STAT5 Activity in Pancreatic β-Cells Influences the Severity of Diabetes in Animal Models of Type 1 and 2 Diabetes

Pancreatic β-cell growth and survival and insulin production are stimulated by growth hormone and prolactin through activation of the transcription factor signal transducer and activator of transcription (STAT)5. To assess the role of STAT5 activity in β-cells in vivo, we generated transgenic mice that expressed a dominant-negative mutant of STAT5a (DNSTAT5) or constitutive active mutant of STAT5b (CASTAT5) under control of the rat insulin 1 promoter (RIP). When subjected to a high-fat diet, RIP-DNSTAT5 mice showed higher body weight, increased plasma glucose levels, and impairment of glucose tolerance, whereas RIP-CASTAT5 mice were more glucose tolerant and less hyperleptinemic than wild-type mice. Although the pancreatic insulin content and relative β-cell area were increased in high-fat diet–fed RIP-DNSTAT5 mice compared with wild-type or RIP-CASTAT5 mice, RIP-DNSTAT5 mice showed reduced β-cell proliferation at 6 months of age. The inhibitory effect of high-fat diet or leptin on insulin secretion was diminished in isolated islets from RIP-DNSTAT5 mice compared with wild-type islets. Upon multiple low-dose streptozotocin treatment, RIP-DNSTAT5 mice exhibited higher plasma glucose levels, lower plasma insulin levels, and lower pancreatic insulin content than wild-type mice, whereas RIP-CASTAT5 mice maintained higher levels of plasma insulin. In conclusion, our results indicate that STAT5 activity in β-cells influences the susceptibility to experimentally induced type 1 and type 2 diabetes.

[1]  B. Friedrichsen,et al.  Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways , 2006 .

[2]  X. Niu,et al.  Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells. , 2005, Diabetes.

[3]  Ying-Chu Lee,et al.  STAT5 activation by human GH protects insulin-producing cells against interleukin-1β, interferon-γ and tumour necrosis factor-α-induced apoptosis independent of nitric oxide production , 2005 .

[4]  S. G. Rønn,et al.  Regulation of pancreatic β-cell mass and proliferation by SOCS-3 , 2005 .

[5]  J. Kushner,et al.  Cyclins D2 and D1 Are Essential for Postnatal Pancreatic β-Cell Growth , 2005, Molecular and Cellular Biology.

[6]  S. G. Rønn,et al.  Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. , 2005, Journal of molecular endocrinology.

[7]  J. Kushner,et al.  Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. , 2005, Molecular and cellular biology.

[8]  R. Vasavada,et al.  Characterization of mice doubly transgenic for parathyroid hormone-related protein and murine placental lactogen: a novel role for placental lactogen in pancreatic beta-cell survival. , 2004, Diabetes.

[9]  Senta Georgia,et al.  β cell replication is the primary mechanism for maintaining postnatal β cell mass , 2004 .

[10]  M. Lipsett,et al.  Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. , 2004, American journal of physiology. Endocrinology and metabolism.

[11]  R. Sorenson,et al.  Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of langerhans. , 2004, Endocrinology.

[12]  S. Akira,et al.  Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice. , 2004, Biochemical and biophysical research communications.

[13]  J. Richardson,et al.  Essential Role of STAT3 in Body Weight and Glucose Homeostasis , 2004, Molecular and Cellular Biology.

[14]  Senta Georgia,et al.  Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. , 2004, The Journal of clinical investigation.

[15]  H. Sone,et al.  Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice , 2004, Diabetologia.

[16]  R. Paschke,et al.  Regulation of adipocytokines and insulin resistance , 2003, Diabetologia.

[17]  B. Friedrichsen,et al.  Signal Transducer and Activator of Transcription 5 Activation Is Sufficient to Drive Transcriptional Induction of Cyclin D2 Gene and Proliferation of Rat Pancreatic β-Cells , 2003 .

[18]  Robert A. Rizza,et al.  β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes , 2003, Diabetes.

[19]  J. Morisset IN PANCREATIC GROWTH AND REGENERATION , 2003 .

[20]  B. Friedrichsen,et al.  Signal transducer and activator of transcription 5 activation is sufficient to drive transcriptional induction of cyclin D2 gene and proliferation of rat pancreatic beta-cells. , 2003, Molecular endocrinology.

[21]  C. Rhodes,et al.  Pancreatic β-cell growth and survival – a role in obesity-linked type 2 diabetes? , 2002 .

[22]  P. Kelly,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Targeted Deletion of the PRL Receptor: Effects on Islet Development, Insulin Production, and Glucose Tolerance , 2022 .

[23]  C. Rhodes,et al.  Pancreatic beta-cell growth and survival--a role in obesity-linked type 2 diabetes? , 2002, Trends in molecular medicine.

