This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gaisano, H. Y. Articles by Efendic, S. Search for Related Content PubMed PubMed Citation Articles by Gaisano, H. Y. Articles by Efendic, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE

Abnormal Expression of Pancreatic Islet Exocytotic Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptors in Goto-Kakizaki Rats Is Partially Restored by Phlorizin Treatment and Accentuated by High Glucose Treatment

Departments of Medicine and Physiology, University of Toronto (H.Y.G., L.S., M.B.W.), Ontario, Canada M5S 1A8; and Department of Molecular Medicine, Endocrine and Diabetes Unit, Rolf Luft Center for Diabetes Research, Karolinska Hospital (C.-G.O., S.E.), S-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Dr. Claes-Goran Ostenson or Dr. Herbert Gaisano, Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, SE-17176 Stockholm, Sweden. E-mail: claesg{at}enk.ks.se or herbert.gaisano{at}utoronto.ca.

The role of glucotoxicity in dysregulation of islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex proteins and insulin response was explored in the hyperglycemic Goto-Kakizaki (GK) rat. Syntaxin-1A and vesicle-associated membrane protein isoform 2, which drive insulin granule exocytotic fusion, and the associated nSec1, which modulates the SNARE complex assembly, were diminished in GK pancreatic islets to approximately 40% of the levels in control Wistar rat islets. Phlorizin treatment (12 d) induced normoglycemic control in GK rats, resulting in partial restoration of the insulin response to glucose. Furthermore, islet SNARE complex and nSec1 proteins increased by about 40%. Phlorizin treatment did not affect levels of islet SNARE proteins in controls or on the same SNARE complex proteins in GK rat brain. To examine the role of hyperglycemia per se, GK and control rat islets were exposed for 5 d in culture to 5.5 and 16.7 mM glucose. High glucose treatment greatly increased the levels of synaptosomal-associated membrane protein of 25 kDa and, less markedly, the levels of syntaxin-1A and nSec1 in control islets more than in GK rat islets, whereas levels were reduced in both. This was accompanied by sustained impairment of the insulin response to glucose in GK islets and a normal response in control islets. Thus, GK islets demonstrate dysregulation of SNARE protein expression, and their compensatory increase by high glucose exposure is abrogated. Conversely, normoglycemic control results in partial replenishment of these critical components of the insulin exocytotic machinery and improvement in the insulin response. We propose that dysregulation of SNARE proteins is an important mechanism behind glucotoxicity-mediated impairment of the insulin response to glucose.

This article has been cited by other articles:

				F. Xia, L. Xie, A. Mihic, X. Gao, Y. Chen, H. Y. Gaisano, and R. G. Tsushima Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic {beta}-Cells Endocrinology, October 1, 2008; 149(10): 5136 - 5145. [Abstract] [Full Text] [PDF]

				Y. M. Leung, E. P. Kwan, B. Ng, Y. Kang, and H. Y. Gaisano SNAREing Voltage-Gated K+ and ATP-Sensitive K+ Channels: Tuning {beta}-Cell Excitability with Syntaxin-1A and Other Exocytotic Proteins Endocr. Rev., October 1, 2007; 28(6): 653 - 663. [Abstract] [Full Text] [PDF]

				B. Ng, Y. Kang, C. L. Elias, Y. He, H. Xie, J. B. Hansen, P. Wahl, and H. Y. Gaisano The Actions of a Novel Potent Islet {beta}-Cell Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1 Diabetes, August 1, 2007; 56(8): 2124 - 2134. [Abstract] [Full Text] [PDF]

				T. Rose, S. Efendic, and M. Rupnik Ca2+-Secretion Coupling Is Impaired in Diabetic Goto Kakizaki rats J. Gen. Physiol., June 1, 2007; 129(6): 493 - 508. [Abstract] [Full Text] [PDF]

				M. Ohara-Imaizumi, T. Fujiwara, Y. Nakamichi, T. Okamura, Y. Akimoto, J. Kawai, S. Matsushima, H. Kawakami, T. Watanabe, K. Akagawa, et al. Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis J. Cell Biol., May 21, 2007; 177(4): 695 - 705. [Abstract] [Full Text] [PDF]

				M. Dubois, P. Vacher, B. Roger, D. Huyghe, B. Vandewalle, J. Kerr-Conte, F. Pattou, N. Moustaid-Moussa, and J. Lang Glucotoxicity Inhibits Late Steps of Insulin Exocytosis Endocrinology, April 1, 2007; 148(4): 1605 - 1614. [Abstract] [Full Text] [PDF]

				T. Wolf-Goldberg, I. Michaelevski, L. Sheu, H. Y. Gaisano, D. Chikvashvili, and I. Lotan Target Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptors (t-SNAREs) Differently Regulate Activation and Inactivation Gating of Kv2.2 and Kv2.1: Implications on Pancreatic Islet Cell Kv Channels Mol. Pharmacol., September 1, 2006; 70(3): 818 - 828. [Abstract] [Full Text] [PDF]

				T. Tsuboi, M. A. Ravier, L. E. Parton, and G. A. Rutter Sustained Exposure to High Glucose Concentrations Modifies Glucose Signaling and the Mechanics of Secretory Vesicle Fusion in Primary Rat Pancreatic {beta}-Cells. Diabetes, April 1, 2006; 55(4): 1057 - 1065. [Abstract] [Full Text] [PDF]

				N. Warwar, S. Efendic, C.-G. Ostenson, E. P. Haber, E. Cerasi, and R. Nesher Dynamics of Glucose-Induced Localization of PKC Isoenzymes in Pancreatic {beta}-Cells: Diabetes-Related Changes in the GK Rat Diabetes, March 1, 2006; 55(3): 590 - 599. [Abstract] [Full Text] [PDF]

				C.-G. Ostenson, H. Gaisano, L. Sheu, A. Tibell, and T. Bartfai Impaired Gene and Protein Expression of Exocytotic Soluble N-Ethylmaleimide Attachment Protein Receptor Complex Proteins in Pancreatic Islets of Type 2 Diabetic Patients Diabetes, February 1, 2006; 55(2): 435 - 440. [Abstract] [Full Text] [PDF]

				P. P.L. Lam, Y.-M. Leung, L. Sheu, J. Ellis, R. G. Tsushima, L. R. Osborne, and H. Y. Gaisano Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model Diabetes, September 1, 2005; 54(9): 2744 - 2754. [Abstract] [Full Text] [PDF]

				E. A. Pasyk, Y. Kang, X. Huang, N. Cui, L. Sheu, and H. Y. Gaisano Syntaxin-1A Binds the Nucleotide-binding Folds of Sulphonylurea Receptor 1 to Regulate the KATP Channel J. Biol. Chem., February 6, 2004; 279(6): 4234 - 4240. [Abstract] [Full Text] [PDF]

				L. Sheu, E. A. Pasyk, J. Ji, X. Huang, X. Gao, F. Varoqueaux, N. Brose, and H. Y. Gaisano Regulation of Insulin Exocytosis by Munc13-1 J. Biol. Chem., July 18, 2003; 278(30): 27556 - 27563. [Abstract] [Full Text] [PDF]