Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Abstract

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.

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

“…We previously studied ZF rats made hyperglycemic by a 60% pancreatectomy and observed subnormal islet expression of PPAR␥ and its target gene GIP receptor versus the hyperexpression in nondiabetic ZF rats (6). The current study has shown the same pattern for PC along with reduced nuclear Pdx1 immunostaining in Px ZF rats, which are in accord with our previous report showing subnormal PC and Pdx1 mRNA expression in Px ZF islets (8).…”

“…Collectively, these genes are key controllers of ␤-cell mass, mitochondrial fuel metabolism, and insulin secretion, suggesting the potential for a central role of PPAR␥ in ␤-cell compensation and/or failure. Consistent with this proposal, we have shown increased expression of PPAR␥ and its target genes in islets from rodents with successful ␤-cell adaption to an experimental reduction of ␤-cell mass (4,6) and to obesity and insulin resistance (6,8) and decreased expression in a diabetic rodent model (6,8). Also, clinical trials with thiazolidinedione PPAR␥ agonists (9) have shown a high success rate at stabilizing ␤-cell function and preventing type 2 diabetes (10).…”

“…We have shown that islet PPAR␥ and its target genes are hyperexpressed in nondiabetic insulin-resistant rats (present study and Refs. 6,8) and rats during the ␤-cell adaptation after a partial pancreatectomy (4, 6), plus we and others have shown impaired expression of these same genes in diabetic animals (6,29,44) and humans with type 2 diabetes (30,45,46). Collectively, these findings support, but do not prove, a FoxO1/PPAR␥-mediated transcriptional network functioning as a core element of how ␤-cells adapt to metabolic stress, with failure of this response causing or exacerbating diabetes.…”

“…Some animals underwent glucose tolerance testing after an overnight fast that consisted of 2 g/kg intraperitoneal glucose with serum glucose measured at 0, 30, 60, 90, and 120 min (Freestyle glucose meter). Zucker lean (ZL, fa/ϩ or ϩ/ϩ) and Zucker fatty (ZF, fa/fa) male rats (Harlan) underwent 60% pancreatectomy (Px) or sham Px surgery at 6 weeks of age as described previously (8). Islets were isolated by pancreas duct perfusion with collagenase, Histopaque gradient separation, and hand picking.…”

“…We previously developed and characterized a diabetic rat model by performing a 60% Px in ZF rats (8). Px ZF rats became hyperglycemic (ϳ15 mM) by 3 weeks after surgery with the same free fatty acid levels and obesity as normoglycemic ZF shams.…”