Title:
Regulation of hepatic glucose production by central insulin action

Hiroshi Inoue, Professor
Brain/Liver Interface Medicine Research Center,
Kanazawa University

Abstract:
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(1). Cutting of the vagus nerve overrides the suppression of hepatic glucose production by central insulin action, which suggests the involvement of autonomic nerves in central insulin action in the liver(2). 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 IL-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(3). In animal models of obesity and insulin resistance, the central insulin action-mediated hepatic glucose production control mechanism is impaired in the liver(4). 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.

References:
1. Obici S, Zhang BB, Karkanias G, Rossetti L: Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376-1382, 2002

2. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L: Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026-1031, 2005

3. Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R, Notohara K, Katayose K, Okamura H, Kahn CR, Noda T, Takeda K, Akira S, Inui A, Kasuga M: Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab 3:267-275, 2006

4. Kimura K, Yamada T, Matsumoto M, Kido Y, Hosooka T, Asahara S, Matsuda T, Ota T, Watanabe H, Sai Y, Miyamoto K, Kaneko S, Kasuga M, Inoue H: Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and Deacetylation. Diabetes 61:61-73, 2012