Central dopamine D₂ receptors regulate plasma glucose levels in mice through autonomic nerves

Area of Science:

• Neuroendocrinology
• Metabolic Regulation
• Dopaminergic Signaling

Background:

• The central nervous system (CNS) role in plasma glucose regulation is increasingly recognized, yet mechanisms remain elusive.
• Dopaminergic pathways within the CNS are implicated in metabolic control, but their specific contribution to glucose homeostasis is not fully understood.

Purpose of the Study:

• To investigate the role of central dopaminergic function, specifically dopamine D1 and D2 receptors, in the regulation of plasma glucose levels in a mouse model.
• To elucidate the downstream pathways, including hepatic gluconeogenesis and autonomic nervous system involvement, mediating the effects of central dopamine receptor stimulation or blockade on glucose metabolism.

Main Methods:

• Intracerebroventricular (i.c.v.) administration of dopamine D1 and D2 receptor agonists and antagonists in mice.
• Assessment of plasma glucose levels and hepatic gene expression of key gluconeogenic enzymes (glucose-6-phosphatase, phosphoenolpyruvate carboxykinase).
• Utilized dopamine D2 receptor knockout mice, beta-2 adrenoceptor antagonist, and hepatic vagotomy to dissect the neural pathways involved.

Main Results:

• Dopamine D1 receptor modulation did not affect plasma glucose. However, both dopamine D2 receptor agonists (quinpirole) and antagonists (l-sulpiride) increased plasma glucose levels.
• This hyperglycemia was abolished in dopamine D2 receptor knockout mice, confirming the specificity of D2 receptor involvement.
• Both quinpirole and l-sulpiride increased mRNA levels of hepatic gluconeogenic enzymes. Quinpirole-induced hyperglycemia was attenuated by hepatic vagotomy, while l-sulpiride-induced hyperglycemia was inhibited by ICI 118,551 (a beta-2 adrenoceptor antagonist).

Conclusions:

• Central dopamine D2 receptor stimulation increases plasma glucose by enhancing hepatic glucose production via parasympathetic nerve activation.
• Central dopamine D2 receptor inhibition increases plasma glucose by enhancing hepatic glucose production via sympathetic nerve activation.
• These findings reveal a dual role for central dopamine D2 receptors in glucose homeostasis, mediated by distinct autonomic pathways.