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J. Biol. Chem., Vol. 282, Issue 4, 2707-2716, January 26, 2007

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Protein Kinase C Plays a Non-redundant Role in Insulin Secretion in Pancreatic Cells^*

Toyoyoshi Uchida, Noseki Iwashita, Mica Ohara-Imaizumi, Takeshi Ogihara, Shintaro Nagai, Jong Bock Choi, Yoshifumi Tamura, Norihiro Tada^¶, Ryuzo Kawamori, Keiichi I. Nakayama^||, Shinya Nagamatsu, and Hirotaka Watada¹

From the Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2-1-1, Tokyo 113-8421, Japan, Department of Biochemistry, Kyorin University School of Medicine, Mitaka, 181-8611, Japan, ^¶Division of Biomedical Research Resources, Juntendo University School of Medicine, Tokyo, 113-8421, Japan, and ^||Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Protein kinase C (PKC) is considered to modulate glucose-stimulated insulin secretion. Pancreatic cells express multiple isoforms of PKCs; however, the role of each isoform in glucose-stimulated insulin secretion remains controversial. In this study we investigated the role of PKC, a major isoform expressed in pancreatic cells on cell function. Here, we showed that PKC null mice manifested glucose intolerance with impaired insulin secretion. Insulin tolerance test showed no decrease in insulin sensitivity in PKC null mice. Studies using islets isolated from these mice demonstrated decreased glucose- and KCl-stimulated insulin secretion. Perifusion studies indicated that mainly the second phase of insulin secretion was decreased. On the other hand, glucose-induced influx of Ca²⁺ into cells was not altered. Immunohistochemistry using total internal reflection fluorescence microscopy and electron microscopic analysis showed an increased number of insulin granules close to the plasma membrane in cells of PKC null mice. Although PKC is thought to phosphorylate Munc18-1 and facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors complex formation, the phosphorylation of Munc18-1 by glucose stimulation was decreased in islets of PKC null mice. We conclude that PKC plays a non-redundant role in glucose-stimulated insulin secretion. The impaired insulin secretion in PKC null mice is associated with reduced phosphorylation of Munc18-1.

Received for publication, November 10, 2006 , and in revised form, November 28, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-3-5802-1578; Fax: 81-3-3813-5996; E-mail: hwatada{at}med.juntendo.ac.jp.

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