PMID- 26868297 OWN - NLM STAT- MEDLINE DCOM- 20170606 LR - 20211204 IS - 1939-327X (Electronic) IS - 0012-1797 (Print) IS - 0012-1797 (Linking) VI - 65 IP - 5 DP - 2016 May TI - PKCzeta Is Essential for Pancreatic beta-Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2. PG - 1283-96 LID - 10.2337/db15-1398 [doi] AB - Adaptive beta-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 beta-cell regeneration therapies. Here we show that glucose and insulin in vitro and insulin resistance in vivo activate protein kinase C zeta (PKCzeta) in pancreatic islets and beta-cells. PKCzeta is required for glucose- and glucokinase activator-induced proliferation of rodent and human beta-cells in vitro. Furthermore, either kinase-dead PKCzeta expression (KD-PKCzeta) or disruption of PKCzeta in mouse beta-cells blocks compensatory beta-cell replication when acute hyperglycemia/hyperinsulinemia is induced. Importantly, KD-PKCzeta inhibits insulin resistance-mediated mammalian target of rapamycin (mTOR) activation and cyclin-D2 upregulation independent of Akt activation. In summary, PKCzeta activation is key for early compensatory beta-cell replication in insulin resistance by regulating the downstream signals mTOR and cyclin-D2. This suggests that alterations in PKCzeta expression or activity might contribute to inadequate beta-cell mass expansion and beta-cell failure leading to type 2 diabetes. CI - (c) 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. FAU - Lakshmipathi, Jayalakshmi AU - Lakshmipathi J AD - 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. FAU - Alvarez-Perez, Juan Carlos AU - Alvarez-Perez JC AD - 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. FAU - Rosselot, Carolina AU - Rosselot C AD - 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. FAU - Casinelli, Gabriella P AU - Casinelli GP AD - Division of Pediatric Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA. FAU - Stamateris, Rachel E AU - Stamateris RE AD - Department of Medicine, University of Massachusetts Medical School, Worcester, MA. FAU - Rausell-Palamos, Francisco AU - Rausell-Palamos F AD - 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. FAU - O'Donnell, Christopher P AU - O'Donnell CP AD - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. FAU - Vasavada, Rupangi C AU - Vasavada RC AD - 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. FAU - Scott, Donald K AU - Scott DK AD - 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. FAU - Alonso, Laura C AU - Alonso LC AD - Department of Medicine, University of Massachusetts Medical School, Worcester, MA. FAU - Garcia-Ocana, Adolfo AU - Garcia-Ocana A AD - 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. LA - eng GR - R01 DK095140/DK/NIDDK NIH HHS/United States GR - R01 HL063767/HL/NHLBI NIH HHS/United States GR - R01 DK078060/DK/NIDDK NIH HHS/United States GR - R01 HL111706/HL/NHLBI NIH HHS/United States GR - R01 DK102893/DK/NIDDK NIH HHS/United States GR - R01 DK105015/DK/NIDDK NIH HHS/United States GR - P30 DK020541/DK/NIDDK NIH HHS/United States GR - R01 DK067351/DK/NIDDK NIH HHS/United States GR - R56 DK065149/DK/NIDDK NIH HHS/United States GR - R01 DK077096/DK/NIDDK NIH HHS/United States GR - R01 DK065149/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20160211 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Ccnd2 protein, mouse) RN - 0 (Cyclin D2) RN - 0 (Insulin) RN - 0 (Recombinant Proteins) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (protein kinase C zeta) RN - EC 2.7.11.13 (Protein Kinase C) RN - IY9XDZ35W2 (Glucose) SB - IM CIN - J Diabetes Investig. 2017 Mar;8(2):149-151. PMID: 27479547 MH - Animals MH - Cell Proliferation MH - Cells, Cultured MH - Cyclin D2/*metabolism MH - Diabetes Mellitus, Type 2/etiology/*metabolism/pathology MH - Enzyme Activation MH - Glucose/metabolism MH - Humans MH - Insulin/metabolism MH - *Insulin Resistance MH - Insulin Secretion MH - Insulin-Secreting Cells/cytology/*metabolism/pathology MH - Islets of Langerhans/cytology/metabolism/pathology MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Overweight/*metabolism/pathology/physiopathology MH - Protein Kinase C/antagonists & inhibitors/chemistry/genetics/*metabolism MH - RNA Interference MH - Recombinant Proteins/chemistry/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism MH - Tissue Banks PMC - PMC4839210 EDAT- 2016/02/13 06:00 MHDA- 2017/06/07 06:00 PMCR- 2017/05/01 CRDT- 2016/02/13 06:00 PHST- 2015/10/08 00:00 [received] PHST- 2016/02/06 00:00 [accepted] PHST- 2016/02/13 06:00 [entrez] PHST- 2016/02/13 06:00 [pubmed] PHST- 2017/06/07 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - db15-1398 [pii] AID - 1398 [pii] AID - 10.2337/db15-1398 [doi] PST - ppublish SO - Diabetes. 2016 May;65(5):1283-96. doi: 10.2337/db15-1398. Epub 2016 Feb 11.