Diabetes, Vol 46, Issue 2 258-264, Copyright © 1997 by American Diabetes Association

ARTICLES

Reduced insulin, GLUT2, and IDX-1 in beta-cells after partial pancreatectomy

DH Zangen, S Bonner-Weir, CH Lee, JB Latimer, CP Miller, JF Habener and GC Weir
Joslin Diabetes Center and the Department of Medicine, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts, USA. zangend@joslab.harvard.edu.

Reduction of GLUT2 is associated with loss of glucose-induced insulin secretion in genetic and chemical diabetes and in transplanted islets exposed to chronic hyperglycemia. To examine the mechanisms for this loss of GLUT2 in normal islets exposed to hyperglycemia, we performed studies on Sprague Dawley rats 4 weeks after a 90% partial pancreatectomy (Px), a well-characterized model of hyperglycemia. GLUT2 immunofluorescence in the beta-cell of Px rats was greatly reduced. Western blot analysis of homogenates of isolated Px islets also showed a reduction in GLUT2 protein; densitometry measurements were 36 +/- 3% of values from islets of sham-operated controls. Insulin protein levels were decreased to a similar extent. Islet GLUT2 and insulin mRNA were measured with quantitative reverse transcriptase-polymerase chain reaction. The level of GLUT2 mRNA from Px islets was 24 +/- 4% of that of islets from sham-operated controls; similar results were obtained for insulin. Because both these beta-cell-specific messages were reduced, we analyzed the Px islets for the pancreas-duodenum-specific transcription factor IDX-1(IPF-1, STF-1, PDX-1) protein. It was markedly reduced (approximately 80%) in islets from the Px rats. These data suggest that 1) the loss of GLUT2 protein associated with hyperglycemia is at least partially explained by reduced levels of the GLUT2 gene transcripts; 2) the reduction of beta-cell insulin content during chronic hyperglycemia may not be completely due to degranulation (reduced levels of gene transcripts may play a role); and 3) the reduction in the transcription factor IDX-1 raises the possibility that dysregulation of transcription factors may contribute to the abnormal beta-cell function found in states of chronic hyperglycemia.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. A. Cano, I. C. Rulifson, P. W. Heiser, L. B. Swigart, S. Pelengaris, M. German, G. I. Evan, J. A. Bluestone, and M. Hebrok Regulated {beta}-Cell Regeneration in the Adult Mouse Pancreas Diabetes, April 1, 2008; 57(4): 958 - 966. [Abstract] [Full Text] [PDF]

				M. Ubeda, J. M. Rukstalis, and J. F. Habener Inhibition of Cyclin-dependent Kinase 5 Activity Protects Pancreatic Beta Cells from Glucotoxicity J. Biol. Chem., September 29, 2006; 281(39): 28858 - 28864. [Abstract] [Full Text] [PDF]

				M. Z. Khaldi, H. Elouil, Y. Guiot, J. C. Henquin, and J. C. Jonas Antioxidants N-acetyl-L-cysteine and manganese(III)tetrakis (4-benzoic acid)porphyrin do not prevent beta-cell dysfunction in rat islets cultured in high glucose for 1 wk Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E137 - E146. [Abstract] [Full Text] [PDF]

				V. Poitout, D. Hagman, R. Stein, I. Artner, R. P. Robertson, and J. S. Harmon Regulation of the Insulin Gene by Glucose and Fatty Acids J. Nutr., April 1, 2006; 136(4): 873 - 876. [Abstract] [Full Text] [PDF]

				D. Z. Ye, M.-H. Tai, K. D. Linning, C. Szabo, and L. K. Olson MafA Expression and Insulin Promoter Activity Are Induced by Nicotinamide and Related Compounds in INS-1 Pancreatic {beta}-Cells Diabetes, March 1, 2006; 55(3): 742 - 750. [Abstract] [Full Text] [PDF]

				D. Kawamori, H. Kaneto, Y. Nakatani, T.-a. Matsuoka, M. Matsuhisa, M. Hori, and Y. Yamasaki The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation J. Biol. Chem., January 13, 2006; 281(2): 1091 - 1098. [Abstract] [Full Text] [PDF]

				M. F. Pino, D. Z. Ye, K. D. Linning, C. D. Green, B. Wicksteed, V. Poitout, and L. K. Olson Elevated Glucose Attenuates Human Insulin Gene Promoter Activity in INS-1 Pancreatic {beta}-Cells via Reduced Nuclear Factor Binding to the A5/Core and Z Element Mol. Endocrinol., May 1, 2005; 19(5): 1343 - 1360. [Abstract] [Full Text] [PDF]

