CONICET | Buscador de Institutos y Recursos Humanos

VMP1, a key regulator of disease induced autophagy,is involved in type 2 diabetes. Diabetes mellitus (DM) is the most prevalent human endocrinedisease, and it results from loss and/or dysfunction of insulin-secreting betacells in pancreatic islets. Type 2 DM is the most common form of the disease.It results from a progressive decline of beta cell function in the context ofinsulin resistance. Patients with type 2 DM have insulin resistance andrelative, rather than absolute, insulin deficiency. There is ample evidencethat type 2 diabetes has a strong genetic basis. The description of SingleNucletoide Polymorphisms (SNPs) in genes were characterized in type 2 DMpatients, defining genetic susceptibility to the disease. Moreover, there is aclose relationship between type 2 DM and pancreatic cancer. Autophagy has beenproposed to participate in the control of insulin content insecretory-deficient pancreas beta cells. We have discovered and characterizedthe essential mammalian autophagy-related protein VMP1 as a trans-membraneprotein which expression triggers the formation of autophagosomes. VMP1 is notconstitutively expressed in pancreas but it is highly activated in acinar cellsundergoing a selective type of autophagy of secretory granules -zymophagy-during acute pancreatitis. Here we show that diabetes induces VMP1 expressionin pancreas beta cells as early cellular events during experimental diabetes.We also demonstrate that VMP1 mediated autophagy is activated in pancreasislets as a direct response to experimental diabetes. Moreover, we perform aclinical study searching for VMP1 SNPs in type 2 DM patients in order todetermine if VMP1 polymorphisms are able to define genetic susceptibility tothis morbid metabolic disease. We analyzed exons 6,7,8,9 and 12 which conformthe hydrophilic region of this transmembrane gene (total 12 exons). We foundthe presence of a coding nonsynonymous missense SNP in exon 7 in 82% ofpatients presenting type 2 DM, comparing with 34% for control patients. Wecloned the human VMP1 cDNA gene into a lentiviral vector system. The sameconstructs were used to obtain the SNP-hVMP1 (A234G), by site directedmutagenesis. We analyzed hVMP1A234G functionality in autophagy using INS-1cells, an insulin-secreting beta cell line that retains normal regulation ofinsulin secretion. We found that hVMP1A234G expression impairs autophagosomeformation in pancreatic beta cells. Therefore, a polymorphism of VMP1 isinvolved in type 2 DM susceptibility and impairs autophagosome formation. Alltogether, our data suggest that the autophagy-related transmembrane protein VMP1is involved in type 2 DM pathophysiology.