REGULATION OF GLUCOSE METABOLISM BY CENTRAL INSULIN ACTION

Insulin has been known to act on the hypothalamus, in particular the arcuate nucleus, in the central nervous system. Such central insulin action is not only involved in the regulation of energy metabolism via the regulation of food intake and heat production, but also plays an important role in glucose metabolism by regulating hepatic glucose production and glucose uptake by skeletal muscles. Studies on the intracerebroventricular administration of PI-3K inhibitors or sulfonylureas have demonstrated that hyperpolarization of agouti-related protein neurons induced by the activation of PI-3K signaling/KATP channels in the hypothalamic arcuate nucleus plays an important role in the suppression of hepatic glucose production mediated by central insulin action. Cutting of the vagus nerve overrides the suppression of hepatic glucose production by intracerebroventricular insulin administration, which suggests the involvement of autonomic nerves in central insulin action in the liver. The central insulin action-mediated suppression of hepatic glucose production is associated with decreased gene expression of enzymes involved in hepatic gluconeogenesis, and both increased interleukin-6 expression in hepatic non-parenchymal cells induced by central insulin action and associated activation of hepatic STAT3 play an important role in the suppression of gene expression of hepatic gluconeogenesis-related enzymes. In animal models of obesity and insulin resistance, the central insulin action-mediated hepatic glucose production control mechanism is impaired in both the hypothalamus and liver. Increased hepatic gluconeogenesis in obesity and type-2 diabetes has been attributed to impaired hepatic insulin signaling and increased expression of enzymes involved in hepatic gluconeogenesis due to hyperglycemia, but may also be partially attributed to the impairment of the central insulin action-mediated suppression of hepatic gluconeogenesis. Biomedical Reviews 2011; 22: 31-39.