INS and hyperinsulinism: Hyperinsulinemia may aggravate systemic insulin resistance through activation of the negative feedback loop of the insulin receptor signaling pathway in insulin target cells, which involves suppression of insulin receptor substrate (IRS) activity by serine kinases including protein kinase B (Akt)/mTOR/S6 kinase (S6K) [9, 27, 42] and inhibition of GLUT4 [9].