Editors' ChoiceMetabolism

Glucose and the brain: A new target in diabetes

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Science Translational Medicine  29 Apr 2020:
Vol. 12, Issue 541, eabb5677
DOI: 10.1126/scitranslmed.abb5677

Abstract

Central insulin-independent modulation of KATP channels by hyperglycemia decreases glucose production by the liver.

Glucose homeostasis involves a complex interplay between several organ systems. Hyperglycemia in diabetes mellitus is traditionally attributed to decreased insulin secretion by the pancreas coupled with lower insulin sensitivity in skeletal muscle and liver. The inability of insulin to suppress endogenous glucose production (EGP) by the liver contributes substantially to hyperglycemia. However, a large body of literature has shown that the central nervous system contributes to control of EGP. It is also known that hyperglycemia suppresses EGP independent of insulin, a phenomenon called glucose effectiveness. One of the mechanisms through which glucose effectiveness affects EGP involves central KATP channels, although the extent to which such channels control EGP is unknown.

Carey et al. sought to answer this question through parallel experiments in healthy humans and Sprague Dawley rats. The authors performed pancreatic clamps to induce euglycemic and hyperglycemic conditions in the humans and rodents by suppressing endogenous insulin and glucagon, both of which affect EGP. Insulin, glucagon, and growth hormone were then infused to mimic basal concentrations, and a variable glucose infusion was administered to create euglycemic and hyperglycemic conditions. In humans, the pancreatic clamp was performed after administration of either placebo or glyburide, an inhibitor of KATP channels, whereas in rodents, antagonism of glyburide was rescued by intracerebral infusion of the KATP agonist diazoxide. In both humans and rodents, hyperglycemia suppressed EGP by ~50% compared with euglycemia in the placebo groups. After inhibition of KATP channels by glyburide, the suppression of EGP by hyperglycemia was attenuated to 32% in humans and 25% in rodents. In rodents, rescue with intracerebral KATP agonist diazoxide restored the ability of hyperglycemia to suppress of EGP similar to that of placebo.

This study highlights important insulin independent pathophysiologic mechanisms in glucose homeostasis, specifically the complex of role of central KATP channels on glucose homeostasis. Further studies need to be performed in individuals with prediabetes and diabetes to understand whether hyperglycemia suppresses EGP through central KATP channels similarly as in healthy people. Nevertheless, results from this study suggest that selective central KATP agonists can be an exciting potential targeting strategy for the treatment of diabetes mellitus.

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