Article

Hypothalamic K (ATP) channels control hepatic glucose production

Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nature (Impact Factor: 42.35). 05/2005; 434(7036):1026-31. DOI: 10.1038/nature03439
Source: PubMed

ABSTRACT Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis. The medial hypothalamus is a major integrator of nutritional and hormonal signals, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance and glucose metabolism. Here we show that activation of ATP-sensitive potassium (K(ATP)) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a K(ATP) blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the K(ATP) channel are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic K(ATP) channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.

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    • "Please cite this article in press as: Bedinger, D.H., Adams, S.H., Metabolic, anabolic, and mitogenic insulin responses: A tissue-specific perspective for insulin receptor activators, Molecular and Cellular Endocrinology (2015), http://dx.doi.org/10.1016/j.mce.2015.08.013 production (Pocai et al., 2005). Although there are some neurons that express insulin-sensitive Glut4 transporters, glucose uptake by most neurons is generally considered to be either insulinindependent or only indirectly regulated by insulin. "
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    • "In this sense, it is important to understand the link between the action of insulin and hepatic production of glucose (HGP), and here we have measured the glucose level directly into the hepatic vein, named as hepatic venous glucose concentration (HVGC), as a predictor of availability of glucose to the circulation provided by the liver. Besides it's peripheral action, there are evidences showing that the brain (more specifically, hypothalamus) is also sensitive to insulin (Baskin et al. 1983; Szabo et al. 1983; Obici et al. 2002; Gerozissis 2003; Pocai et al. 2005). It has been reported that intracarotid (ICA) injection of insulin may enter privileged sites within the CNS (such as the hypothalamus), and evoke a rapid decrease in HGP, resulting in a fall of the blood glucose concentration (Szabo and Szabo 1975). "
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    • "Insulin regulates glucose and lipid metabolism in target tissues, such as the liver and adipose tissue, both through direct effects mediated via the insulin receptors expressed in these tissues and indirectly by orchestrating organ crosstalk where brain insulin signaling plays a critical role. For example, insulin suppresses hepatic glucose production and lipolysis in adipose tissue via cell-autonomous effects and through signaling in the mediobasal hypothalamus (MBH) that alters parasympathetic and sympathetic outflow to these tissues, respectively (Pocai et al., 2005; Scherer et al., 2011). To initially test if BCAA metabolism is regulated through neuroendocrine mechanisms, we infused 2-deox- yglucose (2-DG) intracerebroventricularly (i.c.v.) to induce "
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