Activation of KATP channels suppresses glucose production in humans
Preeti Kishore, … , Gary J. Schwartz, Meredith Hawkins
Preeti Kishore, … , Gary J. Schwartz, Meredith Hawkins
Published November 7, 2011
Citation Information: J Clin Invest. 2011;121(12):4916-4920. https://doi.org/10.1172/JCI58035.
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Brief Report

Activation of KATP channels suppresses glucose production in humans

Abstract

Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (KATP) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the KATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the KATP channel blocker glibenclamide. These results suggest that activation of hypothalamic KATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.

Authors

Preeti Kishore, Laura Boucai, Kehao Zhang, Weijie Li, Sudha Koppaka, Sylvia Kehlenbrink, Anna Schiwek, Yonah B. Esterson, Deeksha Mehta, Samar Bursheh, Ya Su, Roger Gutierrez-Juarez, Radhika Muzumdar, Gary J. Schwartz, Meredith Hawkins

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Figure 2

Effects of KATP channel activation on EGP in rodents.

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Effects of KATP channel activation on EGP in rodents. (A) Protocol s...
(A) Protocol scheme for rat clamp studies. (B) Outline of rationale for oral/i.c.v. studies. Experimental design was as follows: oral diazoxide was administered under pancreatic clamp conditions to examine its effects on EGP and gluconeogenic enzymes (PEPCK and G6Pase). Glibenclamide was administered i.c.v. to block hypothalamic KATP channels, thereby determining whether oral diazoxide exerts its effects centrally. PEP, phosphoenolpyruvate, a gluconeogenic substrate. (C) EGP during the preclamp phase (60–120 minutes) and final hour of the study (180–240 minutes). D+G, diazoxide plus glibenclamide; S+G, saline plus glibenclamide. *P = 0.001 for saline versus diazoxide. (D) Hepatic p-STAT3. G+S, glibenclamide plus saline. *P = 0.004 for saline versus diazoxide. Data represent mean ± SEM.