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 balance 7-10 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 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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1026-1031 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 434 |
| Issue number | 7036 |
| DOIs | |
| State | Published - Apr 21 2005 |
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Cite this
Hypothalamic KATP channels control hepatic glucose production. / Pocal, Alessandro; Lam, Tony K T; Gutierrez-Juarez, Roger; Obici, Silvana; Schwartz, Gary J.; Bryan, Joseph; Aguilar-Bryan, Lydia; Rossetti, Luciano.
In: Nature, Vol. 434, No. 7036, 21.04.2005, p. 1026-1031.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hypothalamic KATP channels control hepatic glucose production
AU - Pocal, Alessandro
AU - Lam, Tony K T
AU - Gutierrez-Juarez, Roger
AU - Obici, Silvana
AU - Schwartz, Gary J.
AU - Bryan, Joseph
AU - Aguilar-Bryan, Lydia
AU - Rossetti, Luciano
PY - 2005/4/21
Y1 - 2005/4/21
N2 - 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 balance 7-10 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 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 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.
AB - 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 balance 7-10 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 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 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.
UR - http://www.scopus.com/inward/record.url?scp=17844379717&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=17844379717&partnerID=8YFLogxK
U2 - 10.1038/nature03439
DO - 10.1038/nature03439
M3 - Article
C2 - 15846348
AN - SCOPUS:17844379717
VL - 434
SP - 1026
EP - 1031
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7036
ER -