Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the β2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.

BACKGROUND: The blood glucose levels are known to be regulated by the balance between glucose metabolism and hepatic glucose production. Recently, the possibility that the central nervous system (CNS) also regulates blood glucose levels is pointed out, but those mechanisms are unknown. To investigate the mechanisms how the CNS regulates blood glucose levels, we focused on dopamine neurons in the CNS, and examined how central dopamine neurons regulate blood glucose levels. METHODS: Male ICR mice (6-7 weeks old) were used. Blood glucose levels were measured by the glucose oxidase method. The mRNA levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), which are the key enzymes for hepatic glucose production, were measured by RT-PCR. RESULTS: The i.c.v. injections of neither dopamine D 1 receptor agonist SKF 38393 nor antagonist SCH 23390 changed the blood glucose levels. In contrast, the i.c.v. injections of both dopamine D 2 receptor agonist quinpirole and antagonist l-sulpiride significantly increased the blood glucose levels. The increase in the blood glucose levels induced by l-sulpiride, but not quinpirole was significantly inhibited by α 2 and β 3 adrenergic receptor antagonists, yohimbine and ICI 118,551, respectively. The increase in the blood glucose levels induced by quinpirole, but not l-sulpiride, was significantly inhibited by hepatic vagotomy. These results suggest that the stimulation of dopamine D 2 receptors increases blood glucose levels through parasympathetic nerves whereas the inhibition of dopamine D 2 receptors increases blood glucose levels through sympathetic nerves. Both quinpirole and l-sulpiride significantly increased the mRNA levels of G6Pase and PEPCK, suggesting that glucose production in the liver is increased by the stimulation or inhibition of dopamine D 2 receptors in the CNS. CONCLUSION: The present study has shown that dopamine D 2 receptors, but not dopamine D 1 receptors, in the CNS regulate the blood glucose levels. Moreover, these results indicated that the stimulation of dopamine D 2 receptors in the CNS increases blood glucose level by increasing hepatic glucose production through parasympathetic nerves whereas the inhibition of dopamine D 2 receptors in the CNS increases blood glucose level by increasing hepatic glucose production through sympathetic nerves.