Letters to Nature

Nature 434, 1026-1031 (21 April 2005) | doi:10.1038/nature03439; Received 22 November 2004; Accepted 19 February 2005

Hypothalamic KATP channels control hepatic glucose production

Alessandro Pocai1, Tony K. T. Lam1, Roger Gutierrez-Juarez1, Silvana Obici1, Gary J. Schwartz1, Joseph Bryan2, Lydia Aguilar-Bryan2 & Luciano Rossetti1

  1. Departments of Medicine, Neuroscience and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
  2. Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA

Correspondence to: Luciano Rossetti1 Correspondence and requests for materials should be addressed to L.R. (Email: rossetti@aecom.yu.edu).

Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus1, 2. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis3. The medial hypothalamus is a major integrator of nutritional and hormonal signals1, 2, 4, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output5, 6. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance7, 8, 9, 10 and glucose metabolism5. Here we show that activation of ATP-sensitive potassium (KATP) channels11 in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a KATP 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 KATP channel12 are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic KATP channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.