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 Leibowitz, G. Articles by Kaiser, N. Search for Related Content PubMed PubMed Citation Articles by Leibowitz, G. Articles by Kaiser, N.

Glucose-Regulated Proinsulin Gene Expression Is Required for Adequate Insulin Production during Chronic Glucose Exposure

Endocrine and Metabolism Service, Division of Internal Medicine, and Hadassah Diabetes Center, Hebrew University-Hadassah Medical Center, 91120 Jerusalem, Israel

Address all correspondence and requests for reprints to: Gil Leibowitz, M.D., Endocrine and Metabolism Service, Hadassah University Hospital, P.O. Box 12000, 91120 Jerusalem, Israel. E-mail: gleib{at}hadassah.org.il.

Psammomys obesus, an animal model of type 2 diabetes, shows rapid and marked depletion of pancreatic insulin content as hyperglycemia develops when fed a high-calorie diet. P. obesus islets do not increase proinsulin gene expression when exposed to high glucose, which may be related to absence of the conserved form of the transcription factor insulin promoter factor 1/pancreatic-duodenal homeobox 1. The present study assesses the importance of regulation of proinsulin gene expression by glucose for insulin production. Islets of diabetes-prone P. obesus and diabetes-resistant Wistar rats, cultured at various glucose concentrations for up to 24 h, were analyzed for proinsulin mRNA by quantitative RT-PCR, proinsulin biosynthesis by leucine incorporation into proinsulin, and insulin content and secretion by RIA. No increase in proinsulin mRNA was observed in P. obesus islets during 24-h exposure to increasing concentrations of glucose. In contrast, rat islets exposed to high glucose responded with a 2- to 3-fold stimulation of proinsulin mRNA. The failure of P. obesus islets to increase proinsulin mRNA was accompanied by a reduced proinsulin biosynthetic response: after 24 h, maximal proinsulin biosynthesis was blunted, associated with depletion of islet insulin content. Inhibition of glucose-stimulated proinsulin gene transcription in rat islets by actinomycin D did not affect the early proinsulin biosynthetic response, which, however, was reduced to the level of P. obesus islets after 24 h in culture.

We conclude that stimulation of proinsulin gene transcription by glucose is necessary for maintaining proinsulin biosynthesis and hence conserving pancreatic insulin stores, under conditions of sustained secretory drive, but not for short-term regulation of proinsulin biosynthesis Our findings support the hypothesis that inadequate regulation of proinsulin gene expression by glucose contributes to the failure of P. obesus to cope with the increased demand for insulin associated with caloric excess, leading to depletion of insulin stores and diabetes.

This article has been cited by other articles:

				V. Poitout and R. P. Robertson Glucolipotoxicity: Fuel Excess and {beta}-Cell Dysfunction Endocr. Rev., May 1, 2008; 29(3): 351 - 366. [Abstract] [Full Text] [PDF]

				D. K. Hagman, M. G. Latour, S. K. Chakrabarti, G. Fontes, J. Amyot, C. Tremblay, M. Semache, J. A. Lausier, V. Roskens, R. G. Mirmira, et al. Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets Diabetes, February 1, 2008; 57(2): 424 - 431. [Abstract] [Full Text] [PDF]

				H. Ghanaat-Pour, Z. Huang, M. Lehtihet, and A. Sjoholm Global expression profiling of glucose-regulated genes in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats J. Mol. Endocrinol., August 1, 2007; 39(2): 135 - 150. [Abstract] [Full Text] [PDF]

				N. Kashemsant and C. B Chan Impact of uncoupling protein-2 overexpression on proinsulin processing J. Mol. Endocrinol., December 1, 2006; 37(3): 517 - 526. [Abstract] [Full Text] [PDF]

				V. Attali, M. Parnes, Y. Ariav, E. Cerasi, N. Kaiser, and G. Leibowitz Regulation of Insulin Secretion and Proinsulin Biosynthesis by Succinate Endocrinology, November 1, 2006; 147(11): 5110 - 5118. [Abstract] [Full Text] [PDF]

				D. Muller, G. C. Huang, S. Amiel, P. M. Jones, and S. J. Persaud Identification of Insulin Signaling Elements in Human {beta}-Cells: Autocrine Regulation of Insulin Gene Expression. Diabetes, October 1, 2006; 55(10): 2835 - 2842. [Abstract] [Full Text] [PDF]

				W. Wente, A. M. Efanov, M. Brenner, A. Kharitonenkov, A. Koster, G. E. Sandusky, S. Sewing, I. Treinies, H. Zitzer, and J. Gromada Fibroblast Growth Factor-21 Improves Pancreatic {beta}-Cell Function and Survival by Activation of Extracellular Signal-Regulated Kinase 1/2 and Akt Signaling Pathways Diabetes, September 1, 2006; 55(9): 2470 - 2478. [Abstract] [Full Text] [PDF]

				N. Kaiser, R. Nesher, M. Y. Donath, M. Fraenkel, V. Behar, C. Magnan, A. Ktorza, E. Cerasi, and G. Leibowitz Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes Diabetes, December 1, 2005; 54(suppl_2): S137 - S144. [Abstract] [Full Text] [PDF]

				D. K. Hagman, L. B. Hays, S. D. Parazzoli, and V. Poitout{paragraph} Palmitate Inhibits Insulin Gene Expression by Altering PDX-1 Nuclear Localization and Reducing MafA Expression in Isolated Rat Islets of Langerhans J. Biol. Chem., September 16, 2005; 280(37): 32413 - 32418. [Abstract] [Full Text] [PDF]

				M. C. Lawrence, K. McGlynn, B.-H. Park, and M. H. Cobb ERK1/2-dependent Activation of Transcription Factors Required for Acute and Chronic Effects of Glucose on the Insulin Gene Promoter J. Biol. Chem., July 22, 2005; 280(29): 26751 - 26759. [Abstract] [Full Text] [PDF]

				N. Kaiser, M. Yuli, G. Uckaya, A. I. Oprescu, M.-F. Berthault, C. Kargar, M. Y. Donath, E. Cerasi, and A. Ktorza Dynamic Changes in {beta}-Cell Mass and Pancreatic Insulin During the Evolution of Nutrition-Dependent Diabetes in Psammomys obesus: Impact of Glycemic Control Diabetes, January 1, 2005; 54(1): 138 - 145. [Abstract] [Full Text] [PDF]

				G. C. Weir and S. Bonner-Weir Five Stages of Evolving Beta-Cell Dysfunction During Progression to Diabetes Diabetes, December 1, 2004; 53(suppl_3): S16 - S21. [Abstract] [Full Text] [PDF]

				B. Wicksteed, C. Alarcon, I. Briaud, M. K. Lingohr, and C. J. Rhodes Glucose-induced Translational Control of Proinsulin Biosynthesis Is Proportional to Preproinsulin mRNA Levels in Islet {beta}-Cells but Not Regulated via a Positive Feedback of Secreted Insulin J. Biol. Chem., October 24, 2003; 278(43): 42080 - 42090. [Abstract] [Full Text] [PDF]

				G. Leibowitz, A. I. Oprescu, G. Uckaya, D. J. Gross, E. Cerasi, and N. Kaiser Insulin Does Not Mediate Glucose Stimulation of Proinsulin Biosynthesis Diabetes, April 1, 2003; 52(4): 998 - 1003. [Abstract] [Full Text] [PDF]