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). As in the rodent, the canine brain–liver insulin axis has been shown to involve CNS insulin signaling and KATP channel activation, a neurally mediated increase in hepatic STAT3 phosphorylation, and changes in glucoregulatory gene expression in the liver (13,14). In one study, a selective increase in brain insulin, brought about by insulin infusion into the carotid and vertebral arteries at a rate that raised insulin in the head but maintained basal insulin levels at the liver, decreased the transcription of gluconeogenic genes but did not suppress EGP under euglycemic clamp conditions (14). Lack of correlation between gluconeogenic gene expression and glucose flux is not surprising given the poor control strength of enzymes such as PEPCK across species (15–17). After several hours, however, there was a modest increase in the ability of the liver to take up glucose. Notably, all of insulin’s central effects were blocked by third ventricle infusion of a phosphatidylinositol 3-kinase (PI3K) inhibitor or a KATP channel blocker (14), the latter of which would block insulin’s effects through both the PI3K and mitogen-activated protein kinase (MAPK) pathways (18). As excess EGP contributes to hyperglycemia in humans with diabetes, it is imperative that regulation of the process be fully understood. In that regard it is necessary to determine whether a brain–liver insulin axis controlling EGP exists in the human, and if so, to what extent it is relevant. These are significant issues because targeting the brain–liver insulin axis may be of therapeutic value, especially if hypothalamic insulin resistance contributes to metabolic dysfunction (5). Although studying brain insulin action in the human is technically challenging, intranasal insulin administration is known to increase cerebrospinal fluid insulin concentrations and to affect cognitive performance, food intake, and satiety (19). Thus, it is a tool with which to address the above questions. Two articles, published in the current issue of Diabetes (20,21), describe the use of intranasal insulin to investigate the impact of brain insulin action on human glucose metabolism. In the study by Dash et al. (20), insulin was administered intranasally (40 IU) on the background of a pancreatic clamp using somatostatin (insulin and glucagon were infused into a peripheral vein to clamp their levels at basal arterial values, meaning that the liver was deficient in both). After 3 h, a modest suppression of EGP became evident (36% reduction at 240 min and 15% during the last hour) in the test group relative to a control group in which insulin was infused peripherally to account for the leakage of intranasally delivered insulin into the bloodstream.