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Physiol Rev. 2016 Oct;96(4):1169-209. doi: 10.1152/physrev.00032.2015. Epub 2016 Aug 3.

Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans.

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Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Tübingen, Germany; Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany; Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; and Department of Pharmacy and Biochemistry, Faculty of Science, Eberhard Karls Universität Tübingen, Tübingen, Germany.


Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

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