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

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)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的处方药之一。然而,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(T2 D)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,目前减少这些代谢症状的治疗方法疗效有限。APD产生代谢紊乱的机制尚不清楚。所有APD的单一统一特性是其阻断多巴胺D2样受体,包括D2(D2 R)和D3(D3 R)受体,表明这些受体在APD诱导的代谢功能障碍中的作用。尽管D2 R和D3 R在中枢神经系统中的下丘脑区域中表达,但针对这些中心的干预性研究并没有减少APD诱导的代谢功能障碍。这表明APD对下丘脑的影响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D2 R和D3 R也在人类和啮齿动物的胰岛素分泌胰腺β细胞中表达,多巴胺抑制葡萄糖刺激的胰岛素分泌(GSIS)。这表明胰腺DA信号调节GSIS,并提出APD也作用于胰腺内分泌细胞以驱动功能障碍的可能性。事实上,我们最近发现:(1)β细胞D2 R/D3 R的APD阻断破坏多巴胺对GSIS的抑制,导致胰岛素分泌升高-T2 D中胰岛素抵抗的潜在驱动因素。我们同样发现β细胞特异性D2 R敲除小鼠在体内表现出高胰岛素血症,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D2 R和D3 R,APD阻断α-细胞D2 R/D3 R可显著提高胰高血糖素分泌。这些数据与显示APD诱导的体内高胰高血糖素血症(其驱动高血糖症)的工作一致。因此,我们假设胰腺α-和β-细胞D2 R/D3 R信号传导对于葡萄糖稳态是重要的,并且破坏该信号传导导致代谢障碍。使用我们开发的新的遗传和药理学工具,我们建议建立α和β细胞中的D2 R和D3 R信号传导如何调节胰岛胰岛素和胰高血糖素分泌。我们还建议更好地理解这些受体信号传导的细胞内机制,以及APD改变细胞内信号传导途径以诱导功能障碍的细胞内机制(目的1,2)。同时,我们将通过确定特异性外周D2 R/D3 R的药理学刺激是否可以改善或预防小鼠和人胰岛中APD诱导的体内功能障碍来检查外周D2 R/D3 R激动的治疗潜力(目的3)。最终,我们的工作可能阐明新的胰腺D2 R/D3 R信号传导机制,APD破坏产生代谢障碍,并导致预防或显着减少APD代谢副作用的新药。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ZACHARY FREYBERG其他文献

ZACHARY FREYBERG的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ZACHARY FREYBERG', 18)}}的其他基金

