Acute increases in plasma levels of long-chain fatty acids raise plasma insulin levels by stimulating insulin secretion or by decreasing insulin clearance. In normal subjects, longterm elevations of fatty acids also stimulate insulin secretion. In fact, they increase insulin precisely to the degree needed to compensate for the fatty acid-induced insulin resistance. In contrast, in individuals who are genetically predisposed to develop type 2 diabetes (prediabetic subjects), the free fatty acid (FFA) stimulation of insulin secretion is not sufficient to fully compensate for the FFAinduced insulin resistance. Therefore, obesity, if associated with elevated fatty acid levels, may lead to hyperglycemia in prediabetic but not in normal individuals.