Novel dopaminergic mechanisms of islet hormone secretion and antipsychotic drug-induced metabolic disturbances

抗精神病药物(APD)治疗几种高度流行的精神疾病，包括精神分裂症、双相情感障碍和严重抑郁障碍，使它们成为当今最广泛的处方药物之一。然而，APDS也会引起严重的代谢紊乱，包括体重增加、糖耐量异常和胰岛素抵抗，并增加患2型糖尿病(T2D)和心血管疾病的风险。值得注意的是，所有APD都会引起不同程度的代谢副作用，目前减轻这些代谢症状的治疗效果有限。APDS产生代谢紊乱的机制还不是很清楚。所有APD的唯一统一特性是它们阻断了多巴胺D2样受体，包括D2(D2R)和D3(D3R)受体，这表明这些受体在APD诱导的代谢功能障碍中发挥了作用。虽然D2R和D3R在调节食欲和摄食行为的下丘脑区域的中枢神经系统中表达，但针对这些中心的干预性研究并未减少雪崩引起的代谢功能障碍。这表明，下丘脑的动作电位反应并不能完全解释这些药物的代谢效应。值得注意的是，我们和其他人发现D2R和D3R也在人类和啮齿动物分泌胰岛素的β细胞中表达，而多巴胺抑制葡萄糖刺激的胰岛素分泌(GSI)。这表明胰腺DA信号调节GSIS，并增加了APDS也作用于胰腺内分泌细胞以驱动血糖紊乱的可能性。事实上，我们最近发现：(1)APDAP阻断β细胞D2R/D3R可阻断多巴胺对GSI的抑制，导致胰岛素分泌增加--这是T2D患者胰岛素抵抗的潜在驱动因素。我们同样发现，β细胞特异性的D2R基因敲除小鼠在体内表现出高胰岛素血症，进一步支持了D2样受体作为胰岛素释放调节器的作用。(2)α-细胞也表达D2R和D3R，阻断α-细胞D2R/D3R可显著增加胰升糖素的分泌。这些数据与研究结果相一致，该研究结果表明，雪崩可在体内诱导高血糖，从而导致高血糖。因此，我们假设胰腺α和β细胞D2R/D3R信号对血糖稳态很重要，破坏这一信号会导致血糖紊乱。利用我们开发的新的遗传学和药理学工具，我们建议建立α-和β-细胞中的D2R和D3R信号如何调节胰岛胰岛素和胰升糖素的分泌。我们还建议更好地了解这些受体发出信号的细胞内机制，以及APD通过改变细胞内信号通路诱导血糖紊乱的机制(目标1，2)。同时，我们将通过确定特定外周D2R/D3R的药理刺激是否可以改善或防止在小鼠体内和在人类胰岛中由apd诱导的血糖紊乱来检验外周D2R/D3R激动剂的治疗潜力(目标3)。最终，我们的工作可能会阐明APDS干扰产生血糖紊乱的新的胰腺D2R/D3R信号机制，并导致预防或显著减少APDS代谢副作用的新药。

Antipsychotic drugs (APDs) treat several highly prevalent psychiatric illnesses including schizophrenia, bipolar disorder and major depressive disorder, making them among the most widely prescribed medications today. Yet, APDs also cause profound metabolic disturbances including weight gain, glucose intolerance, and insulin resistance, and increase risks of type 2 diabetes (T2D) and cardiovascular disease. Significantly, all APDs cause metabolic side effects to differing degrees, and current treatments to reduce these metabolic symptoms have only limited efficacy. The mechanisms by which APDs produce metabolic disturbances are not well understood. The single unifying property of all APDs is their blockade of dopamine D2-like receptors, including D2 (D2R) and D3 (D3R) receptors, suggesting a role for these receptors in APD-induced metabolic dysfunction. Though D2R and D3R are expressed in the central nervous system in hypothalamic regions that mediate appetite and feeding behavior, interventional studies targeting these centers have not reduced APD-induced metabolic dysfunction. This suggests that APD effects on the hypothalamus do not fully explain the metabolic effects of these drugs. Notably, we and others found D2R and D3R are also expressed in human and rodent insulin-secreting pancreatic β-cells, and dopamine inhibits glucose-stimulated insulin secretion (GSIS). This suggests pancreatic DA signaling modulates GSIS and raises the possibility that APDs also act on pancreatic endocrine cells to drive dysglycemia. Indeed, we recently found: (1) APD blockade of β-cell D2R/D3R disrupts dopamine’s inhibition of GSIS, leading to elevated insulin secretion – a potential driver of insulin resistance in T2D. We similarly found that β-cell-specific D2R knockout mice exhibit hyperinsulinemia in vivo, further supporting a role for D2-like receptors as modulators of insulin release. (2) α-cells also express D2R and D3R, and APD blockade of α-cell D2R/D3R profoundly elevates glucagon secretion. These data are consistent with work showing APD-induced hyperglucagonemia in vivo which drives hyperglycemia. Thus, we hypothesize that pancreatic α- and β-cell D2R/D3R signaling is important for glucose homeostasis and disrupting this signaling leads to dysglycemia. Using new genetic and pharmacologic tools we developed, we propose to establish how D2R and D3R signaling in α- and β-cells regulates islet insulin and glucagon secretion. We also propose to better understand the intracellular mechanisms by which these receptors signal, and by which APDs alter intracellular signaling pathways to induce dysglycemia (Aims 1, 2). In parallel, we will examine the therapeutic potential of peripheral D2R/D3R agonism by determining if pharmacological stimulation of specifically peripheral D2R/D3R can ameliorate or prevent APD-induced dysglycemia in vivo in mice and in human islets (Aim 3). Ultimately, our work may elucidate new pancreatic D2R/D3R signaling mechanisms that APDs disrupt to produce dysglycemia, and lead to novel drugs that prevent or significantly reduce APDs’ metabolic side effects.