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Originally published In Press as doi:10.1074/jbc.M211352200 on January 1, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9715-9721, March 14, 2003
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Insulin Secretory Deficiency and Glucose Intolerance in Rab3A Null Mice*

Kazuro YaekuraDagger , Richard JulyanDagger , Barton L. WicksteedDagger , Lori B. HaysDagger , Cristina AlarconDagger , Scott SommersDagger , Vincent PoitoutDagger §, Denis G. Baskin§, Yong Wang, Louis H. Philipson, and Christopher J. RhodesDagger ||**

From the Dagger  Pacific Northwest Research Institute and Departments of || Pharmacology and § Medicine, University of Washington, Seattle, Washington 98122 and the  Department of Medicine, University of Chicago, Chicago, Illinois 60637

Insulin secretory dysfunction of the pancreatic beta -cell in type-2 diabetes is thought to be due to defective nutrient sensing and/or deficiencies in the mechanism of insulin exocytosis. Previous studies have indicated that the GTP-binding protein, Rab3A, plays a mechanistic role in insulin exocytosis. Here, we report that Rab3A-/- mice develop fasting hyperglycemia and upon a glucose challenge show significant glucose intolerance coupled to ablated first-phase insulin release and consequential insufficient insulin secretion in vivo, without insulin resistance. The in vivo insulin secretory response to arginine was similar in Rab3A-/- mice as Rab3A+/+ control animals, indicating a phenotype reminiscent of insulin secretory dysfunction found in type-2 diabetes. However, when a second arginine dose was given 10 min after, there was a negligible insulin secretory response in Rab3A-/- mice, compared with that in Rab3A+/+ animals, that was markedly increased above that to the first arginine stimulus. There was no difference in beta -cell mass or insulin production between Rab3A-/- and Rab3A+/+ mice. However, in isolated islets, secretagogue-induced insulin release (by glucose, GLP-1, glyburide, or fatty acid) was ~60-70% lower in Rab3A-/- islets compared with Rab3A+/+ controls. Nonetheless, there was a similar rate of glucose oxidation and glucose-induced rise in cytosolic [Ca2+]i flux between Rab3A-/- and Rab3A+/+ islet beta -cells, indicating the mechanistic role of Rab3A lies downstream of generating secondary signals that trigger insulin release, at the level of secretory granule transport and/or exocytosis. Thus, Rab3A plays an important in vivo role facilitating the efficiency of insulin exocytosis, most likely at the level of replenishing the ready releasable pool of beta -granules. Also, this study indicates, for the first time, that the in vivo insulin secretory dysfunction found in type-2 diabetes can lie solely at the level of defective insulin exocytosis.

* This work was supported by grants from the National Institutes of Health DK47919 and DK5061.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Pacific Northwest Research Inst., 720 Broadway, Seattle, WA 98122. Tel.: 206-860-6777; Fax: 206-726-1202; E-mail: cjr@pnri.org.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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