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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}

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Mol. Cell. Biol. 34, 1290-1299
   Abstract »    Full Text »    PDF »
A Critical Role for the Neural Zinc Factor ST18 in Pancreatic {beta}-Cell Apoptosis.
C. Henry, A.-F. Close, and J. Buteau (2014)
J. Biol. Chem. 289, 8413-8419
   Abstract »    Full Text »    PDF »
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J. Endocrinol. 220, T1-T23
   Abstract »    Full Text »    PDF »
MicroRNA-24/MODY Gene Regulatory Pathway Mediates Pancreatic {beta}-Cell Dysfunction.
Y. Zhu, W. You, H. Wang, Y. Li, N. Qiao, Y. Shi, C. Zhang, D. Bleich, and X. Han (2013)
Diabetes 62, 3194-3206
   Abstract »    Full Text »    PDF »
Direct Autocrine Action of Insulin on {beta}-Cells: Does It Make Physiological Sense?.
C. J. Rhodes, M. F. White, J. L. Leahy, and S. E. Kahn (2013)
Diabetes 62, 2157-2163
   Abstract »    Full Text »    PDF »
Involvement of the Ca2+-responsive transactivator in high glucose-induced {beta}-cell apoptosis.
X. Men, L. Peng, H. Wang, W. Zhang, S. Xu, Q. Fang, H. Liu, W. Yang, and J. Lou (2013)
J. Endocrinol. 216, 231-243
   Abstract »    Full Text »    PDF »
Molecular Mechanisms That Differentiate Apoptosis from Programmed Necrosis.
G. W. Dorn II (2013)
Toxicol Pathol 41, 227-234
   Abstract »    Full Text »    PDF »
Ciliary Neurotrophic Factor Protects Mice Against Streptozotocin-induced Type 1 Diabetes through SOCS3: THE ROLE OF STAT1/STAT3 RATIO IN {beta}-CELL DEATH.
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   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor-Mediated Islet Hypervascularization and Inflammation Contribute to Progressive Reduction of {beta}-Cell Mass.
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   Abstract »    Full Text »    PDF »
DPP4 inhibitor vildagliptin preserves {beta}-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice.
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Mechanisms of Cell Death in Heart Disease.
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Specific Glucose-Induced Control of Insulin Receptor Substrate-2 Expression Is Mediated via Ca2+-Dependent Calcineurin/NFAT Signaling in Primary Pancreatic Islet {beta}-Cells.
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Regulation of MafA Expression in Pancreatic {beta}-Cells in db/db Mice With Diabetes.
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PNAS 107, 10214-10219
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{beta}-cell development and turnover during prenatal life in humans.
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Glucose Induces Pancreatic Islet Cell Apoptosis That Requires the BH3-Only Proteins Bim and Puma and Multi-BH Domain Protein Bax.
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Diabetes 59, 644-652
   Abstract »    Full Text »    PDF »
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Diabetes 59, 440-447
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   Abstract »    Full Text »    PDF »
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Am J Physiol Endocrinol Metab 298, E49-E58
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Islet Inflammation Impairs the Pancreatic {beta}-Cell in Type 2 Diabetes.
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Physiology 24, 325-331
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Expression of the NH2-Terminal Fragment of RasGAP in Pancreatic {beta}-Cells Increases Their Resistance to Stresses and Protects Mice From Diabetes.
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Validation of a Multimarker Model for Assessing Risk of Type 2 Diabetes from a Five-Year Prospective Study of 6784 Danish People (Inter99).
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Journal of Diabetes Science and Technology 3, 748-755
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Upregulation of the Mammalian Target of Rapamycin Complex 1 Pathway by Ras Homolog Enriched in Brain in Pancreatic {beta}-Cells Leads to Increased {beta}-Cell Mass and Prevention of Hyperglycemia.
S. Hamada, K. Hara, T. Hamada, H. Yasuda, H. Moriyama, R. Nakayama, M. Nagata, and K. Yokono (2009)
Diabetes 58, 1321-1332
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TRPM2 Functions as a Lysosomal Ca2+-Release Channel in {beta} Cells.
