Impaired insulin action in the human brain: causes and metabolic consequences

Key Points

  • The human brain is an insulin-sensitive organ

  • Insulin in the human brain modulates food intake, body weight and peripheral metabolism

  • The human brain can become insulin resistant, a condition found in obesity as well as in people with visceral fat accumulation or specific genetic backgrounds

  • Overcoming brain insulin resistance could be a novel approach for the prevention and treatment of metabolic diseases such as type 2 diabetes mellitus

Abstract

Over the past few years, evidence has accumulated that the human brain is an insulin-sensitive organ. Insulin regulates activity in a limited number of specific brain areas that are important for memory, reward, eating behaviour and the regulation of whole-body metabolism. Accordingly, insulin in the brain modulates cognition, food intake and body weight as well as whole-body glucose, energy and lipid metabolism. However, brain imaging studies have revealed that not everybody responds equally to insulin and that a substantial number of people are brain insulin resistant. In this Review, we provide an overview of the effects of insulin in the brain in humans and the relevance of the effects for physiology. We present emerging evidence for insulin resistance of the human brain. Factors associated with brain insulin resistance such as obesity and increasing age, as well as possible pathogenic factors such as visceral fat, saturated fatty acids, alterations at the blood–brain barrier and certain genetic polymorphisms, are reviewed. In particular, the metabolic consequences of brain insulin resistance are discussed and possible future approaches to overcome brain insulin resistance and thereby prevent or treat obesity and type 2 diabetes mellitus are outlined.

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Figure 1: Insulin-sensitive brain areas in humans.
Figure 2: Physiologic effects of insulin action in the brain.
Figure 3: Possible causes of brain insulin resistance.

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Acknowledgements

The authors apologize to colleagues whose important contributions they were unable to cite owing to space limitations. The authors are partly supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Centre for Diabetes Research (DZD e.V.: 01GI09) and the Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases.

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Heni, M., Kullmann, S., Preissl, H. et al. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol 11, 701–711 (2015). https://doi.org/10.1038/nrendo.2015.173

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