Anti-MAFA (aa 222-308) polyclonal antibody

beta-cell dedifferentiation has been accounted as one of the major mechanisms for beta-cell failure; thus, is a cause to diabetes. We study direct impacts of liraglutide treatment on ex vivo 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, ex vivo dedifferentiated islets showed more than 50% reduced insulin contents while number of glucagon increased from 10% to about 20%. beta-cell specific genes: PDX1, MAFA, as well as beta-cell functional markers: GLUT1 and SUR1, were significantly depleted more than 40%. Notably, we found increased levels of glucagon regulator, ARX and pre-glucagon transcripts, and remarkably upregulated progenitor expressions: NEUROG3 and ALDH1A identified as beta-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: ACTA2, CDH-2, SNAIL2, and VIM. These effects of liraglutide were blunted when FOXO1 transcripts were depleted. This work illustrates that ex vivo human isolated islets can be used as a tool to study different aspects of beta-cell dedifferentiation. Our novel finding suggests a role of GLP-1 pathway in beta-cell maintenance in FOXO1-dependent manner. Importantly, dedifferentiated islets ex vivo is a useful model that can be utilized to verify the actions of potential drugs to diabetic beta-cell failure.

Di(2-ethylhexyl) phthalate, a distinctive endocrine-disrupting chemical (EDC), is widely used as plasticizer. Gestational exposure to EDCs like DEHP may program a permanent diabetes disposition. We investigated whether gestational DEHP exposure disrupts glucose homeostasis in the rat F-1 offspring as a result of early impairment in the functions of endocrine pancreas. Pregnant Wistar rats were administered with DEHP (1, 10 and 100 mg kg(-1) day(-1)) or olive oil from gestational day 9-21 by oral gavage. DEHP-exposed offspring exhibited elevated blood glucose, impaired insulin, glucose tolerance, glucose-stimulated insulin secretion and decreased pancreatic insulin content at postnatal day 60 (PND60). Global DNA methylation level was increased while the expression of genes involved in the development and function of beta-cells were down regulated in islets in DEHP exposed groups. Gestational exposure to DEHP favours beta-cell dysfunction and the whole body glucometabolic abnormalities in the F-1 offspring by down regulating the expression of critical genes. Further, DEHP-induced epigenetic changes in genes involved in beta-cell development and function appear to play a significant role. (C) 2014 Elsevier Ireland Ltd. All rights reserved.