LEP and hyperinsulinism: Insufficient leptin signaling in the hypothalamus, which is caused by either decreased availability of leptin for transport to the hypothalamus (in the case of leptinopenia), or restricted leptin entry across the BBB (imposed by hyperleptinemia in obese subjects), is primarily responsible for inducing hyperglycemia and hyperinsulinemia; the persistence of these pathophysiologic sequelae culminates in diabetes mellitus (Kalra, 2011; Figure 2).