Gene expression regulated by pioglitazone and exenatide in normal and diabetic rat islets exposed to lipotoxicity

Abstract Background Hyperlipidaemia has been suggested to contribute by pro‐apoptotic actions to the loss of β‐cell mass, its secretory defects, and thereby impaired β‐cell function in type 2 diabetes. Treatment of genetically diabetic rats and also type 2 diabetic patients with pioglitazone, a PPAR‐γ agonist, lowers fasting levels of plasma glucose and triglycerides, and has been suggested to protect β‐cells against diabetic lipotoxicity in vitro and in vivo . Another recently launched anti‐diabetic drug, exenatide, an incretin mimetic, has been shown to stimulate insulin secretion, growth, and proliferation of pancreatic β‐cells and to protect them against apoptosis. We aimed to investigate global alterations in β‐cell gene expression under lipotoxic conditions and the influence of in vitro treatment with pioglitazone and exenatide. Methods Global gene expression profiling was thus performed to characterize genes differently regulated by palmitate, pioglitazone, and exenatide in isolated islets from non‐diabetic Wistar rats and type 2 diabetic Goto‐Kakizaki (GK) rats. Results Gene expression profiling revealed significant changes in islet mRNAs involved in control of several aspects of β‐cell function, e.g. epigenetic regulation of gene expression, cell differentiation and morphogenesis, also metabolism, response to stimulus, transport, and signal transduction. Pioglitazone and exenatide appear to significantly impact epigenetic processes, e.g. stable alterations in gene expression potential, which arise during development and cell proliferation. Bcl2‐like 1 (Bcl2l1), an anti‐apoptotic protein, and Bcl2 modifying factor (Bmf), a pro‐apoptotic protein, were both down‐regulated by pioglitazone and exenatide in the presence of palmitate in diabetic GK islets. In contrast, Bmf was downregulated by pioglitazone in the presence of palmitate in non‐diabetic Wistar islets. Exposure of non‐diabetic Wistar islets to palmitate led to a reduction in the expression of PPAR β/δ. This suggests that palmitate may increase the accumulation of triglycerides by reducing PPAR signalling. Moreover, treatment with either pioglitazone or exenatide restored and increased the expression of PPAR β/δ in non‐diabetic Wistar islets. Conclusions Taking into account that these drugs target different components of the epigenetic machinery, our findings suggest that they might participate in restoring normal gene activity in dysfunctional islets and that additive benefits may occur. Whether such events contribute to the β‐cell sparing, proliferative, and anti‐apoptotic effects of these drugs in diabetes remains to be elucidated. Copyright © 2008 John Wiley & Sons, Ltd.