PKCζ is essential for pancreatic β-cell replication during insulin resistance by regulating mTOR and cyclin-D2

Jayalakshmi Lakshmipathi, Juan Carlos Alvarez-Perez, Carolina Rosselot, Gabriella P. Casinelli, Rachel E. Stamateris, Francisco Rausell-Palamos, Christopher P. O'Donnell, Rupangi C. Vasavada, Donald K. Scott, Laura C. Alonso, Adolfo Garcia-Ocaña

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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 glucoseand glucokinase activator-induced proliferation of rodent and human β-cells in vitro. Furthermore, either kinasedead 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.

Original languageEnglish
Pages (from-to)1283-1296
Number of pages14
Issue number5
StatePublished - May 2016


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