Direct suppression of human islet dedifferentiation, progenitor genes, but not epithelial to mesenchymal transition by liraglutide.

β-cell dedifferentiation has been accounted as one of the major mechanisms for β-cell failure; thus, is a cause to diabetes. We study direct impacts of liraglutide treatment on human dedifferentiated islets, and its effects on genes important in endocrine function, progenitor states, and epithelial mesenchymal transition (EMT). Human islets from non-diabetic donors, were purified and incubated until day 1 and day 4, and were determined insulin contents, numbers of insulin (INS) and glucagon (GCG) cells. The islets from day 3 to day 7 were treated with diabetic drugs, the long acting GLP-1 receptor agonist, liraglutide. As observed in pancreatic islets of type 2 diabetic patients, dedifferentiated islets showed more than 50% reduced insulin contents while number of glucagon increased from 10% to about 20%. β-cell specific genes: , , as well as β-cell functional markers: were significantly depleted more than 40%. Notably, we found increased levels of glucagon regulator, and pre-glucagon transcripts, and remarkably upregulated progenitor expressions: and identified as β-cell dysfunction markers in diabetic models. Hyperglucagonemia was often observed in type 2 patients that could lead to over production of gluconeogenesis by the liver. Liraglutide treatments resulted in decreased number of GCG cells, increased numbers of GLP-1 positive cells but did not alter elevated levels of EMT marker genes: and . These effects of liraglutide were blunted when transcripts were depleted. This work illustrates that human isolated islets can be used as a tool to study different aspects of β-cell dedifferentiation. Our novel finding suggests a role of GLP-1 pathway in beta-cell maintenance in FOXO1-dependent manner. Importantly, dedifferentiated islets is a useful model that can be utilized to verify the actions of potential drugs to diabetic β-cell failure.