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

胰岛激素分泌和抗精神病药物引起的代谢紊乱的新多巴胺能机制

基本信息

批准号：
10297121
负责人：
ZACHARY FREYBERG
金额：
$ 39.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-17 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10297121
关键词：
Agonist Alpha Cell Antipsychotic Agents Appetitive Behavior Attenuated Beta Cell Bipolar Disorder Blood Brain Bromocriptine Cardiovascular Diseases Cells Clozapine DRD2 gene Data Desire for food Development Diabetes Mellitus Dopamine Drug Prescriptions Exhibits FDA approved Feeding behaviors GTP-Binding Proteins Genetic Glucagon Glucose Glucose Intolerance Haloperidol Hormone secretion Hormones Human Hyperglycemia Hyperinsulinism Hypothalamic structure In Vitro Insulin Insulin Resistance Intervention Studies Islets of Langerhans Knock-out Knockout Mice Lead Life Major Depressive Disorder Mediating Mental disorders Metabolic Metabolic dysfunction Morbidity - disease rate Mus Neuraxis Non-Insulin-Dependent Diabetes Mellitus Pancreas Peripheral Pharmaceutical Preparations Pharmacology Property Receptor Signaling Risk Rodent Role Schizophrenia Signal Pathway Signal Transduction Structure of alpha Cell of islet Structure of beta Cell of islet Symptoms Therapeutic Weight Gain Work arrestin 2 beta-arrestin blood glucose regulation compliance behavior feeding hyperglucagonemia improved in vivo insulin regulation insulin secretion islet novel novel therapeutics olanzapine prevent receptor recruit side effect tool

项目摘要

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.

抗精神病药物 (APD) 可治疗几种高度流行的精神疾病，包括精神分裂症、双相情感障碍和重度抑郁症，使其成为当今最广泛使用的药物之一，但 APD 也会引起严重的代谢紊乱，包括体重增加、葡萄糖耐受不良和胰岛素抵抗。并增加 2 型糖尿病 (T2D) 和心血管疾病的风险值得注意的是，所有 APD 都会不同程度地引起代谢副作用，而目前减轻这些代谢症状的治疗方法效果有限。 APD 产生代谢紊乱的机制尚不清楚，所有 APD 的单一统一特性是它们对多巴胺 D2 样受体的阻断，包括 D2 (D2R) 和 D3 (D3R) 受体，这表明这些受体在 APD 中发挥作用。尽管 D2R 和 D3R 在介导食欲和进食行为的下丘脑区域的中枢神经系统中表达，但针对这些中心的介入研究并未减少 APD 代谢引起的。这表明 APD 对下丘脑的影响并不能完全解释这些药物的代谢作用。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胰腺 β 细胞中表达，并且多巴胺抑制葡萄糖。这表明胰腺 DA 信号调节 GSIS 并增加了 APD 也作用于胰腺内分泌细胞以驱动血糖异常的可能性。我们最近发现：(1) APD 阻断 β 细胞 D2R/D3R 会破坏多巴胺对 GSIS 的抑制，导致胰岛素分泌增加——这是 T2D 胰岛素抵抗的潜在驱动因素。我们同样发现 β 细胞特异性 D2R 敲除小鼠表现出胰岛素抵抗。体内高胰岛素血症，进一步支持 D2 样受体作为胰岛素释放调节剂的作用 (2) α 细胞也表达 D2R 和 D3R，以及 APD 阻断。 α 细胞 D2R/D3R 显着提高胰高血糖素分泌，这些数据与 APD 诱导的体内高血糖素血症导致高血糖的研究一致，因此，我们认为胰腺 α 细胞和 β 细胞 D2R/D3R 信号传导对于葡萄糖稳态很重要。使用我们开发的新遗传和药理学工具，破坏该信号传导会导致血糖异常，我们建议确定 α- 和 D3R 信号传导如何发生。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 改变细胞内信号传导途径以诱导血糖异常的机制（目标 1、2）。通过确定特定外周 D2R/D3R 的药理刺激是否可以改善或预防体内 APD 诱导的血糖异常，评估外周 D2R/D3R 激动的治疗潜力最终，我们的工作可能会阐明 APD 破坏新的胰腺 D2R/D3R 信号传导机制，从而产生血糖异常，并开发出预防或显着减少 APD 代谢副作用的新药物。