Striatal dopamine regulates systemic glucose metabolism in humans and mice

• Published in: Science translational medicine 2018-05, Vol.10 (442)
• Main Authors: Ter Horst, Kasper W, Lammers, Nicolette M, Trinko, Richard, Opland, Darren M, Figee, Martijn, Ackermans, Mariette T, Booij, Jan, van den Munckhof, Pepijn, Schuurman, P Richard, Fliers, Eric, Denys, Damiaan, DiLeone, Ralph J, la Fleur, Susanne E, Serlie, Mireille J
• Format: Article
• Language: English
• Subjects: Deep brain stimulation; Diabetes mellitus; Dopamine D1 receptors; Glucose metabolism; Glucose tolerance; Insulin; Neostriatum; Nucleus accumbens; Obsessive compulsive disorder
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aar3752

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 D 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.