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 (K ATP ) 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 K ATP 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 K ATP channel blocker glibenclamide. These results suggest that activation of hypothalamic K ATP 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.

Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology

“…Furthermore, in humans, oral diazoxide, a KATP channel activator, decreases HGP, likely via KATP channel activation in the brain, consistent with the fact that, in rodents, central blockade of the KATP channel abolishes the effect of oral diazoxide (Kishore et al, 2011). Additionally, in type 1 diabetics, 6 months of diazoxide treatment improves metabolic control independent of changes in insulin production, possibly due to the aforementioned mechanism (Radtke et al, 2010), while intranasal insulin delivery reduces HGP in healthy men (Dash et al, 2015).…”

Deep Brain Stimulation of the Subthalamic Nucleus Regulates Postabsorptive Glucose Metabolism in Patients With Parkinson's Disease

“…The regulation of EGP by a central pathway in humans remains unclear. Recently human study showed that diazoxide, an oral ATP-sensitive potassium channel activator, decreased EGP in human independently of pancreatic hormone secretion (11). From the results of the present study, it is anticipated that modifications in the regional activity of the hypothalamic neurons induced by STN-DBS in humans might affect peripheral glucose metabolism via vagal efferent fibers because no change in hormones like insulin or glucagon was detected.…”

Impaired insulin action in the human brain: causes and metabolic consequences

“…88,89 The first hint that the human brain contributes to the control of peripheral metabolism was provided by a study assessing the effect of a pharmacologic K ATP channel opener on endogenous glucose production. 90 Experiments in rodents had already shown that acti vation of this channel in the hypothalamus decreased hepatic gluconeogenesis. Concordantly, oral administra tion of this drug reduced endogenous glucose production in humans during a hyperinsulinaemic glucose clamp.…”

“…Concordantly, oral administra tion of this drug reduced endogenous glucose production in humans during a hyperinsulinaemic glucose clamp. 90 The first human study to specifically address the effects of insulin in the brain in this regard compared plasma levels of glucose and insulin before and after intranasal insulin administration in >100 healthy participants. 25 These measurements were used to make a rough estimate of peripheral insulin resistance, namely, insulin resis tance as defined by HOMA.…”