We reported that peroxisome proliferator-activated receptor ␥ (PPAR␥) transcriptionally regulates the ␤-cell differentiation factor pancreatic duodenal homeobox (PDX)-1 based on in vitro RNA interference studies. We have now studied mice depleted of PPAR␥ within the pancreas (PANC PPAR␥ Peroxisome proliferator-activated receptor ␥ (PPAR␥) 4 is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors (1) and contributes significantly to diverse biological processes such as glucose homeostasis, lipid metabolism, cellular proliferation, and differentiation (2-4). PPAR␥ regulates transcriptional activity of target genes by forming a heterodimer with retinoid X receptor (RXR), and binding to a specific PPAR␥ response element sequence (PPRE) within the promoter region (5, 6). The PPRE consists of two hexamer repeats (DR1 and DR2) separated by a single nucleotide, with PPAR␥ and RXR occupying the 5Ј-and 3Ј-half-sites, respectively (7,8). Thiazolidinediones are PPAR␥ agonists used for the treatment of type 2 diabetes based on insulin-sensitizing effects in adipose tissue and muscle (9). However, a recent finding is PPAR␥-mediated anti-proliferation and pro-survival of islet ␤-cells (10 -12). This is of interest as clinical trials showing glycemic benefits of thiazolidinediones in prediabetes and early type 2 diabetes (13-17) have usually been interpreted that the insulin sensitization effect unloads overstimulated insulin secretion, so-called "␤-cell rest." On the other hand, the possibility of direct PPAR␥ regulatory effects in islet ␤-cells is controversial, as a ␤-cell-specific PPAR␥ knock-out mouse was normoglycemic basally and after fat feeding (11). Also little is known about PPAR␥ target genes in ␤-cells.؊PPAR␥ regulates the function and survival of tissues by acting through a triad of effects as follows: anti-proliferation, prosurvival, and pro-differentiation (18). Because PPAR␥-mediated pro-survival and anti-proliferation had been reported for ␤-cells (10 -12), one might also expect pro-differentiation properties. Our group has studied a model of ␤-cell adaptation to a loss of ␤-cell mass, 60% pancreatectomy (Px) SpragueDawley rats. They are normoglycemic because of partial ␤-cell regeneration during the 1st week post-Px (19,20) that is followed by ␤-cell hyperfunction secondary to increased glucokinase activity (21). We investigated the transition phase, 14 days

The onset of type 2 diabetes is characterized by transition from successful to failed insulin secretory compensation to obesity-related insulin resistance and dysmetabolism. Energy-rich diets in rodents are commonly studied models of compensatory increases in both insulin secretion and β cell mass. However, the mechanisms of these adaptive responses are incompletely understood, and it is also unclear why these responses eventually fail. We measured the temporal trends of glucose homeostasis, insulin secretion, β cell morphometry, and islet gene expression in C57BL/6NTac mice fed a 60% high-fat diet (HFD) or control diet for up to 16 weeks. A 2-fold increased hyperinsulinemia was maintained for the first 4 weeks of HFD feeding and then further increased through 16 weeks. β cell mass increased progressively starting at 4 weeks, principally through nonproliferative growth. Insulin sensitivity was not significantly perturbed until 11 weeks of HFD feeding. Over the first 8 weeks, we observed two distinct waves of increased expression of β cell functional and prodifferentiation genes. This was followed by activation of the unfolded protein response at 8 weeks and overt β cell endoplasmic reticulum stress at 12-16 weeks. In summary, β cell adaptation to an HFD in C57BL/6NTac mice entails early insulin hypersecretion and a robust growth phase along with hyperexpression of related genes that begin well before the onset of observed insulin resistance. However, continued HFD exposure results in cessation of gene hyperexpression, β cell functional failure, and endoplasmic reticulum stress. These data point to a complex but not sustainable integration of β cell-adaptive responses to nutrient overabundance, obesity development, and insulin resistance.

ABSTRACT:Diabetes has been classified as a disease of glucose overproduction by tissues, mainly liver and glucose underutilization by insulin requiring tissues like liver, adipose and muscle due to lack of insulin. There is, however, glucose over utilization in tissues not dependent on insulin for glucose transport like kidney, nerve and brain. There are serious complications due to this excess glucose in these tissues and their reversal is important for a good metabolic control and normalisation of other parameters. Insulin, trace metals and some plant extracts have been used to see the reversal effects of the complications of diabetes in liver and kidney in experimental diabetes. Almost complete reversal of the metabolic changes has been achieved in the activities of key enzymes of metabolic pathways in liver and kidney and an effective glucose control has been achieved suggesting a combination of therapies in the treatment of metabolic disturbance of the diabetic state.

In the 60% pancreatectomy (Px) rat model of ␤-cell adaptation, normoglycemia is maintained by an initial week of ␤-cell hyperplasia that ceases and is followed by enhanced ␤-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 ␤-cell nuclear peroxisome proliferator-activated receptor (PPAR)-␥ protein, along with a 2-fold increase in nuclear pancreatic duodenal homeobox (Pdx)-1 protein and a 1.4-fold increase in ␤-cell nuclear Nkx6.1 immunostaining. As PPAR-␥ activation is known to both lower proliferation and have prodifferentiation effects in many tissues, we studied PPAR-␥ actions in INS-1 cells. A 3-day incubation with the PPAR-␥ agonist troglitazone reduced proliferation and increased Pdx-1 and Nkx6.1 immunostaining, along with glucokinase and GLUT2. Also, a 75% knockdown of PPAR-␥ 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-␥ 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-␥ signaling in the ␤-cell adaptation following a 60% Px in rats. Diabetes 56:88 -95, 2007

Aims/hypothesis The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model. Methods Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured. Results ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression. Conclusions/interpretation Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.