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Cooperation between brain and islet in glucose homeostasis and diabetes

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Abstract

Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as ‘glucose effectiveness’, account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.

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Figure 1: Insulin signal transduction.
Figure 2: Schematic illustrations of brain- and islet-centred glucoregulatory systems.
Figure 3: Proposed contributions of defective brain- and islet-centred glucoregulatory systems to T2D pathogenesis.

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Acknowledgements

The authors would like to thank A. G. Bell for inspiration and D. Porte Jr for comments. This work was partly funded by National Institutes of Health (NIH) grants DK083042 (M.W.S.), DK093848 (R.J.S.) and DK089053 (G.J.M.), and the Nutrition Obesity Research Centre and Diabetes Research Centre at the University of Washington, and the Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases), through the Initiative and Networking Fund of the Helmholtz Association.

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Correspondence to Michael W. Schwartz.

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Schwartz, M., Seeley, R., Tschöp, M. et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503, 59–66 (2013). https://doi.org/10.1038/nature12709

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