Loss of pancreatic islet b-cell mass and b-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulincontaining b-cells can convert into glucagon-containing a-cells ex vivo. This loss of b-cell identity was characterized by the presence of b-cell transcription factors (Nkx6.1, Pdx1) in glucagon + cells. Here, we investigated whether the loss of b-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin + cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1 + but insulin 2 coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1 + glucagon + insulin 2 cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1 + glucagon + insulin 2 cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of b-cell identity occurs in T2DM and could contribute to the decrease of functional b-cell mass. Maintenance of b-cell identity is a potential novel strategy to preserve b-cell function in diabetes.Loss of pancreatic b-cell mass and b-cell dysfunction are central in the development of type 2 diabetes (T2DM) and, in combination with peripheral insulin resistance, lead to hyperglycemia (1). Whereas b-cells, on the one hand, fail to properly secrete insulin at a given glucose level, there is also a progressive decline in the number of b-cells (2,3). Loss of b-cell mass has been ascribed to increased apoptosis in T2DM (4). In patients with T2DM, b-cell mass can be up to 40-60% lower than in healthy control subjects (4-6). In addition, abnormal function of glucagon-producing a-cells leading to hyperglucagonemia is associated with T2DM (7). b-cell dedifferentiation and subsequent transition to other islet cell types were suggested as an alternative explanation for the loss of functional b-cell mass in mice (8,9). In this concept, b-cells lose insulin content and insulin secretory capacity followed by the production of other endocrine hormones such as glucagon (8). We recently showed (10) that loss of b-cell identity with the conversion of b-cells into glucagon-containing a-cells can occur in human pancreatic islets ex vivo.A number of transcription factors have been identified to be essential for the development and maintenance of functional b-cells (11,12). Recent reports (13,14) indicate that a selective loss of transcription factors MafA, Nkx6.1, and Pdx1 is associated with b-cell dysfunction and T2DM. Chronic hyperglycemia in rats is accompanied by the loss of b-cell transcription factors (15). Moreover, mouse b-cells that genetically lack FOXO1 can dedifferentiate in vivo under conditions of metabolic stress and subsequently can convert (or transdifferentiate) into glucagonproducing a-cells...

Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet–induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.

BackgroundProtein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.MethodsPancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.ResultsPrmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.ConclusionPRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

No abstract