Although Munc18-1 was originally identified as a syntaxin1-interacting protein, the physiological significance of this interaction remains unclear. In fact, recent studies of Munc18-1 mutants have suggested that Munc18-1 plays a critical role for docking of secretory vesicles, independent of syntaxin1 regulation. Here we investigated the role of Munc18-1 in syntaxin1 localization by generating stable neuroendocrine cell lines in which Munc18-1 was strongly down-regulated. In these cells, the secretion capability, as well as the docking of dense-core vesicles, was significantly reduced. More importantly, not only was the expression level of syntaxin1 reduced, but the localization of syntaxin1 at the plasma membrane was also severely perturbed. The mislocalized syntaxin1 resided primarily in the perinuclear region of the cells, in which it was highly colocalized with Secretogranin II, a marker protein for dense-core vesicles. In contrast, the expression level and the plasma membrane localization of SNAP-25 were not affected. Furthermore, the syntaxin1 localization and the secretion capability were restored upon transfection-mediated reintroduction of Munc18-1. Our results indicate that endogenous Munc18-1 plays a critical role for the plasma membrane localization of syntaxin1 in neuroendocrine cells and therefore necessitates the interpretation of Munc18-1 mutant phenotypes to be in terms of mislocalized syntaxin1.
Type 2 diabetes is characterized by impaired insulin secretion from pancreatic b-cells and/ or reduced response of target tissues to insulin. Good glycemic control delays the development and slows the progression of micro-and macrovascular complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of type 2 diabetic patients achieve glycemic control, and undesirable side-effects often hamper treatment in those treated with the medications. There is a need for novel treatment options that can help overcome these difficulties. Sodium glucose cotransporter 2 (SGLT2) inhibitors have recently been developed as a novel potential therapeutic option for the treatment of type 2 diabetes. These drugs lower the plasma glucose concentration through inhibition of glucose reuptake in the kidney, independent of insulin secretion and insulin action, with a consequent lower risk of hypoglycemia. The data of clinical trials with monotherapy as well as combination therapy show that SGLT2 inhibitors have a blood glucose-lowering effect and also reduce bodyweight. A follow-up study shows long-term efficacy and the durability of these effects. SGLT2 inhibitors have the potential to reverse glucose toxicity, and to improve insulin resistance, blood pressure and lipid profile. The available data suggest a good tolerability profile. However, clinicians should carefully prescribe these drugs in light of already reported and/or unexpected side-effects. Further studies in larger numbers and longer-term clinical use data are required to place these agents in standard treatment of type 2 diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.