Insulin Regulates Brain Function, but how Does it get There?

Sarah M. Gray; Rick I. Meijer; Eugene J. Barrett


Diabetes. 2014;63(12):3992-3997. 

In This Article

Brain Insulin Action

Because bulk brain glucose uptake is not affected by insulin in either rats[1] or humans,[2,3] the brain had long been considered "insulin insensitive." While there is evidence for the expression and activity of glucose transport with the insulin-sensitive GLUT4 in a few selected nuclei, glucose transport into most neurons is GLUT3 dependent, while the glia and brain endothelial cells depend on GLUT1 activity for glucose uptake from brain interstitial fluid (ISF) and plasma, respectively.[4] As insulin is not required for GLUT1- or GLUT3-mediated glucose transport, insulin is not needed for glucose transport into most brain cells. Insulin does, however, play a role as a neuroregulatory peptide, and this role is slowly being unraveled.[5] Early, provocative studies showed that chronic intracerebroventricular (ICV) insulin administration markedly decreased food intake and body weight in primates.[6] In contrast, intravenous insulin administration to humans during an euglycemic clamp did not acutely affect food intake.[7] However, chronic intranasal insulin administration, which allows more direct access to the cerebrospinal fluid (CSF) than systemic insulin administration, decreased food intake in fasting men and acutely affected postprandial selection of palatable food by women without causing hypoglycemia.[8,9] In addition, the correlation between adiposity and basal plasma insulin level led to the hypothesis that insulin in the central nervous system (CNS) could, like leptin, be a chronic signal regulating or reporting on energy reserves, as opposed to an acute satiety signal.[10] Consistent with an important role for CNS insulin action, neuron-specific knockout of the insulin receptor (NIRKO mouse) enhanced diet-induced obesity and provoked insulin resistance, hypertriglyceridemia, and reproductive dysfunction.[11] Thus, insulin in the brain appears to be important for the regulation of feeding behavior and monitoring energy stores.

During the past decade, acute insulin action in the CNS has been reported to regulate whole-body metabolic function. Obici et al.[12] demonstrated that acute delivery of insulin via ICV injection suppressed hepatic glucose production (HGP) in conscious rats. Moreover, ICV-delivered antisense oligonucleotide knockdown of the insulin receptor (IR) blocked the ability of insulin to regulate HGP in rats.[13] In addition, the ability of ICV insulin to regulate HGP is lost in NIRKO mice.[11] The arcuate nucleus in the hypothalamus appears to be critical, as IR deletion in Agouti-related protein–expressing neurons from this area blunted the ability of both systemic and ICV insulin to inhibit HGP in mice.[14] ICV insulin can also acutely regulate lipolysis in white adipose tissue.[15] In contrast to these findings in rodents, studies in a canine model have convincingly demonstrated that insulin acts directly at the liver to suppress HGP, and, while insulin acting via the CNS can influence the expression of certain gluconeogenic enzymes, it adds little to the acute physiologic regulation of hepatic glucose metabolism.[16–18] Species and significant methodological differences cloud the resolution of these disparate findings, and definitive addressing of the question in humans is technically beyond reach.

Beyond the CNS effects of insulin on nutrient intake and acute metabolic effects, there is tantalizing emerging data on the effects of insulin on memory and cognition.[19,20] Recent work suggests that insulin has functional effects in multiple brain areas. Most particularly, insulin affects areas in the hippocampus that are active in reward recognition, as well as areas involved in more global cognitive and memory functions.[21] These insights have arisen from studies using either ICV or nasal insulin delivery, circumventing the metabolic effects of peripherally delivered insulin that would limit such treatment to improve cognitive function. Indeed, clinical trials examining the effect of intranasal insulin as a potential therapy in early Alzheimer disease are ongoing (see