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Profound sensitivity of the liver to the direct effect of insulin allows peripheral insulin delivery to normalize hepatic but not muscle glucose uptake in the healthy dog

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posted on 2022-10-24, 23:14 authored by Guillaume Kraft, Katie C. Coate, Marta Smith, Ben Farmer, Melanie Scott, Jon Hastings, Alan D. Cherrington, Dale S. Edgerton

Endogenous insulin secretion is a key regulator of postprandial hepatic glucose metabolism, but this process is dysregulated in diabetes. Subcutaneous insulin delivery alters normal insulin distribution, causing relative hepatic insulin deficiency and peripheral hyperinsulinemia, a major risk factor for metabolic disease. Our aim was to determine whether insulin’s direct effect on the liver is preeminent even when insulin is given into a peripheral vein. Postprandial-like conditions were created (hyperinsulinemia, hyperglycemia, and a positive portal vein to arterial glucose gradient) in healthy dogs. Peripheral (leg vein) insulin infusion elevated arterial and hepatic levels 8 and 2.8-fold, respectively. In one group, insulin’s full effects were allowed. In another, insulin’s indirect hepatic effects were blocked with the infusion of triglyceride, glucagon, and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids and glucagon, while blocking increased hypothalamic insulin signaling. Despite peripheral insulin delivery the liver retained its full ability to store glucose, even when insulin’s peripheral effects were blocked, whereas muscle glucose uptake markedly increased, creating an aberrant distribution of glucose disposal between liver and muscle. Thus, the healthy liver’s striking sensitivity to direct insulin action can overcome the effect of relative hepatic insulin deficiency, whereas excess insulin in the periphery produces metabolic abnormalities in non-hepatic tissues.

Funding

This work was funded by NIH R01DK018243. Hormone analysis was performed by Vanderbilt’s Hormone Assay and Analytical Services Core, supported by DK020593. Surgical and experimental expertise was provided by Vanderbilt’s Large Animal Core, supported by DK020593

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