Gelling et al. has shown that central infusion of PI3K inhibitor attenuated insulin-induced glucose lowering by 35%–40% in both acute and chronic insulin treatment paradigms, while hypothalamic overexpression of either IRS-2, a upstream kinase of PI3K, or protein kinase B (PKB/Akt), a key downstream mediator of PI3K action, enhanced the glycemic response to insulin by 2 folds in STZ-induced diabetic rats, suggesting that hypothalamic insulin signaling is an important determinant of the response to insulin in the management of uncontrolled diabetes [115]. This evidence concerns the gene INS and diabetes mellitus.