Title | PKCζ Is Essential for Pancreatic β-Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Lakshmipathi J, Alvarez-Perez JCarlos, Rosselot C, Casinelli GP, Stamateris RE, Rausell-Palamos F, O'Donnell CP, Vasavada RC, Scott DK, Alonso LC, Garcia-Ocaña A |
Journal | Diabetes |
Volume | 65 |
Issue | 5 |
Pagination | 1283-96 |
Date Published | 2016 05 |
ISSN | 1939-327X |
Keywords | Animals, Cell Proliferation, Cells, Cultured, Cyclin D2, Diabetes Mellitus, Type 2, Enzyme Activation, Glucose, Humans, Insulin, Insulin Resistance, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Overweight, Protein Kinase C, Recombinant Proteins, RNA Interference, Signal Transduction, Tissue Banks, TOR Serine-Threonine Kinases |
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. |
DOI | 10.2337/db15-1398 |
Alternate Journal | Diabetes |
PubMed ID | 26868297 |
PubMed Central ID | PMC4839210 |
Grant List | R01 DK095140 / DK / NIDDK NIH HHS / United States R01 HL063767 / HL / NHLBI NIH HHS / United States R01 DK078060 / DK / NIDDK NIH HHS / United States R01 HL111706 / HL / NHLBI NIH HHS / United States R01 DK102893 / DK / NIDDK NIH HHS / United States R01 DK105015 / DK / NIDDK NIH HHS / United States P30 DK020541 / DK / NIDDK NIH HHS / United States R01 DK067351 / DK / NIDDK NIH HHS / United States R56 DK065149 / DK / NIDDK NIH HHS / United States R01 DK077096 / DK / NIDDK NIH HHS / United States R01 DK065149 / DK / NIDDK NIH HHS / United States |