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Science Signaling 2, ra23
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Degradation of cAMP-Responsive Element-Binding Protein by the Ubiquitin-Proteasome Pathway Contributes to Glucotoxicity in {beta}-Cells and Human Pancreatic Islets.
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Diabetes 58, 1105-1115
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Glycogen Synthase Kinase-3 and Mammalian Target of Rapamycin Pathways Contribute to DNA Synthesis, Cell Cycle Progression, and Proliferation in Human Islets.
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Diabetes 58, 663-672
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Diabetes 58, 682-692
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pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic {beta} cells.
J. Zehetner, C. Danzer, S. Collins, K. Eckhardt, P. A. Gerber, P. Ballschmieter, J. Galvanovskis, K. Shimomura, F. M. Ashcroft, B. Thorens, et al. (2008)
Genes & Dev. 22, 3135-3146
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Selective Small-Molecule Agonists of G Protein-Coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose in Mice.
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Diabetes 57, 2211-2219
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Increased Pancreatic Beta-Cell Apoptosis following Fetal and Neonatal Exposure to Nicotine Is Mediated via the Mitochondria.
J. E. Bruin, H. C. Gerstein, K. M. Morrison, and A. C. Holloway (2008)
Toxicol. Sci. 103, 362-370
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Glucose and leptin induce apoptosis in human {beta}-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases.
K. Maedler, F. T. Schulthess, C. Bielman, T. Berney, C. Bonny, M. Prentki, M. Y. Donath, and R. Roduit (2008)
FASEB J 22, 1905-1913
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{beta}-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic {beta} cells.
N. Sonoda, T. Imamura, T. Yoshizaki, J. L. Babendure, J.-C. Lu, and J. M. Olefsky (2008)
PNAS 105, 6614-6619
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Rab GTPase-Activating Protein AS160 Is a Major Downstream Effector of Protein Kinase B/Akt Signaling in Pancreatic {beta}-Cells.
K. Bouzakri, P. Ribaux, A. Tomas, G. Parnaud, K. Rickenbach, and P. A. Halban (2008)
Diabetes 57, 1195-1204
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Thioredoxin-Interacting Protein: A Critical Link Between Glucose Toxicity and {beta}-Cell Apoptosis.
J. Chen, G. Saxena, I. N. Mungrue, A. J. Lusis, and A. Shalev (2008)
Diabetes 57, 938-944
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mTOR Inhibition by Rapamycin Prevents {beta}-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes.
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Diabetes 57, 945-957
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Transcription Factor 7-Like 2 Regulates {beta}-Cell Survival and Function in Human Pancreatic Islets.
L. Shu, N. S. Sauter, F. T. Schulthess, A. V. Matveyenko, J. Oberholzer, and K. Maedler (2008)
Diabetes 57, 645-653
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Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals.
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Eur. J. Endocrinol. 158, 217-221
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ICA512 signaling enhances pancreatic -cell proliferation by regulating cyclins D through STATs.
H. Mziaut, S. Kersting, K.-P. Knoch, W.-H. Fan, M. Trajkovski, K. Erdmann, H. Bergert, F. Ehehalt, H.-D. Saeger, and M. Solimena (2008)
PNAS 105, 674-679
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PHYSIOLOGY: An Integrative View of Obesity.
B. E. Wisse, F. Kim, and M. W. Schwartz (2007)
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PNAS 104, 15466-15471
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Distinct In Vivo Roles of Caspase-8 in {beta}-Cells in Physiological and Diabetes Models.
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Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long-chain fatty acids in pancreatic {beta}-cells.
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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.
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Diabetes 56, 2124-2134
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Fetal and neonatal nicotine exposure and postnatal glucose homeostasis: identifying critical windows of exposure.
J. E Bruin, L. D Kellenberger, H. C Gerstein, K. M Morrison, and A. C Holloway (2007)
J. Endocrinol. 194, 171-178
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SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse.
