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PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells
Naoko Hashimoto, … , Tetsuo Noda, Masato Kasuga
Naoko Hashimoto, … , Tetsuo Noda, Masato Kasuga
Published January 3, 2005
Citation Information: J Clin Invest. 2005;115(1):138-145. https://doi.org/10.1172/JCI22232.
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Article Metabolism

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

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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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Figure 1

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Generation of β cell–specific PKCλ knockout mice. (A) PCR analysis of ge...
Generation of β cell–specific PKCλ knockout mice. (A) PCR analysis of genomic DNA isolated from islets of control (PKCλflox/flox) and βPKCλ–/– mice. The primers were targeted to regions external to the loxP sites of PKCλflox/flox mice. (B and C) Immunoblot analysis of PKCλ in the islets (B) or the brain, hypothalamus, heart, liver, skeletal muscle, and fat (C) of control and βPKCλ–/– mice. Tissue homogenates were subjected to immunoprecipitation and subsequent immunoblot analysis with antibodies against PKCλ. The expression of PKCλ in islets was similarly analyzed. (D) Immunostaining of islets in pancreatic sections of control and βPKCλ–/– mice with antibodies against PKCλ and FITC-conjugated secondary antibodies. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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