Research ArticleDiabetes

Striatal dopamine regulates systemic glucose metabolism in humans and mice

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Science Translational Medicine  23 May 2018:
Vol. 10, Issue 442, eaar3752
DOI: 10.1126/scitranslmed.aar3752

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A stimulating therapy for diabetes

Blood glucose concentration is controlled by the hormone insulin. In patients with type 2 diabetes, insulin resistance leads to elevated blood glucose concentration and increased risk of developing cardiovascular disorders. The brain has been shown to participate in glucose metabolism; however, whether and how modulation of brain activity affects systemic blood concentrations of glucose is poorly understood. ter Horst et al. show that in diabetic and nondiabetic patients, striatal dopamine release induced by deep brain electrical stimulation of the ventral anterior limb of the internal capsule improved insulin sensitivity. Conversely, pharmacological systemic dopamine depletion reduced the insulin-mediated blood glucose uptake. The findings open up a potential avenue for treating pharmacoresistant type 2 diabetes.

Abstract

The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. First, we present the case of a diabetes patient who displayed strongly reduced insulin requirements after treatment with bilateral deep brain stimulation (DBS) targeting the anterior limb of the internal capsule. Next, we show that DBS in this striatal area, which induced dopamine release, increased hepatic and peripheral insulin sensitivity in 14 nondiabetic patients with obsessive-compulsive disorder. Conversely, systemic dopamine depletion reduced peripheral insulin sensitivity in healthy subjects. Supporting these human data, we demonstrate that optogenetic activation of dopamine D1 receptor–expressing neurons in the nucleus accumbens increased glucose tolerance and insulin sensitivity in mice. Together, these findings support the hypothesis that striatal neuronal activity regulates systemic glucose metabolism.

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