M. O. Goodarzi, D. M. Lehman, K. D. Taylor, X. Guo, J. Cui, M. J. Quinones, S. M. Clee, B. S. Yandell, J. Blangero, W. A. Hsueh, et al. (2007)
Diabetes 56, 1922-1929
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SOX6 Suppresses Cyclin D1 Promoter Activity by Interacting with beta-Catenin and Histone Deacetylase 1, and Its Down-regulation Induces Pancreatic beta-Cell Proliferation.
H. Iguchi, Y. Urashima, Y. Inagaki, Y. Ikeda, M. Okamura, T. Tanaka, A. Uchida, T. T. Yamamoto, T. Kodama, and J. Sakai (2007)
J. Biol. Chem. 282, 19052-19061
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The emerging role of FOXO transcription factors in pancreatic {beta} cells.
D. A Glauser and W. Schlegel (2007)
J. Endocrinol. 193, 195-207
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Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells.
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Diabetes 56, 1069-1077
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The Fas pathway is involved in pancreatic beta cell secretory function.
D. M. Schumann, K. Maedler, I. Franklin, D. Konrad, J. Storling, M. Boni-Schnetzler, A. Gjinovci, M. O. Kurrer, B. R. Gauthier, D. Bosco, et al. (2007)
PNAS 104, 2861-2866
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Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner.
A. Hambrock, C. B. de Oliveira Franz, S. Hiller, A. Grenz, S. Ackermann, D. U. Schulze, G. Drews, and H. Osswald (2007)
J. Biol. Chem. 282, 3347-3356
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Molecular regulation of pancreatic {beta}-cell mass development, maintenance, and expansion.
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J. Mol. Endocrinol. 38, 193-206
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Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress.
C. Santangelo, P. Matarrese, R. Masella, M. C. Di Carlo, A. Di Lillo, B. Scazzocchio, E. Vecci, W. Malorni, R. Perfetti, and E. Anastasi (2007)
J. Mol. Endocrinol. 38, 147-158
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Metabolic syndrome: a fata morgana?.
S. J. L. Bakker, R. T. Gansevoort, and D. de Zeeuw (2007)
Nephrol. Dial. Transplant. 22, 15-20
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Pro-Survival Role of Gelsolin in Mouse {beta}-Cells.
B. Yermen, A. Tomas, and P. A. Halban (2007)
Diabetes 56, 80-87
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Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance.
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Am J Physiol Endocrinol Metab 291, E1341-E1350
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Low Concentration of Interleukin-1{beta} Induces FLICE-Inhibitory Protein-Mediated {beta}-Cell Proliferation in Human Pancreatic Islets..
K. Maedler, D. M. Schumann, N. Sauter, H. Ellingsgaard, D. Bosco, R. Baertschiger, Y. Iwakura, J. Oberholzer, C. B. Wollheim, B. R. Gauthier, et al. (2006)
Diabetes 55, 2713-2722
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Fibroblast Growth Factor-21 Improves Pancreatic {beta}-Cell Function and Survival by Activation of Extracellular Signal-Regulated Kinase 1/2 and Akt Signaling Pathways.
W. Wente, A. M. Efanov, M. Brenner, A. Kharitonenkov, A. Koster, G. E. Sandusky, S. Sewing, I. Treinies, H. Zitzer, and J. Gromada (2006)
Diabetes 55, 2470-2478
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Type 1, type 1.5, and type 2 diabetes: NOD the diabetes we thought it was.
M. Y. Donath and J. A. Ehses (2006)
PNAS 103, 12217-12218
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Maternal developmental stress reduces reproductive success of female offspring in zebra finches.
M. Naguib, A. Nemitz, and D. Gil (2006)
Proc R Soc B 273, 1901-1905
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Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death..
L. Marzban, C. J. Rhodes, D. F. Steiner, L. Haataja, P. A. Halban, and C. B. Verchere (2006)
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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