The normal action of insulin to promote glucose disposal varies over 600% in the population, with those individuals who are least sensitive to insulin having to mount sustained increased levels to maintain optimum serum glucose levels. Some of these individuals develop type 2 diabetes mellitus (DM2), but even those who do not develop DM2 are at increased risk for dyslipidemia, hypertension and atherosclerotic cardiovascular disease. While up to a third of the US population has this insulin resistance (IR) syndrome, our ability to identify individuals with (or at risk) for IR is extremely limited, and there are few treatment options for IR. Insulin sensitivity (IS) is largely determined at the genetic level, with heritability estimated at -50%. To aid in the search for genetic variation that underlies the extreme variance in IS, and the pathophysiology of IR, we are performing genome-wide association study of all individuals in the world phenotyped by insulin clamp measures of IS, through the Genetics of Insulin Sensitivity (GENESIS-2) consortium. Further insights into the cellular and molecular basis of IR could be gained through the study of metabolic and vascular cells from subjects with known insulin sensitivity and genetic architecture. Toward this end, we propose here to develop induced pluripotent cell (iPSC) lines from several hundred individuals of the GENESIS-2 cohort, as a sustainable resource for the production of metabolic and vascular cells in culture, the Genetics of Insulin Sensitivity iPSC (GENESiPS) study. We will develop methods for optimized differentiation of iPSC to the skeletal muscle (or adipose) and vascular endothelial cell lineages. The cellular phenotype of these cells will be investigated through whole genome transcriptome sequencing, as well as cell-based assays of insulin signaling and action. By combining the known human IS phenotype and whole genome variation with the differentiated cellular phenotypes at baseline and in response to insulin stimulation, we will undertake a systems biology approach to defining the cellular IR phenotype. These analyses will leverage novel network approaches that improve power, and provide added insights into the genes and pathways that may be targeted for the development of next generation insulin sensitizing therapies.
