Insulin has many energy modulating actions that take place in the hypothalamus, such as inhibition of feeding. The investigators studied the effects of infusing insulin, an insulin mimetic, and inhibitors of insulin action.  Infusion was done in the intra-third cerebral ventricle (ICV). Hepatic glucose production and peripheral glucose consumption were determined. Steady state of serum insulin concentrations were achieved by using systemic pancreatic-insulin clamps.

ICV infusion of insulin/insulin mimetic at basal insulin concentrations led to a 7-fold increase in glucose infusion rate to maintain euglycemia.  Thus, ICV glucose enhanced peripheral insulin action.  Employing radiolabeled glucose and kinetic glucose studies, the investigators demonstrated that ICV insulin decreased the rate of hepatic glucose production by 40+% while not altering peripheral glucose consumption.  Inhibition of insulin action in the hypothalamus by co-infusion of insulin antibodies or an antisense disrupter of insulin receptor synthesis antagonized the effect of insulin on glucose production.  Further studies demonstrated that the intracellular mechanism(s) through which hypothalamic insulin exerted its effect on glucose production involved the phosphoinositide-3-kinase signal transduction pathway and ATP sensitive potassium channels.  However, the manner in which hypothalamic insulin impaired hepatic glucose production was not identified by these studies.  The authors suggest that hypothalamic insulin (as well as other factors such as leptin and melanocortins) may monitor and modulate exogenous energy intake relative to endogenous energy consumption.  Failure of hypothalamic insulin function may lead to peripheral insulin resistance and may be a factor in the pathogenesis of the dysmetabolic syndrome and type 2 diabetes mellitus.

Obici S, et al.  Nature Med 2002;8:1376-1382.

Editor’s Comment: The physiological importance of insulin action within the central nervous system is well described in the content of this manuscript.  The demonstrations reported open yet another site at which a metabolic error may lead to clinical illness.  It is crucial to determine the specific mechanisms by which the hypothalamic action of insulin is recognized at the hepatic level and to develop a method(s) by which one may assess hypothalamic insulin function in the intact human.

Allen W. Root, MD