Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes

• DOI: 10.1074/jbc.m116.754077
• Publication Date: 2017-01-19T02:01:01Z
• Authors: So Yoon Kim; Ji-Hyeon Lee; Matthew J. Merrins; Oksana Gavrilova; Xavier Bisteau; Philipp Kaldis; Leslie S. Satin; Sushil G. Rane
• Keywords: Male; 0301 basic medicine; beta cell function; Mice; Cyclin-Dependent Kinase 2 -- genetics -- metabolism; Insulin-Secreting Cells; Insulin Secretion; Insulin; Phosphorylation; Mice, Knockout; Microscopy; diabetes; Insulin-Secreting Cells -- cytology -- pathology; Sciences bio-médicales et agricoles; cyclin-dependent kinase (CDK); Glucose -- chemistry; Phenotype; Disease Progression; cell cycle; Female; Experimental -- pathology; Biologie; Pancreas -- pathology; CDK2; Genotype; Insulin -- metabolism; Knockout; Diet, High-Fat; Fluorescence; Diabetes Mellitus, Experimental -- pathology; Diabetes Mellitus, Experimental; 03 medical and health sciences; Diabetes Mellitus; Animals; Humans; Pancreas; Cell Proliferation; Diabétologie; beta cell (B-cell); beta cell mass; Body Weight; Cyclin-Dependent Kinase 2; Biologie moléculaire; Glucose Tolerance Test; Diet; High-Fat; Glucose; Microscopy, Fluorescence; foxo1; Biologie cellulaire; FOXO

The failure of pancreatic islet β-cells is a major contributor to the etiology type 2 diabetes. β-Cell dysfunction and declining β-cell mass are two mechanisms that contribute this failure, although it unclear whether they molecularly linked. Here, we show cell cycle regulator, cyclin-dependent kinase (CDK2), couples primary progressive deterioration in Mice with pancreas-specific deletion Cdk2 glucose-intolerant, primarily due defects glucose-stimulated insulin secretion. Accompanying loss secretion metabolism perturbed mitochondrial structure. Persistent culminate deficits proliferation, reduced mass, These outcomes may be mediated directly by CDK2, which binds phosphorylates transcription factor FOXO1 glucose-dependent manner. Further, identified requirement for CDK2 compensatory increases occur response age- diet-induced stress. Thus, serves as an important nexus linking