The beta-cell is one of four major types of cells present in the islets of Langerhans, which are islands of cells distributed throughout the endocrine pancreas in most mammals. The beta-cell synthesizes and secretes the hormone insulin mainly in response to glucose but also in response to several nutrients, hormones and nervous stimuli. In adult rodents the beta-cell has a slow mitotic rate. Recent studies provide novel insights into the functions of the beta-cell. The presence of functional insulin-like growth factor-1 and insulin receptors and components of their signaling pathway indicate an important role for insulin/IGF-1 signaling in the regulation of beta-cell function. Further, the recent discovery of glucokinase (GK) and the ATP-dependent potassium channels on insulin secretory granules, the detection of AMP-protein kinase in the beta-cell and the identification of a new beta-cell transcription factor, mMafA, are some exciting new areas of research currently underway to further understand the complex pathways that regulate the functions of beta-cells.
"Emerging evidence indicates that proliferation of pancreatic beta cells is an important mechanism not only to maintain homeostasis in the endocrine pancreas but also for adapting islet function to changes in metabolic demands [9, 28, 29]. The inability of the beta cells to expand and compensate for the changing insulin demand can contribute to the pathogenesis of diabetes. "
[Show abstract][Hide abstract] ABSTRACT: The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.
Journal of Diabetes Research 02/2014; 2014:873679. DOI:10.1155/2014/873679 · 2.16 Impact Factor
"To resist diabetes, pancreatic beta cells then need to overcompensate with sufficient insulin release (Saltiel, 2001). Pancreatic beta cells produce and secrete insulin mainly in response to blood glucose, which is taken up into the cells through the glucose transporter isotype 2 (GLUT2) and subsequently phosphorylated into glucose-6-phosphate by glucokinase (GCK) (Kulkarni, 2004; Saltiel, 2001). This metabolic activity in the pancreatic beta cell leads to an increase in the ATP/ADP ratio and closure of the ATP-sensitive potassium (K ATP ) channel, which is composed of the inward rectifying K + channel (Kir6.2) and the sulfonylurea receptor (SUR1; encoded by ABCC8). "
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARgamma and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.
Twin Research and Human Genetics 11/2008; 11(5):505-16. DOI:10.1375/twin.11.5.505 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transplantation of functional islets of Langerhans may emerge as a useful therapy for some patients with type 1 diabetes mellitus (DM), but donor islet shortages motivate the search for new sources of transplantable islets. Pluripotent embryonic stem (ES) cells are expandable in culture and have the potential to give rise to all cell types in the body. The recent isolation of pluripotent ES cells from humans has generated excitement over the possibility of engineering glucose-responsive islet replacement tissue from these cells in large quantities. In this study, we review the recent advances in generating insulin-producing cells (IPC) from mouse and human ES (hES) cells.
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