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Hypothalamic insulin signaling is required for inhibition of glucose production


Circulating insulin inhibits endogenous glucose production. Here we report that bidirectional changes in hypothalamic insulin signaling affect glucose production. The infusion of either insulin or a small-molecule insulin mimetic in the third cerebral ventricle suppressed glucose production independent of circulating levels of insulin and of other glucoregulatory hormones. Conversely, central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. Finally, third-cerebral-ventricle administration of inhibitors of ATP-sensitive potassium channels, but not of antagonists of the central melanocortin receptors, also blunted the effect of hyperinsulinemia on glucose production. These results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.

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This work was supported by grants from the National Institutes of Health (to L.R., DK 48321 and DK 45024) and the AECOM Diabetes Research & Training Center (DK 20541). S.O. was the recipient of a post-doctoral fellowship and a Junior Faculty Award from the American Diabetes Association.

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Competing interests

B.B.Z. is employed by the Merck Research Laboratories, and Cpd1 was originally reported by their group. L.R. has a consultation agreement (in unrelated areas) with Merck Research Laboratories.

Correspondence to Luciano Rossetti.

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Figure 1: Effect of ICV administration of insulin and insulin mimetic on glucose uptake and production.
Figure 2: Antagonism of hypothalamic insulin action in the presence of peripheral hyperinsulinemia.
Figure 3: Effect of ICV administration of insulin antagonists on peripheral and hepatic insulin action.
Figure 4: Effect of hypothalamic KATP channels or melanocortin receptors blockade on peripheral and hepatic insulin action.