Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

Abstract

In the past few years, insulin action in the central nervous system (CNS) has attracted a growing interest to better understand the association between neurodegenerative diseases and insulin resistance (IR). Rodent studies have indicated that insulin signaling in the CNS is critical for the suppression of endogenous glucose production (EGP) in the liver (1) and for the regulation of adipose tissue lipolysis (2). These central insulin effects likely depend on PI3K-mediated regulation of several proteins and transcription factors, among which are FoxO1 (3) and AMPK (4), and on the activation of K ATP channels (5) in the hypothalamus (Fig. 1). Recent findings show that subsequent activation of hepatic Kupffer cells and an increase in hepatic interleukin-6 induce signal transducer and activator of transcription 3 (STAT3) phosphorylation to inhibit gluconeogenic gene expression (6). Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7).In humans, intranasal insulin (IN) application has been established as one approach to noninvasively examine brain insulin action in vivo. The IN spray application transiently increases the insulin concentration in liquor (8), likely due to bulk flow within the perivascular space of cerebral blood vessels (9). Using this technique, evidence for the central insulin regulation of systemic lipolysis (10), modulation of liver fat content and hepatic energy metabolism (11), and improvement in whole-body insulin sensitivity (12) has been provided. Interestingly, effects of IN on EGP seem to depend on the experimental conditions with no changes in the fasting state (11) but with reduction during pancreatic clamps (13). Modulation of energy-demanding processes might contribute to the rise in hepatic energy status after IN application. Of note, central insulin regulation of peripheral insulin sensitivity and hepatic energy metabolism was blunted in obese humans and patients with type 2 diabetes (11,12), suggesting that the presence of a combined central and peripheral IR and a dysregulation of a brain-liver cross talk in type 2 diabetes. Nevertheless, IN may have some limitations resulting from variable cerebral insulin delivery and/or peripheral insulin spillover.Another approach to mimic brain insulin action in humans is the administration of the K ATP -channel opener and sulfonylurea drug diazoxide. Dr. Hawkins' group showed that diazoxide treatment can suppress EGP in lean healthy humans, and complementary studies in rodents revealed increased hepatic STAT3 phosphorylation along with reduced hepatic gluconeogenic protein levels (14). The same group now presents a carefully planned and nicely performed follow-up study investigating the effects of diazoxide on EGP in patients with type 2 diabetes. Esterson et al. (15) combined diazoxide admini...

L1-79 and the Role of Catecholamines in Autism

“…Eating, satiety and similar energy mediated events in the brain are known to be modulated by the sympathetic nervous system, predominantly by dopaminergic systems [170]. Sympathetic afferents from the hypothalamus and other central site, under the control of various agents such as catecholamines and leptin are known to regulate glucose synthesis, insulin sensitivity and similar events (reviewed in [171][172][173][174]). Severing the autonomic projections to the islets of Langerhans resulted in a 75-90% impairment in the ability to regulate serum glucose in response to insulin induced hypoglycemia [175].…”