title: Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2.
abstract: Type 2 diabetes results from impaired insulin action and beta-cell dysfunction. There are at least two components to beta-cell dysfunction: impaired insulin secretion and decreased beta-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired beta-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, approximately 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased beta-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as beta-cell mass gradually declined, indicating that replication-defective beta-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous beta-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of beta-cell dysfunction in type 2 diabetes should positively affect both aspects of beta-cell physiology.
authors.affiliation: Deparment of Pediatrics, University of California, San Diego, California, USA.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000222:Adaptation, Physiological; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D003920:Diabetes Mellitus / Q000235:genetics; D005951:Glucose Tolerance Test; D006130:Growth Disorders / Q000235:genetics; D006946:Hyperinsulinism / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009929:Organ Size; D009994:Osmolar Concentration; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D052242:Adiponectin; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D020738:Leptin; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt