title: Loss of Cyclin-dependent Kinase 2 in the Pancreas Links Primary β-Cell Dysfunction to Progressive Depletion of β-Cell Mass and Diabetes.
abstract: The failure of pancreatic islet β-cells is a major contributor to the etiology of type 2 diabetes. β-Cell dysfunction and declining β-cell mass are two mechanisms that contribute to this failure, although it is unclear whether they are molecularly linked. Here, we show that the cell cycle regulator, cyclin-dependent kinase 2 (CDK2), couples primary β-cell dysfunction to the progressive deterioration of β-cell mass in diabetes. Mice with pancreas-specific deletion ofCdk2are glucose-intolerant, primarily due to defects in glucose-stimulated insulin secretion. Accompanying this loss of secretion are defects in β-cell metabolism and perturbed mitochondrial structure. Persistent insulin secretion defects culminate in progressive deficits in β-cell proliferation, reduced β-cell mass, and diabetes. These outcomes may be mediated directly by the loss of CDK2, which binds to and phosphorylates the transcription factor FOXO1 in a glucose-dependent manner. Further, we identified a requirement for CDK2 in the compensatory increases in β-cell mass that occur in response to age- and diet-induced stress. Thus, CDK2 serves as an important nexus linking primary β-cell dysfunction to progressive β-cell mass deterioration in diabetes.
authors.affiliation: From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and.
authors.forename: So Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and.
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin, Madison, Wisconsin 53705.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Merrins
authors.affiliation: the Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, Clinical Research Center, Bethesda, Maryland 20892.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: the Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos#3-09, Singapore 138673, Singapore.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bisteau
authors.affiliation: the Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos#3-09, Singapore 138673, Singapore.|the Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore, and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
authors.affiliation: the Department of Pharmacology and Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.affiliation: From the Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch and ranes@mail.nih.gov.
authors.forename: Sushil G
authors.initials: SG
authors.lastname: Rane
mesh_terms: D000818:Animals; D001835:Body Weight; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D059305:Diet, High-Fat; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005947:Glucose / Q000737:chemistry; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation
chemical_list: D007328:Insulin; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D005947:Glucose
keywords: CDK2; FOXO; beta cell (B-cell); beta cell function; beta cell mass; cell cycle; cyclin-dependent kinase (CDK); diabetes; foxo1