Figure 3. Plausible pathways whereby nutrient-induced hyperinsulinemia is the initiating response to high fat diet feeding and obesity to cause insulin resistance, hyperglycemia and hyperlipidemia.

High fat diets and overfeeding, either directly or indirectly through gut secretions, cause increased insulin release from islet beta cells and primary hyperinsulinemia. Insulin increases muscle glycolysis and lactate formation, which is released to the circulation as a substrate to increase gluconeogenesis in liver. The hyperinsulinemia also activates hepatic lipogenesis and increased secretion of VLDL, causing hyperlipidemia. In the adipose tissue, hyperinsulinemia activates an inflammatory response, which through cytokine action on adipocytes compromises their lipogenic capacity and increases lipolysis. Fatty acid flow (from overnutrition and decreased lipid storage and increased lipolysis in adipocytes) to the liver promotes gluconeogenesis through metabolic allosteric regulation.