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: 41.46). 05/2005; 434(7036):1026-31. DOI: 10.1038/nature03439
Source: PubMed


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), 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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    ABSTRACT: Insulin acts as the major regulator of the fasting-to-fed metabolic transition by altering substrate metabolism, promoting energy storage, and helping activate protein synthesis. In addition to its glucoregulatory and other metabolic properties, insulin can also act as a growth factor. The metabolic and mitogenic responses to insulin are regulated by divergent post-receptor signaling mechanisms downstream from the activated insulin receptor (IR). However, the anabolic and growth-promoting properties of insulin require tissue-specific inter-relationships between the two pathways, and the nature and scope of insulin-regulated processes vary greatly across tissues. Understanding the nuances of this interplay between metabolic and growth-regulating properties of insulin would have important implications for development of novel insulin and IR modulator therapies that stimulate insulin receptor activation in both pathway- and tissue-specific manners. This review will provide a unique perspective focusing on the roles of "metabolic" and "mitogenic" actions of insulin signaling in various tissues, and how these networks should be considered when evaluating selective pharmacologic approaches to prevent or treat metabolic disease. Copyright © 2015. Published by Elsevier Ireland Ltd.
    No preview · Article · Aug 2015 · Molecular and Cellular Endocrinology
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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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    ABSTRACT: Glucose is the most important energy substrate for the maintenance of tissues function. The liver plays an essential role in the control of glucose production, since it is able to synthesize, store, and release glucose into the circulation under different situations. Hormones like insulin and catecholamines influence hepatic glucose production (HGP), but little is known about the role of the central actions of physiological doses of insulin in modulating HGP via the autonomic nervous system in nonanesthetized rats especially in SHR where we see a high degree of insulin resistance and metabolic dysfunction. Wistar and SHR received ICV injection of insulin (100 nU/μL) and hepatic venous glucose concentration (HVGC) was monitored for 30 min, as an indirect measure of HGP. At 10 min after insulin injection, HVGC decreased by 27% in Wistar rats, with a negligible change (3%) in SHR. Pretreatment with atropine totally blocked the reduction in HVGC, while pretreatment with propranolol and phentolamine induced a decrease of 8% in HVGC after ICV insulin injection in Wistar. Intracarotid infusion of insulin caused a significant increase in subdiaphragmatic vagus nerve (SVN) activity in Wistar (12 ± 2%), with negligible effects on the lumbar splanchnic sympathetic nerve (LSSN) activity (-6 ± 3%). No change was observed in SVN (-2 ± 2%) and LSSN activities (2 ± 3%) in SHR after ICA insulin infusion. Taken together, these results show, in nonanesthetized animals, the importance of the parasympathetic nervous system in controlling HVGC, and subdiaphragmatic nerve activity following central administration of insulin; a mechanism that is impaired in the SHR. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    Full-text · Article · May 2015
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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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    ABSTRACT: Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain a-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.
    Full-text · Article · Nov 2014 · Cell Metabolism
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