Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive.
Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]-glucose infusion to measure endogenous glucose production and glucose disappearance. On two days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an iv insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by fMRI.
Glucose infusion rates had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean, but not in overweight persons. The increase in glucose infusion rates was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants.
By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese persons appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1380/-/DC1.
- © 2017 by the American Diabetes Association.