title: PKCζ Is Essential for Pancreatic β-Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2.
abstract: Adaptive β-cell replication occurs in response to increased metabolic demand during insulin resistance. The intracellular mediators of this compensatory response are poorly defined and their identification could provide significant targets for β-cell regeneration therapies. Here we show that glucose and insulin in vitro and insulin resistance in vivo activate protein kinase C ζ (PKCζ) in pancreatic islets and β-cells. PKCζ is required for glucose- and glucokinase activator-induced proliferation of rodent and human β-cells in vitro. Furthermore, either kinase-dead PKCζ expression (KD-PKCζ) or disruption of PKCζ in mouse β-cells blocks compensatory β-cell replication when acute hyperglycemia/hyperinsulinemia is induced. Importantly, KD-PKCζ inhibits insulin resistance-mediated mammalian target of rapamycin (mTOR) activation and cyclin-D2 upregulation independent of Akt activation. In summary, PKCζ activation is key for early compensatory β-cell replication in insulin resistance by regulating the downstream signals mTOR and cyclin-D2. This suggests that alterations in PKCζ expression or activity might contribute to inadequate β-cell mass expansion and β-cell failure leading to type 2 diabetes.
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Jayalakshmi
authors: J
authors: Lakshmipathi
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Juan Carlos
authors: JC
authors: Alvarez-Perez
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Carolina
authors: C
authors: Rosselot
authors: Division of Pediatric Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA.
authors: Gabriella P
authors: GP
authors: Casinelli
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors: Rachel E
authors: RE
authors: Stamateris
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Francisco
authors: F
authors: Rausell-Palamos
authors: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors: Christopher P
authors: CP
authors: O'Donnell
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Rupangi C
authors: RC
authors: Vasavada
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Donald K
authors: DK
authors: Scott
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors: Laura C
authors: LC
authors: Alonso
authors: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY adolfo.g.ocana@mssm.edu.
authors: Adolfo
authors: A
authors: Garcia-Ocaña
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D056742:Cyclin D2 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050177:Overweight / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014015:Tissue Banks; D000099221:Protein Kinase C zeta
chemical_list: D056742:Cyclin D2; D005947:Glucose; D007328:Insulin; D011493:Protein Kinase C; D011994:Recombinant Proteins; D058570:TOR Serine-Threonine Kinases; D000099221:Protein Kinase C zeta; C486196:Ccnd2 protein, mouse; C546843:mTOR protein, mouse