				M. Brissova, M. Blaha, C. Spear, W. Nicholson, A. Radhika, M. Shiota, M. J. Charron, C. V. E. Wright, and A. C. Powers Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E707 - E714. [Abstract] [Full Text] [PDF]

				Y. Nakatani, H. Kaneto, D. Kawamori, M. Hatazaki, T. Miyatsuka, T.-a. Matsuoka, Y. Kajimoto, M. Matsuhisa, Y. Yamasaki, and M. Hori Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status J. Biol. Chem., October 29, 2004; 279(44): 45803 - 45809. [Abstract] [Full Text] [PDF]

				D. Kawamori, Y. Kajimoto, H. Kaneto, Y. Umayahara, Y. Fujitani, T. Miyatsuka, H. Watada, I. B. Leibiger, Y. Yamasaki, and M. Hori Oxidative Stress Induces Nucleo-Cytoplasmic Translocation of Pancreatic Transcription Factor PDX-1 Through Activation of c-Jun NH2-terminal Kinase Diabetes, December 1, 2003; 52(12): 2896 - 2904. [Abstract] [Full Text] [PDF]

				G. Leibowitz, G. Uckaya, A. I. Oprescu, E. Cerasi, D. J. Gross, and N. Kaiser Glucose-Regulated Proinsulin Gene Expression Is Required for Adequate Insulin Production during Chronic Glucose Exposure Endocrinology, September 1, 2002; 143(9): 3214 - 3220. [Abstract] [Full Text] [PDF]

				H. Kaneto, G. Xu, N. Fujii, S. Kim, S. Bonner-Weir, and G. C. Weir Involvement of c-Jun N-terminal Kinase in Oxidative Stress-mediated Suppression of Insulin Gene Expression J. Biol. Chem., August 9, 2002; 277(33): 30010 - 30018. [Abstract] [Full Text] [PDF]

				S. E. Samaras, M. A. Cissell, K. Gerrish, C. V. E. Wright, M. Gannon, and R. Stein Conserved Sequences in a Tissue-Specific Regulatory Region of the pdx-1 Gene Mediate Transcription in Pancreatic {beta} Cells: Role for Hepatocyte Nuclear Factor 3{beta} and Pax6 Mol. Cell. Biol., July 1, 2002; 22(13): 4702 - 4713. [Abstract] [Full Text] [PDF]

				H. Kaneto, A. Sharma, K. Suzuma, D. R. Laybutt, G. Xu, S. Bonner-Weir, and G. C. Weir Induction of c-Myc Expression Suppresses Insulin Gene Transcription by Inhibiting NeuroD/BETA2-mediated Transcriptional Activation J. Biol. Chem., April 5, 2002; 277(15): 12998 - 13006. [Abstract] [Full Text] [PDF]

				M. Brissova, M. Shiota, W. E. Nicholson, M. Gannon, S. M. Knobel, D. W. Piston, C. V. E. Wright, and A. C. Powers Reduction in Pancreatic Transcription Factor PDX-1 Impairs Glucose-stimulated Insulin Secretion J. Biol. Chem., March 22, 2002; 277(13): 11225 - 11232. [Abstract] [Full Text] [PDF]

				G. Leibowitz, S. Ferber, A. Apelqvist, H. Edlund, D. J. Gross, E. Cerasi, D. Melloul, and N. Kaiser IPF1/PDX1 Deficiency and {beta}-Cell Dysfunction in Psammomys obesus, an Animal With Type 2 Diabetes Diabetes, August 1, 2001; 50(8): 1799 - 1806. [Abstract] [Full Text] [PDF]

				C. Tourrel, D. Bailbe, M.-J. Meile, M. Kergoat, and B. Portha Glucagon-Like Peptide-1 and Exendin-4 Stimulate {beta}-Cell Neogenesis in Streptozotocin-Treated Newborn Rats Resulting in Persistently Improved Glucose Homeostasis at Adult Age Diabetes, July 1, 2001; 50(7): 1562 - 1570. [Abstract] [Full Text] [PDF]

				M. K. Thomas, J. H. Lee, N. Rastalsky, and J. F. Habener Hedgehog Signaling Regulation of Homeodomain Protein Islet Duodenum Homeobox-1 Expression in Pancreatic {{beta}}-Cells Endocrinology, March 1, 2001; 142(3): 1033 - 1040. [Abstract] [Full Text] [PDF]

				M Gannon, M. Ray, K Van Zee, F Rausa, R. Costa, and C. Wright Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function Development, January 7, 2000; 127(13): 2883 - 2895. [Abstract] [PDF]

