Soluble SorCS1 binds the insulin receptor to enhance insulin sensitivity

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.

[1]  T. Hansen,et al.  ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations , 2019, Diabetes.

[2]  B. Janssen,et al.  Structural insights into SorCS2–Nerve Growth Factor complex formation , 2018, Nature Communications.

[3]  Torsten Schwede,et al.  SWISS-MODEL: homology modelling of protein structures and complexes , 2018, Nucleic Acids Res..

[4]  S. Thirup,et al.  Hidden Twins: SorCS Neuroreceptors Form Stable Dimers. , 2017, Journal of molecular biology.

[5]  J. Nyengaard,et al.  SorCS2 is required for BDNF-dependent plasticity in the hippocampus , 2016, Molecular Psychiatry.

[6]  Dietmar Kuhl,et al.  SorCS1 variants and amyloid precursor protein (APP) are co‐transported in neurons but only SorCS1c modulates anterograde APP transport , 2015, Journal of neurochemistry.

[7]  J. Yates,et al.  The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors , 2015, Neuron.

[8]  M. Nielsen,et al.  Sortilin, Encoded by the Cardiovascular Risk Gene SORT1, and Its Suggested Functions in Cardiovascular Disease , 2015, Current Atherosclerosis Reports.

[9]  E. Falk,et al.  Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis. , 2014, The Journal of clinical investigation.

[10]  K. Eliceiri,et al.  SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells. , 2014, The Journal of clinical investigation.

[11]  M. Blagosklonny.  TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists , 2013, Cell Death and Disease.

[12]  P. Nordlund,et al.  Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay , 2013, Science.

[13]  B. Su,et al.  mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. , 2012, Molecular cell.

[14]  Zhuyuan Fang,et al.  Sortilin‐related VPS10 domain containing receptor 1 and Alzheimer's disease‐associated allelic variations preferentially exist in female or type 2 diabetes mellitus patients in southern Han Chinese , 2012, Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society.

[15]  T. Willnow,et al.  Sortilins: new players in lipoprotein metabolism , 2011, Current opinion in lipidology.

[16]  P. Madsen,et al.  Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. , 2010, Cell metabolism.

[17]  Gregory J Morton,et al.  Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice , 2010, Disease Models & Mechanisms.

[18]  Angelo J. Canty,et al.  A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose , 2009, Diabetes.

[19]  T. Willnow,et al.  VPS10P-domain receptors — regulators of neuronal viability and function , 2008, Nature Reviews Neuroscience.

[20]  A. Amon,et al.  Emerging roles for centromeres in meiosis I chromosome segregation , 2008, Nature Reviews Genetics.

[21]  R. Dankner,et al.  Insulin Resistance and Hyperinsulinemia , 2008, Diabetes Care.

[22]  Yu Li,et al.  Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance , 2007, Proceedings of the National Academy of Sciences.

[23]  B. Yandell,et al.  SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse , 2007, Diabetes.

[24]  T. Kerppola,et al.  Design and implementation of bimolecular fluorescence complementation (BiFC) assays for the visualization of protein interactions in living cells , 2006, Nature Protocols.

[25]  H. Luthman,et al.  High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals <800 kb in the Species-Conserved Niddm1i of the GK Rat , 2006, Genetics.

[26]  Philipp W. Raess,et al.  Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus , 2006, Nature Genetics.

[27]  J. Gliemann,et al.  Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members. , 2006, The Biochemical journal.

[28]  P. Madsen,et al.  Characterization of sorCS1, an Alternatively Spliced Receptor with Completely Different Cytoplasmic Domains That Mediate Different Trafficking in Cells* , 2003, The Journal of Biological Chemistry.

[29]  S. Frost,et al.  Effect of Alternative Glycosylation on Insulin Receptor Processing* , 1999, The Journal of Biological Chemistry.

[30]  K Nakayama,et al.  Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. , 1997, The Biochemical journal.

[31]  A. Krolewski,et al.  Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. , 1990, Annals of internal medicine.

[32]  E. Aikawa,et al.  Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. , 2018, Arteriosclerosis, thrombosis, and vascular biology.

[33]  C. Kahn,et al.  Insulin receptor signaling in normal and insulin-resistant states. , 2014, Cold Spring Harbor perspectives in biology.

[34]  J. Nyengaard,et al.  Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling , 2011, Nature Neuroscience.