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.

GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

“…Studies relevant to the mechanisms of autophagy indicated that mTOR pathway was involved in pancreatic beta cell, myoblasts, gastric cancer cell, and non-small cell lung cancer [23,24,25,26], but the associated research in hepatocytes was rare. To reveal these potential mechanisms, the effect of mTOR signaling pathway was explored.…”

Replicative capacity of β-cells and type 1 diabetes

“…Studies of intact and dispersed human islets overexpressing AKT directly have shown increased β-cell proliferation [17], and Yap, another activator of AKT/mTOR signaling, appeared to induce proliferation, though nonspecifically in endocrine cells [18]. PKCζ, which is less often studied as part of the PI3K/mTOR cascade, was recently shown to be necessary for “compensatory” human β-cell replication induced by glucose [19]. Indirect activation of Akt by TGFβ has led to context-dependent effects on β-cell proliferation [20], which suggests that ligands such as TGFβ may activate multiple signaling cascades simultaneously.…”

“…There is robust data indicating that insulin resistance and/or hyperglycemia stimulates β-cell proliferation in rodents [13,19,39]. Porat and colleagues showed that glucose-induced proliferation was regulated by GK metabolism, with increased glycolytic rate causing the β-cell to upregulate proliferative pathways [39].…”

Protein kinase C isoforms in the normal pancreas and in pancreatic disease

“…In addition, the knockout of PKCζ in beta cells of mice blocks their proliferation in response to insulin resistance [43]. PKCζ drives beta cell proliferation through activation of mammalian target of rapamycin (mTOR) [42, 43]. Activation of mTOR then increases expression of cyclin-D2, which drives proliferation [44].…”