				Y. Tanaka, C. E. Gleason, P. O. T. Tran, J. S. Harmon, and R. P. Robertson Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants PNAS, September 14, 1999; 96(19): 10857 - 10862. [Abstract] [Full Text] [PDF]

				R. Seijffers, O. Ben-David, Y. Cohen, A. Karasik, M. Berezin, C. B. Newgard, and S. Ferber Increase in PDX-1 Levels Suppresses Insulin Gene Expression in RIN 1046-38 Cells Endocrinology, July 1, 1999; 140(7): 3311 - 3317. [Abstract] [Full Text]

				J.-C. Jonas, A. Sharma, W. Hasenkamp, H. Ilkova, G. Patane, R. Laybutt, S. Bonner-Weir, and G. C. Weir Chronic Hyperglycemia Triggers Loss of Pancreatic beta  Cell Differentiation in an Animal Model of Diabetes J. Biol. Chem., May 14, 1999; 274(20): 14112 - 14121. [Abstract] [Full Text] [PDF]

				F. J. Service, N. Natt, G. B. Thompson, C. S. Grant, J. A. van Heerden, J. C. Andrews, E. Lorenz, A. Terzic, and R. V. Lloyd Noninsulinoma Pancreatogenous Hypoglycemia: A Novel Syndrome of Hyperinsulinemic Hypoglycemia in Adults Independent of Mutations in Kir6.2 and SUR1 Genes J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1582 - 1589. [Abstract] [Full Text]

				B. Lee, J.-C. Jonas, G. C. Weir, and S. G. Laychock Glucose Regulates Expression of Inositol 1,4,5-Trisphosphate Receptor Isoforms in Isolated Rat Pancreatic Islets Endocrinology, May 1, 1999; 140(5): 2173 - 2182. [Abstract] [Full Text]

				K. Josefsen, K. Buschard, L. R. Sorensen, M. Wollike, R. Ekman, and M. Birkenbach Glucose Stimulation of Pancreatic {beta}-Cell Lines Induces Expression and Secretion of Dynorphin Endocrinology, October 1, 1998; 139(10): 4329 - 4336. [Abstract] [Full Text] [PDF]

				J. L. Leahy and M. S. Fineman Impaired phasic insulin and amylin secretion in diabetic rats Am J Physiol Endocrinol Metab, September 1, 1998; 275(3): E457 - E462. [Abstract] [Full Text] [PDF]

				L. K. Olson, J. Qian, and V. Poitout Glucose Rapidly and Reversibly Decreases INS-1 Cell Insulin Gene Transcription via Decrements in STF-1 and C1 Activator Transcription Factor Activity Mol. Endocrinol., February 1, 1998; 12(2): 207 - 219. [Abstract] [Full Text]

				M. Lu, J. Seufert, and J. F. Habener Pancreatic beta -Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein beta . INHIBITORY INTERACTIONS WITH BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR E47 J. Biol. Chem., November 7, 1997; 272(45): 28349 - 28359. [Abstract] [Full Text] [PDF]

				Q. Gong, L. J. Brown, and M. J. MacDonald Functional Analysis of Two Promoters for the Human Mitochondrial Glycerol Phosphate Dehydrogenase Gene J. Biol. Chem., November 22, 2000; 275(48): 38012 - 38021. [Abstract] [Full Text] [PDF]

				R. H. Harrington and A. Sharma Transcription Factors Recognizing Overlapping C1-A2 Binding Sites Positively Regulate Insulin Gene Expression J. Biol. Chem., January 5, 2001; 276(1): 104 - 113. [Abstract] [Full Text] [PDF]

				H. Kaneto, G. Xu, K.-H. Song, K. Suzuma, S. Bonner-Weir, A. Sharma, and G. C. Weir Activation of the Hexosamine Pathway Leads to Deterioration of Pancreatic beta -Cell Function through the Induction of Oxidative Stress J. Biol. Chem., August 10, 2001; 276(33): 31099 - 31104. [Abstract] [Full Text] [PDF]

				H. Kaneto, K. Suzuma, A. Sharma, S. Bonner-Weir, G. L. King, and G. C. Weir Involvement of Protein Kinase C beta 2 in c-myc Induction by High Glucose in Pancreatic beta -Cells J. Biol. Chem., January 25, 2002; 277(5): 3680 - 3685. [Abstract] [Full Text] [PDF]

				J. Meyer, J. Sturis, M. Katschinski, R. Arnold, B. Goke, and M. M. Byrne Acute hyperglycemia alters the ability of the normal beta -cell to sense and respond to glucose Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E917 - E922. [Abstract] [Full Text] [PDF]