Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models
Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models
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DOI：
10.1016/j.ejphar.2023.175984
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发表时间：
2023-08-16
影响因子：
5
通讯作者：
Waddington，John L.
中科院分区：
文献类型：
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作者：
Ikeda，Hiroko;Mikami，Risa;Waddington，John L.
据报道，葡萄糖代谢受中枢神经系统调节，但尚不清楚这种调节是否在糖尿病中改变。我们研究了在1型和2型糖尿病模型中，中枢多巴胺D2受体对葡萄糖代谢的调节是否改变。侧脑室注射多巴胺D2受体激动剂喹吡罗和拮抗剂l-舒必利在对照小鼠中诱导高血糖，但在链脲佐菌素（STZ）诱导的糖尿病小鼠（1型糖尿病模型）中不诱导高血糖。禁食后，喹吡罗或l-舒必利诱导的高血糖减少，这些药物对丙酮酸耐量试验中的高血糖没有影响。此外，无论是喹吡罗和l-舒必利增加肝葡萄糖-6-磷酸酶（G6 β）的mRNA。在STZ诱导的糖尿病小鼠中，下丘脑中调节葡萄糖稳态的多巴胺和多巴胺D2受体mRNA减少。STZ诱导的糖尿病小鼠的肝糖原和G6 β mRNA也减少。在STZ诱导的糖尿病小鼠中，喹吡罗和l-舒必利均未增加肝脏G6 β mRNA。在饮食诱导的肥胖小鼠2型糖尿病模型中，喹吡罗和l-舒必利均诱导高血糖，下丘脑多巴胺和多巴胺D2受体mRNA未发生改变。这些结果表明：（i）多巴胺D2受体的刺激或阻断通过增加肝糖原分解引起高血糖症，和（ii）多巴胺D2受体的刺激或阻断不影响1型糖尿病模型中的血糖水平，但在2型糖尿病模型中会影响血糖水平。此外，在1型糖尿病模型中，下丘脑多巴胺能功能和肝糖原分解降低，这减少了由多巴胺D2受体的刺激或阻断诱导的高血糖症。
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 D2receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D2receptor 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 D2receptor 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 D2receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D2receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D2receptors 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 D2receptors.