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Science 307 (5708): 380-384

Copyright © 2005 by the American Association for the Advancement of Science

Type 2 Diabetes-a Matter of ß-Cell Life and Death?

Christopher J. Rhodes

Abstract: In type 2 diabetes, the ß cells of the pancreas fail to produce enough insulin to meet the body's demand, in part because of an acquired decrease in ß-cell mass. In adults, pancreatic ß-cell mass is controlled by several mechanisms, including ß-cell replication, neogenesis, hypertrophy, and survival. Here, I discuss evidence supporting the notion that increased ß-cell apoptosis is an important factor contributing to ß-cell loss and the onset of type 2 diabetes. Interestingly, a key signaling molecule that promotes ß-cell growth and survival, insulin receptor substrate 2 (IRS-2), is a member of a family of proteins whose inhibition contributes to the development of insulin resistance in the liver and other insulin-responsive tissues. Thus, the IRS-2 pathway appears to be a crucial participant in the tenuous balance between effective pancreatic ß-cell mass and insulin resistance.

The Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA, and Department of Pharmacology, University of Washington, Seattle, WA 98122, USA.

E-mail: cjr{at}pnri.org


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Diabetes 55, 2192-2201
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ERK1/2 Control Phosphorylation and Protein Level of cAMP-Responsive Element-Binding Protein: A Key Role in Glucose-Mediated Pancreatic {beta}-Cell Survival..
S. Costes, C. Broca, G. Bertrand, A.-D. Lajoix, D. Bataille, J. Bockaert, and S. Dalle (2006)
Diabetes 55, 2220-2230
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Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation: A Crossroad between Cancer and Diabetes?.
S. Di Paolo, A. Teutonico, D. Leogrande, C. Capobianco, and P. F. Schena (2006)
J. Am. Soc. Nephrol. 17, 2236-2244
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Pancreatic beta cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival.
J. Wang, Y. Cao, Y. Chen, Y. Chen, P. Gardner, and D. F. Steiner (2006)
PNAS 103, 10636-10641
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Specific Regulation of IRS-2 Expression by Glucose in Rat Primary Pancreatic Islet beta-Cells.
M. K. Lingohr, I. Briaud, L. M. Dickson, J. F. McCuaig, C. Alarcon, B. L. Wicksteed, and C. J. Rhodes (2006)
J. Biol. Chem. 281, 15884-15892
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WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic {beta}-cells.
T. Yamada, H. Ishihara, A. Tamura, R. Takahashi, S. Yamaguchi, D. Takei, A. Tokita, C. Satake, F. Tashiro, H. Katagiri, et al. (2006)
Hum. Mol. Genet. 15, 1600-1609
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Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4..
F. Ranta, D. Avram, S. Berchtold, M. Dufer, G. Drews, F. Lang, and S. Ullrich (2006)
Diabetes 55, 1380-1390
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Glucose-stimulated DNA Synthesis through Mammalian Target of Rapamycin (mTOR) Is Regulated by KATP Channels: EFFECTS ON CELL CYCLE PROGRESSION IN RODENT ISLETS.
G. Kwon, C. A. Marshall, H. Liu, K. L. Pappan, M. S. Remedi, and M. L. McDaniel (2006)
J. Biol. Chem. 281, 3261-3267
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The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation.
D. Kawamori, H. Kaneto, Y. Nakatani, T.-a. Matsuoka, M. Matsuhisa, M. Hori, and Y. Yamasaki (2006)
J. Biol. Chem. 281, 1091-1098
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A Functional Variant in the Human Betacellulin Gene Promoter Is Associated With Type 2 Diabetes.
Y. Nakano, H. Furuta, A. Doi, S. Matsuno, T. Nakagawa, H. Shimomura, S. Sakagashira, Y. Horikawa, M. Nishi, H. Sasaki, et al. (2005)
Diabetes 54, 3560-3566
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Insulin Resistance Syndrome in Subjects With Mutated RING Finger Protein TRIM37.
N. Karlberg, H. Jalanko, J. Kallijarvi, A.-E. Lehesjoki, and M. Lipsanen-Nyman (2005)
Diabetes 54, 3577-3581
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Mechanisms of Pancreatic {beta}-Cell Death in Type 1 and Type 2 Diabetes: Many Differences, Few Similarities.
M. Cnop, N. Welsh, J.-C. Jonas, A. Jorns, S. Lenzen, and D. L. Eizirik (2005)
Diabetes 54, S97-S107
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Mechanisms of {beta}-Cell Death in Type 2 Diabetes.
M. Y. Donath, J. A. Ehses, K. Maedler, D. M. Schumann, H. Ellingsgaard, E. Eppler, and M. Reinecke (2005)
Diabetes 54, S108-S113
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Phosphatase and Tensin Homolog Regulation of Islet Growth and Glucose Homeostasis.
J. A. Kushner, L. Simpson, L. M. Wartschow, S. Guo, M. M. Rankin, R. Parsons, and M. F. White (2005)
J. Biol. Chem. 280, 39388-39393
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SOX6 Attenuates Glucose-stimulated Insulin Secretion by Repressing PDX1 Transcriptional Actvity and Is Down-regulated in Hyperinsulinemic Obese Mice.
H. Iguchi, Y. Ikeda, M. Okamura, T. Tanaka, Y. Urashima, H. Ohguchi, S. Takayasu, N. Kojima, S. Iwasaki, R. Ohashi, et al. (2005)
J. Biol. Chem. 280, 37669-37680
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Is There a Role for Locally Produced Interleukin-1 in the Deleterious Effects of High Glucose or the Type 2 Diabetes Milieu to Human Pancreatic Islets?.
N. Welsh, M. Cnop, I. Kharroubi, M. Bugliani, R. Lupi, P. Marchetti, and D. L. Eizirik (2005)
Diabetes 54, 3238-3244
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Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague-Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction.
K. P. Keenan, C.-M. Hoe, L. Mixson, C. L. Mccoy, J. B. Coleman, B. A. Mattson, G. A. Ballam, L. A. Gumprecht, and K. A. Soper (2005)
Toxicol Pathol 33, 650-674
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Increased Fatty Acid Desaturation and Enhanced Expression of Stearoyl Coenzyme A Desaturase Protects Pancreatic {beta}-Cells from Lipoapoptosis.
A. K. Busch, E. Gurisik, D. V. Cordery, M. Sudlow, G. S. Denyer, D. R. Laybutt, W. E. Hughes, and T. J. Biden (2005)
Diabetes 54, 2917-2924
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