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Exenatide and Pioglitazone Regulate Fatty Acid-Induced Gene Expression in Normal and Diabetic Human Islets

Abstract

Hamedeh Ghanaat-Pour and Åke Sjöholm

Chronically elevated free fatty acids (FFAs) are believed to have a detrimental effect on glucose-stimulated insulin secretion (GSIS), ?-cell function, and ?-cell survival in type 2 diabetes, a phenomenon often referred to as lipotoxicity. The objective of the present study was to investigate the global alterations in gene expression induced by long term exposure to palmitate with or without the PPAR-? agonist pioglitazone (a thiazolidinedione) or the GLP-1 receptor agonist exenatide (synthetic exendin-4, an incretin mimetic) in human diabetic and non-diabetic pancreatic islets, using microarray technology and confirmed by qRT-PCR. Gene expression profiling revealed alterations in several functional categories, such as epigenetic regulation of gene expression, cell proliferation and differentiation, metabolism, response to stimulus, transport, and signal transduction. Moreover, PPY, TCF4/TCF7L2, REG3A, GADD45B, TXNIP, ARNT, EGFR, CEL, ACACA, and GAPDH are some of the interesting genes that were differently regulated in our study. The apoptotic pathway was not substantially influenced by either pioglitazone or exenatide in the presence of palmitate. The function and survival of the human ?-cell seems to be controlled directly through the epigenetic control of gene expression rather than a direct effect on the apoptotic pathway. Considering that the nutritional state directly induces the epigenetic modifications, pioglitazone and exenatide appear to normalize these epigenetic misregulations and may protect the ?-cell from lipotoxic insult. The epigenetic modifications of the genome provide new promising targets for clinical diagnostics and also therapeutic purposes in the treatment of human type 2 diabetes by conferring ?-cell protection from lipotoxicity.