INSR and Insulin resistance: Mechanisms underlying the contribution of IRS-1 and/or -2 variants to insulin resistance include [37] (Figure 3): i) altering IRS-1 and/or-2 expression and function, ii) reduced IRS-1 and/or -2 binding to the insulin receptor, iii) a defect in binding of IRS-1 and/or -2 variant (s) to the p85 regulatory subunit of the PI3-kinase and a decrease in PI3-kinase activity.