Peroxisome proliferator-activated receptor-γ regulates expression of PDX-1 and NKX6.1 in INS-1 cells

Abstract

In the 60% pancreatectomy (Px) rat model of β-cell adaptation, normoglycemia is maintained by an initial week of β-cell hyperplasia that ceases and is followed by enhanced β-cell function. It is unknown how this complex series of events is regulated. We studied isolated islets and pancreas sections from 14-day post-Px versus sham-operated rats and observed a doubling of β-cell nuclear peroxisome proliferator-activated receptor (PPAR)-γ protein, along with a 2-fold increase in nuclear pancreatic duodenal homeobox (Pdx)-1 protein and a 1.4-fold increase in β-cell nuclear Nkx6.1 immunostaining. As PPAR-γ activation is known to both lower proliferation and have prodifferentiation effects in many tissues, we studied PPAR-γ actions in INS-1 cells. A 3-day incubation with the PPAR-γ agonist troglitazone reduced proliferation and increased Pdx-1 and Nkx6.1 immunostaining, along with glucokinase and GLUT2. Also, a 75% knockdown of PPAR-γ using RNA interference lowered the mRNA levels of Pdx-1, glucokinase, GLUT2, and proinsulin II by more than half. Our results show a dual effect of PPAR-γ in INS-1 cells: to curtail proliferation and promote maturation, the latter via enhanced expression of Pdx-1 and Nkx6.1. Additional studies are needed to determine whether there is a regulatory role for PPAR-γ signaling in the β-cell adaptation following a 60% Px in rats. © 2007 by the American Diabetes Association.