Nykjær, Anders

Abstract Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

BackgroundEfforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life‐threatening seizures. Although previous studies ofAWand relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.MethodsWe conducted a genome‐wide association study ofAWsymptom count in uniformly assessed subjects with histories of seriousAW, followed by additional genotyping in independentAWsubjects.ResultsThe top association signal forAWseverity was in sortilin family neurotrophin receptor geneSORCS2on chromosome 4 (European American meta‐analysisn = 1,478,p = 4.3 × 10−9). There were no genome‐wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high‐throughput transcriptomic and epigenomic data sets, showing that in humansSORCS2is most highly expressed in the nervous system. The identifiedSORCS2risk haplotype is predicted to disrupt a stress hormone‐modulated regulatory element that has tissue‐specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels andSORCS2expression, and show thatSORCS2levels in culture are increased upon ethanol exposure and withdrawal.ConclusionsTaken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.