[24]  Y. Oka,et al.  Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis. , 2001, Endocrinology.

[25]  F. Pociot,et al.  Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-γ-mediated toxicity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Zhu,et al.  Signal transduction via the growth hormone receptor. , 2001, Cellular signalling.

[27]  M. Tadayyon,et al.  Fatty acids inhibit leptin signalling in BRIN-BD11 insulinoma cells. , 2001, Journal of molecular endocrinology.

[28]  B. Friedrichsen,et al.  Regulation of beta-cell mass by hormones and growth factors. , 2001, Diabetes.

[29]  F. Pociot,et al.  Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-1beta - and interferon-gamma -mediated toxicity. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  B. Friedrichsen,et al.  Growth hormone- and prolactin-induced proliferation of insulinoma cells, INS-1, depends on activation of STAT5 (signal transducer and activator of transcription 5). , 2001, Molecular endocrinology.

[31]  B. Friedrichsen,et al.  Regulation of-Cell Mass by Hormones and Growth Factors , 2001 .

[32]  V. Emilsson,et al.  Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells , 2000, International Journal of Obesity.

[33]  F. Talamantes,et al.  Targeted Expression of Placental Lactogen in the Beta Cells of Transgenic Mice Results in Beta Cell Proliferation, Islet Mass Augmentation, and Hypoglycemia* , 2000, The Journal of Biological Chemistry.

[34]  J. Habener,et al.  The adipoinsular axis: effects of leptin on pancreatic β-cells , 2000 .

[35]  J. Habener,et al.  The adipoinsular axis: effects of leptin on pancreatic beta-cells. , 2000, American journal of physiology. Endocrinology and metabolism.

[36]  S. Sandler,et al.  Prolactin protects against diabetes induced by multiple low doses of streptozotocin in mice. , 1999, The Journal of endocrinology.

[37]  H. Lodish,et al.  Fetal Anemia and Apoptosis of Red Cell Progenitors in Stat5a−/−5b−/− Mice A Direct Role for Stat5 in Bcl-XL Induction , 1999, Cell.

[38]  F. Cavagnini,et al.  Growth hormone in obesity , 1999, International Journal of Obesity.

[39]  C. Ricordi,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Me , 2022 .

[40]  J. Beavo,et al.  Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. , 1998, The Journal of clinical investigation.

[41]  C. Newgard,et al.  Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. McMahon,et al.  Identification and Characterization of a Constitutively Active STAT5 Mutant That Promotes Cell Proliferation , 2022 .

[43]  P. Kelly,et al.  Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. , 1998, Endocrine reviews.

[44]  G. Reach,et al.  Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. , 1998, Endocrinology.

[45]  Y. Oka,et al.  Leptin induces proliferation of pancreatic beta cell line MIN6 through activation of mitogen-activated protein kinase. , 1997, Biochemical and biophysical research communications.

[46]  V. Emilsson,et al.  Expression of the Functional Leptin Receptor mRNA in Pancreatic Islets and Direct Inhibitory Action of Leptin on Insulin Secretion , 1997, Diabetes.

[47]  N. Sarvetnick Pancreatic growth and regeneration , 1997 .

[48]  B. Groner,et al.  Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype , 1996, Molecular and cellular biology.

[49]  P. Serup,et al.  Identification of a growth hormone-responsive STAT5-binding element in the rat insulin 1 gene. , 1996, Molecular endocrinology.

[50]  D. Allan,et al.  BETA‐CELL APOPTOSIS IS RESPONSIBLE FOR THE DEVELOPMENT OF IDDM IN THE MULTIPLE LOW‐DOSE STREPTOZOTOCIN MODEL , 1996, The Journal of pathology.

[51]  B. Groner,et al.  Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Feinglos,et al.  Impaired second phase insulin response of diabetes-prone C57BL/6J mouse islets , 1995, Physiology & Behavior.

[53]  D. Bucchini,et al.  Tissue-specific expression of the rat insulin 1 gene in vivo requires both the enhancer and promoter regions. , 1995, Differentiation; research in biological diversity.

[54]  J. Nielsen,et al.  Rat insulinoma cells express both a 115-kDa growth hormone receptor and a 95-kDa prolactin receptor structurally related to the hepatic receptors. , 1990, The Journal of biological chemistry.

[55]  C. J. Hedeskov,et al.  Phorbol-ester-induced down-regulation of protein kinase C in mouse pancreatic islets. Potentiation of phase 1 and inhibition of phase 2 of glucose-induced insulin secretion. , 1990, The Biochemical journal.

[56]  V. Bonnevie-Nielsen Experimental diets affect pancreatic insulin and glucagon differently in male and female mice. , 1980, Metabolism: clinical and experimental.

[57]  A. Rossini,et al.  Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. , 1976, Science.