Is Brain Insulin Action Relevant to the Control of Plasma Glucose in Humans?

The notion that central nervous system (CNS) insulin action plays an important role in mediating the inhibition of endogenous glucose production (EGP) is becoming increasingly accepted (1–5). In the rodent, insulin’s effect in the brain involves transport of insulin across the blood–brain barrier, activation of insulin signaling, opening of neuronal ATP-sensitive potassium (KATP) channels, signaling via vagal hepatic efferents, phosphorylation of liver STAT3, and suppression of gluconeogenic gene expression, with subsequent reduction of EGP due to inhibition of gluconeogenesis but not glycogenolysis (6–10). The effect was relatively slow in onset (requiring several hours to appear) and was evident under nonphysiological circumstances because infusion of insulin into a peripheral vein results in absolute or relative hepatic insulin deficiency (Fig. 1) (11,12). In addition, glucagon was not replaced, raising the possibility that insulin’s brain–liver effect is only manifest when the liver is deprived of other normal regulatory inputs. Despite such limitations, these studies have led some to conclude that brain insulin action is “required,” “necessary,” or even “essential” for the suppression of EGP by insulin (2,5,7–10).Figure 1 In the basal state, arterial and hepatic portal vein insulin concentrations are approximately 10 and 30 µU/mL, respectively, such that the concentration of insulin in blood entering the hepatic sinusoids is ∼25 µU/mL. A threefold increase in basal insulin secretion or portal vein insulin infusion ( A ) increases both arterial (brain) and liver insulin concentrations by threefold. When insulin is acutely elevated in this way, insulin’s direct hepatic effect drives the rapid suppression of EGP, and the CNS effects of insulin on the liver are masked. In response to a threefold rise in insulin brought about by infusion into a peripheral vein ( B ), arterial (brain) insulin concentrations are also elevated threefold, but in …