Hypothalamic KATP channels control hepatic glucose production

Abstract

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.

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Figure 1: Activation of hypothalamic KATP channels lowers plasma glucose by inhibiting glucose production.
Figure 2: Role of SUR1 and efferent vagus in hepatic insulin action.
Figure 3: Hepatic vagus and activation of hypothalamic KATP channels are required for the effect of physiological hyperinsulinaemia on glucose production.

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Acknowledgements

We wish to thank B. Liu, S. Gaweda and C. Baveghems for expert technical assistance. This work was supported by the NIH, ADA and the Skirball Foundation.

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Correspondence to Luciano Rossetti.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figures S1-S3

Supplementary Figure S1 shows that the activation of hypothalamic KATP channels lowers plasma glucose through inhibition of GP. Supplementary Figure S2 details the expression of SUR mRNA within the hypothalamus and effect of ICV insulin on glucose kinetics. Supplementary Figure S3 demonstrates that the hepatic vagus and activation of hypothalamic KATP channels are required for the effect of physiological hyperinsulinemia on GP. (PDF 1006 kb)

Supplementary Figure Legends

This file contains Supplementary Figure Legends for Supplementary Figures S1-S3. (DOC 27 kb)

Supplementary Tables S1-S8

This file contain the Supplementary Tables with metabolic parameters before and during the clamp and the specific activities of substrates used to calculate the hepatic glucose fluxes. (DOC 124 kb)

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Pocai, A., Lam, T., Gutierrez-Juarez, R. et al. Hypothalamic KATP channels control hepatic glucose production. Nature 434, 1026–1031 (2005). https://doi.org/10.1038/nature03439

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