β-Cell proliferation after a partial pancreatectomy is independent of IRS-2 in mice.

The glucokinase-induced up-regulation of insulin receptor substrate 2 (IRS-2) plays an important role in β-cell adaptive proliferation in response to high-fat diet-induced insulin resistance. This study aimed to investigate the role of IRS-2 in the proliferation of β-cells after a 60% partial pancreatectomy. IRS-2-deficient (IRS-2(-/-)) mice or wild-type mice were subjected to a pancreatectomy (60% partial pancreatectomy) or a sham operation (Sham). The β-cell proliferation and gene expression profiles of the islets were then assessed. Gene expression in islets from pancreatectomized and Sham C57BL/6J male mice was analyzed using a cDNA microarray analysis. To compare with β-cell proliferation induced by a high-fat diet, Gck(+/-) mice subjected to a pancreatectomy were also analyzed. The IRS-2(-/-) mice exhibited β-cell expansion and a significant increase in β-cell proliferation after the pancreatectomy, compared with the Sham group. Although glucose-stimulated insulin secretion from islets was not impaired, IRS-2(-/-) mice manifested severe hyperglycemia after the pancreatectomy. The expression levels of Aurora kinase B, Cyclin A, and Cyclin B1 in the pancreatectomized islets were also enhanced in the IRS-2(-/-) mice. A gene set enrichment analysis suggested an association between the genes that were up-regulated in the pancreatectomized islets and those involved in M phase progression in the cell cycle. β-Cell proliferation after a pancreatectomy was observed even in the Gck(+/-) mice. In conclusion, IRS-2 was not required for β-cell proliferation but might be needed for functional β-cell mass, after a pancreatectomy. A partial pancreatectomy in mice may be an attractive model for the development of new strategy for exploring the unique nature of β-cell proliferation.

[1]  Mark A. Hall,et al.  Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. , 2010, Blood.

[2]  W. Uhl,et al.  Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration , 2008, Diabetes.

[3]  S. Bonner-Weir,et al.  Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats , 2010, Journal of Cell Science.

[4]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[5]  Y. Terauchi,et al.  Protective Effects of Dipeptidyl Peptidase-4 (DPP-4) Inhibitor against Increased β Cell Apoptosis Induced by Dietary Sucrose and Linoleic Acid in Mice with Diabetes* , 2011, The Journal of Biological Chemistry.

[6]  R. Costa,et al.  β-Cell Proliferation, but Not Neogenesis, Following 60% Partial Pancreatectomy Is Impaired in the Absence of FoxM1 , 2008, Diabetes.

[7]  P. Halban,et al.  Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications , 2004, Diabetologia.

[8]  H. Aburatani,et al.  Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. , 2007, The Journal of clinical investigation.

[9]  H. Kasai,et al.  Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. , 1995, The Journal of biological chemistry.

[10]  M. White,et al.  The IRS-signalling system: A network of docking proteins that mediate insulin action , 1998, Molecular and Cellular Biochemistry.

[11]  C. Kahn,et al.  Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. , 1999, The Journal of clinical investigation.

[12]  J. Leahy,et al.  Enhanced expression of insulin receptor substrate–2 and activation of protein kinase B/Akt in regenerating pancreatic duct epithelium of 60 %-partial pancreatectomy rats , 2001, Diabetologia.

[13]  P. Herrera,et al.  β-Cell regeneration: the pancreatic intrinsic faculty , 2011, Trends in Endocrinology & Metabolism.

[14]  S. Bonner-Weir,et al.  Prior streptozotocin treatment does not inhibit pancreas regeneration after 90% pancreatectomy in rats. , 1999, The American journal of physiology.

[15]  S. Kahn,et al.  Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation , 2005, Diabetologia.

[16]  R. Sorenson,et al.  Adaptation of Islets of Langerhans to Pregnancy: β-Cell Growth, Enhanced Insulin Secretion and the Role of Lactogenic Hormones , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[17]  L. Tecott,et al.  Serotonin Regulates Pancreatic β-Cell Mass during Pregnancy , 2010, Nature Medicine.

[18]  Y. Goshima,et al.  Effects of liraglutide on β-cell-specific glucokinase-deficient neonatal mice. , 2012, Endocrinology.

[19]  Frank J. Gonzalez,et al.  Loss of ARNT/HIF1β Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes , 2005, Cell.

[20]  T. Noda,et al.  Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. , 2004, The Journal of clinical investigation.

[21]  S. Aizawa,et al.  Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. , 2000, Diabetes.

[22]  J. Leahy,et al.  Regulation of Pancreatic β-Cell Regeneration in the Normoglycemic 60% Partial-Pancreatectomy Mouse , 2006, Diabetes.

[23]  P. Marchetti,et al.  Altered Insulin Receptor Signalling and β-Cell Cycle Dynamics in Type 2 Diabetes Mellitus , 2011, PloS one.

[24]  H. Kaneto,et al.  Pdx1 Expression in Irs2-deficient Mouse β-Cells Is Regulated in a Strain-dependent Manner* , 2003, Journal of Biological Chemistry.

[25]  M. Malumbres,et al.  Aurora B prevents delayed DNA replication and premature mitotic exit by repressing p21Cip1 , 2013, Cell cycle.

[26]  Vladimir Petrovic,et al.  Forkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase , 2005, Molecular and Cellular Biology.

[27]  M. Gannon,et al.  Gestational Diabetes Mellitus Resulting From Impaired β-Cell Compensation in the Absence of FoxM1, a Novel Downstream Effector of Placental Lactogen , 2009, Diabetes.

[28]  C. Kahn,et al.  Insulin Augmentation of Glucose-Stimulated Insulin Secretion Is Impaired in Insulin-Resistant Humans , 2012, Diabetes.

[29]  Douglas A. Melton,et al.  Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation , 2004, Nature.

[30]  K. Kaestner,et al.  Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment. , 2006, Physiological genomics.

[31]  J. Kushner,et al.  Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age , 2009, Diabetes.

[32]  G. Lienhard,et al.  Impact of Genetic Background and Ablation of Insulin Receptor Substrate (IRS)-3 on IRS-2 Knock-out Mice* , 2003, The Journal of Biological Chemistry.

[33]  M. Matsuhisa,et al.  Both Insulin Signaling Defects in the Liver and Obesity Contribute to Insulin Resistance and Cause Diabetes in Irs2–/– Mice* , 2004, Journal of Biological Chemistry.

[34]  E. Bertelli,et al.  Intermediate endocrine-acinar pancreatic cells in duct ligation conditions. , 1997, American journal of physiology. Cell physiology.

[35]  Jiang Hu,et al.  Cyclin D2 Is Essential for the Compensatory β-Cell Hyperplastic Response to Insulin Resistance in Rodents , 2010, Diabetes.

[36]  D. Melton,et al.  Recovery from diabetes in mice by β cell regeneration , 2007 .

[37]  G. Seghieri,et al.  Are the available experimental models of type 2 diabetes appropriate for a gender perspective? , 2008, Pharmacological research.

[38]  E. Montanya,et al.  Mechanisms of glucose hypersensitivity in beta-cells from normoglycemic, partially pancreatectomized mice. , 1999, Diabetes.