Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Eur J Pharmacol. 2023 Oct 5;956:175984. doi: 10.1016/j.ejphar.2023.175984. Epub 2023 Aug 10.
Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. In addition, both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were also decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D receptors.
葡萄糖代谢据报道受中枢神经系统调节，但尚不清楚糖尿病是否会改变这种调节。我们研究了中枢多巴胺 D 受体对葡萄糖代谢的调节是否在 1 型和 2 型糖尿病模型中发生改变。侧脑室注射多巴胺 D 受体激动剂喹吡罗和拮抗剂 l-硫必利均可引起对照小鼠高血糖，但 1 型糖尿病模型链脲佐菌素（STZ）诱导的糖尿病小鼠则不会。禁食后，喹吡罗或 l-硫必利诱导的高血糖减轻，这些药物不会影响丙酮酸耐量试验中的高血糖。此外，喹吡罗和 l-硫必利均可增加肝葡萄糖-6-磷酸酶（G6Pase）mRNA。在 STZ 诱导的糖尿病小鼠中，调节葡萄糖稳态的下丘脑多巴胺和多巴胺 D 受体 mRNA 减少。肝糖原和 G6Pase mRNA 也减少在 STZ 诱导的糖尿病小鼠中。STZ 诱导的糖尿病小鼠中，喹吡罗或 l-硫必利均未增加肝 G6Pase mRNA。在饮食诱导肥胖小鼠（2 型糖尿病模型）中，喹吡罗和 l-硫必利均可引起高血糖，下丘脑多巴胺和多巴胺 D 受体 mRNA 未改变。这些结果表明：（i）刺激或阻断多巴胺 D 受体通过增加肝糖原分解引起高血糖，（ii）刺激或阻断多巴胺 D 受体不会影响 1 型糖尿病模型中的血糖水平，但会影响 2 型糖尿病模型中的血糖水平。此外，1 型糖尿病模型中下丘脑多巴胺能功能和肝糖原分解减少，从而减少了多巴胺 D 受体刺激或阻断引起的高血糖。