Request for a ThermoFisher Helios 5UC DualBeam
索取 ThermoFisher Helios 5UC DualBeam
  • 批准号:
    10719755
  • 财政年份:
    2023
  • 资助金额:
    $ 39.75万
  • 项目类别:
Novel roles of VGLUT in sex differences in dopamine neuron vulnerability to environmental toxicant-induced neurodegeneration
VGLUT 在多巴胺神经元易受环境毒物诱导的神经变性的性别差异中的新作用
  • 批准号:
    10582080
  • 财政年份:
    2023
  • 资助金额:
    $ 39.75万
  • 项目类别:
A novel role for midbrain glutamate co-transmitting neurons in alcohol drinking and motivated behaviors
中脑谷氨酸共传递神经元在饮酒和动机行为中的新作用
  • 批准号:
    10307442
  • 财政年份:
    2021
  • 资助金额:
    $ 39.75万
  • 项目类别:
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
  • 批准号:
    10297121
  • 财政年份:
    2021
  • 资助金额:
    $ 39.75万
  • 项目类别:
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
  • 批准号:
    10657548
  • 财政年份:
    2021
  • 资助金额:
    $ 39.75万
  • 项目类别:
A novel role for midbrain glutamate co-transmitting neurons in alcohol drinking and motivated behaviors
中脑谷氨酸共传递神经元在饮酒和动机行为中的新作用
  • 批准号:
    10491170
  • 财政年份:
    2021
  • 资助金额:
    $ 39.75万
  • 项目类别:
Ultra-fast high-resolution imaging of whole mouse brain for the study of drug addiction
用于药物成瘾研究的小鼠全脑超快高分辨率成像
  • 批准号:
    10359049
  • 财政年份:
    2021
  • 资助金额:
    $ 39.75万
  • 项目类别:
Mechanisms for Preserving Neurons in Alzheimer's Disease-Related Dementias Across Drosophila and Mouse Models
果蝇和小鼠模型中阿尔茨海默病相关痴呆的神经元保护机制
  • 批准号:
    10264846
  • 财政年份:
    2020
  • 资助金额:
    $ 39.75万
  • 项目类别:
Mechanisms for Preserving Neurons in Alzheimer's Disease-Related Dementias Across Drosophila and Mouse Models
果蝇和小鼠模型中阿尔茨海默病相关痴呆的神经元保护机制
  • 批准号:
    10040481
  • 财政年份:
    2020
  • 资助金额:
    $ 39.75万
  • 项目类别:
Revealing Novel Mechanisms of Amphetamine Action in a Drosophila Model
揭示果蝇模型中苯丙胺作用的新机制
  • 批准号:
    8902527
  • 财政年份:
    2014
  • 资助金额:
    $ 39.75万
  • 项目类别:

相似海外基金

The Role of Arginine Transport on Pancreatic Alpha Cell Proliferation and Function
精氨酸转运对胰腺α细胞增殖和功能的作用
  • 批准号:
    10678248
  • 财政年份:
    2023
  • 资助金额:
    $ 39.75万
  • 项目类别:
Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production
α细胞来源的细胞外囊泡和母体胰岛素的产生
  • 批准号:
    10681939
  • 财政年份:
    2023
  • 资助金额:
    $ 39.75万
  • 项目类别:
Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia
靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
  • 批准号:
    10427574
  • 财政年份:
    2022
  • 资助金额:
    $ 39.75万
  • 项目类别:
Arginine regulation of alpha cell proliferation and function
精氨酸调节α细胞增殖和功能
  • 批准号:
    10609909
  • 财政年份:
    2022
  • 资助金额:
    $ 39.75万
  • 项目类别:
Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis
线粒体回补-回补对α细胞胰高血糖素分泌的调节
  • 批准号:
    10607392
  • 财政年份:
    2022
  • 资助金额:
    $ 39.75万
  • 项目类别:
Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia
靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
  • 批准号:
    10675646
  • 财政年份:
    2022
  • 资助金额:
    $ 39.75万
  • 项目类别:
Elucidating alpha cell defects in human type 1 diabetes using precision cut pancreas slice-on-a-chip coupled with high spatio-temporal microscopy
使用精密切割的胰腺切片结合高时空显微镜阐明人类 1 型糖尿病的 α 细胞缺陷
  • 批准号:
    457552
  • 财政年份:
    2021
  • 资助金额:
    $ 39.75万
  • 项目类别:
    Studentship Programs
Defining alpha-cell proglucagon processing for type 2 diabetes treatment
定义 2 型糖尿病治疗的 α 细胞胰高血糖素原加工过程
  • 批准号:
    10331361
  • 财政年份:
    2020
  • 资助金额:
    $ 39.75万
  • 项目类别:
In vivo systems to discover mechanisms regulating human islet alpha cell function
体内系统发现调节人类胰岛α细胞功能的机制
  • 批准号:
    10623306
  • 财政年份:
    2020
  • 资助金额:
    $ 39.75万
  • 项目类别:
Defining alpha-cell PC1/3 expression regulation for type 2 diabetes
定义 2 型糖尿病的 α 细胞 PC1/3 表达调控
  • 批准号:
    10376866
  • 财政年份:
    2020
  • 资助金额:
    $ 39.75万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了