Hypothalamic KATP channels control hepatic glucose production
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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Effects of central insulin are blocked by PI3K inhibitor and require activation of KATP channels.
“these effects of insulin are blocked by infusion of the PI3K inhibitor and also appear to require activation of KATP channels (135, 145).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [145]
Accumulating evidence suggests that leptin, insulin, and nutrient-related signals in the CNS improve hepatic insulin sensitivity.
“Although accumulating evidence suggests that leptin (10 -13), insulin (14,15), and nutrient-related signals (16 -18) in the CNS improve hepatic insulin sensitivity”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [15]
Insulin action in the brain of nondiabetic animals lowers ambient glycemia by increasing hepatic insulin sensitivity.
“Several lines of evidence suggest that like leptin, insulin action in the brain of nondiabetic animals lowers ambient glycemia by increasing hepatic insulin sensitivity (14,15).”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [15]
Central nervous insulin signalling contributes to peripheral energy and glucose homeostasis, growth and neuronal plasticity.
“central nervous insulin signalling contributes to functions as diverse as peripheral energy and glucose homeostasis, 6,7 growth 8 and neuronal plasticity.9”
From Intranasal insulin (2021) · cites this paper as [7]
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- Authors
- Pocai, A., Lam, T. K. T., Gutierrez-Juarez, R., Obici, S., Schwartz, G. J., Bryan, J., Aguilar-Bryan, L., & Rossetti, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Baylor College of Medicine (US)
- Corresponding author
- Rossetti, Luciano
- Venue
- Nature
- Published
- 2005-04
- Volume
- 434
- Issue
- 7036
- Pages
- 1026-1031
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2089541211
- Cited by
- 645
- References
- 30
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 22 · 2023: 16 · 2022: 20 · 2021: 23 · 2020: 21 · 2019: 32 · 2018: 23 · 2017: 34 · 2016: 30 · 2015: 31 · 2014: 35 · 2013: 33 · 2012: 41
- FWCI
- 41.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Skirball Foundation
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- hepatic gluconeogenesis, hepatic glucose production, mediobasal hypothalamus, insulin signaling, vagus nerve, hyperglycemia, type 2 diabetes, energy balance, axon competition, neural circuit development
- MeSH terms
- Adenosine Triphosphate, Animals, Diabetes Mellitus, Type 2, Gluconeogenesis, Glucose, Hyperinsulinism, Hypothalamus, Insulin, Liver, Male, Receptors, Drug, RNA, Messenger, Vagus Nerve, Potassium Channels, Rats, Sprague-Dawley, ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, ATP-Binding Cassette, Sub-Family C Proteins, Mice, Rats, Sulfonylurea Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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