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Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery
Dale S. Edgerton, … , Erica Nishimura, Alan D. Cherrington
Dale S. Edgerton, … , Erica Nishimura, Alan D. Cherrington
Published February 26, 2019
Citation Information: JCI Insight. 2019;4(7):e126974. https://doi.org/10.1172/jci.insight.126974.
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Research Article Endocrinology Metabolism

Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery

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Abstract

Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects that include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle glucose metabolism that occur when insulin is delivered via a peripheral vein compared to when it is given through its endogenous secretory route (the hepatic portal vein) in overnight-fasted conscious dogs. The second aim was to determine if peripheral delivery of a hepato-preferential insulin analog could restore the physiologic response to insulin that occurs under meal-feeding conditions. This study is the first to our knowledge to show that hepatic glucose uptake correlates with insulin’s direct effects on the liver under hyperinsulinemic-hyperglycemic conditions. In addition, glucose uptake was equally divided between the liver and muscle when insulin was infused into the portal vein, but when it was delivered into a peripheral vein the percentage of glucose taken up by muscle was 4-fold greater than that going to the liver, with liver glucose uptake being less than half of normal. These defects could not be corrected by adjusting the dose of peripheral insulin. On the other hand, hepatic and nonhepatic glucose metabolism could be fully normalized by a hepato-preferential insulin analog.

Authors

Dale S. Edgerton, Melanie Scott, Ben Farmer, Phillip E. Williams, Peter Madsen, Thomas Kjeldsen, Christian L. Brand, Christian Fledelius, Erica Nishimura, Alan D. Cherrington

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Figure 5

Metabolite parameters.

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Metabolite parameters.
(A) Arterial plasma free fatty acid levels, (B) n...
(A) Arterial plasma free fatty acid levels, (B) net hepatic free fatty acid uptake, (C) arterial blood glycerol levels, (D) net hepatic glycerol uptake, (E) arterial blood lactate levels, (F) net hepatic lactate balance during the basal (–30 to 0 minutes) and experimental periods (0–180 minutes), and (G) net hepatic carbon retention during the last 2 hours of the experimental period in the portal vein insulin (PoHI), peripheral vein insulin (PeHI), peripheral vein insulin half dose (PeHI-half), and peripheral vein insulin-327 (Pe327) infusion groups (mean ± SEM; n = 5, 5, 5, and 7, respectively; *P < 0.05 vs. PoHI) in overnight-fasted conscious dogs. (H) Linear regression of endogenous glucose production versus arterial plasma free fatty acids during the experimental period (the coefficients of determination were r2 = 0.052 for portal human insulin [P = 0.71], r2 = 0.267 for peripheral human insulin [P = 0.13], and r2 = 0.264 for peripheral insulin-327 [P = 0.24]).

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