta, Yasuo Uchiyama, Kazunori Akimoto, Shigeo Ohno, Tetsuo Noda, Masato Kasuga
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Article Metabolism

PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells

Abstract

Altered regulation of insulin secretion by glucose is characteristic of individuals with type 2 diabetes mellitus, although the mechanisms that underlie this change remain unclear. We have now generated mice that lack the λ isoform of PKC in pancreatic β cells (βPKCλ–/– mice) and show that these animals manifest impaired glucose tolerance and hypoinsulinemia. Furthermore, insulin secretion in response to high concentrations of glucose was impaired, whereas the basal rate of insulin release was increased, in islets isolated from βPKCλ–/– mice. Neither the β cell mass nor the islet insulin content of βPKCλ–/– mice differed from that of control mice, however. The abundance of mRNAs for Glut2 and HNF3β was reduced in islets of βPKCλ–/– mice, and the expression of genes regulated by HNF3β was also affected (that of Sur1 and Kir6.2 genes was reduced, whereas that of hexokinase 1 and hexokinase 2 genes was increased). Normalization of HNF3β expression by infection of islets from βPKCλ–/– mice with an adenoviral vector significantly reversed the defect in glucose-stimulated insulin secretion. These results indicate that PKCλ plays a prominent role in regulation of glucose-induced insulin secretion by modulating the expression of genes important for β cell function.

Authors

Naoko Hashimoto, Yoshiaki Kido, Tohru Uchida, Tomokazu Matsuda, Kazuhisa Suzuki, Hiroshi Inoue, Michihiro Matsumoto, Wataru Ogawa, Sakan Maeda, Hiroaki Fujihara, Yoichi Ueta, Yasuo Uchiyama, Kazunori Akimoto, Shigeo Ohno, Tetsuo Noda, Masato Kasuga

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Effects of adenovirus-mediated restoration of PKCλ or HNF3β expression o...
Effects of adenovirus-mediated restoration of PKCλ or HNF3β expression on insulin secretion in islets of βPKCλ–/– mice. (A–C) Islets isolated from control mice or βPKCλ–/– mice were infected with an adenovirus encoding either β-galactosidase (AxCALacZ) or wild-type PKCλ (AxCAλwt). The islets were then either subjected to immunoblot analysis with antibodies against PKCλ or β actin (A); assayed for insulin secretion in the presence of 2.8 or 16.8 mM glucose (white bars, control islets plus AxCALacZ; black bars, βPKCλ–/– islets plus AxCALacZ; gray bars, βPKCλ–/– islets plus AxCAλwt) (B); or subjected to real-time RT-PCR analysis of mRNAs for HNF3β, hexokinase 1, or Kir6.2 (C). (D and E) Islets isolated from control or βPKCλ–/– mice were infected with either AxCALacZ or an adenovirus encoding wild-type HNF3β (AxCAHNF3β). The islets were then either subjected to immunoblot analysis with antibodies against HNF3β or β actin (D) or assayed for insulin secretion in the presence of 2.8 or 16.8 mM glucose (E). Data are means ± SE of values from 6 mice (B and E) or of triplicates for pooled total RNA samples from 5 mice (C). *P < 0.05 (ANOVA) for the indicated comparisons.