Preventative Biomarkers and Potential Pharmacotherapies for Nicotine Use and Diabetes

尼古丁使用和糖尿病的预防性生物标志物和潜在药物疗法

• 批准号: 10412369
• 负责人: LAURA ELENA ODELL
• 金额: $ 15.33万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412369
• 关键词: Address; Behavioral; Biological Factors; Biological Markers; Bromocriptine; Bupropion; Chronic; Clinical; Clinical effectiveness; Dependence; Development; Diabetes Mellitus; Disease; Dopamine Agonists; Drug usage; Female; Goals; Health; High Fat Diet; Inflammation; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intake; Intervention; Knowledge; Lead; Measures; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic syndrome; Mission; Modeling; Nicotine; Nicotine Dependence; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiology; Plasma; Positioning Attribute; Predisposition; Prevalence; Procedures; Public Health; Rattus; Reduce health disparities; Regimen; Reporting; Research; Research Support; Rewards; Risk; Rodent; Rodent Model; Self Administration; Severities; Smoking; Smoking Cessation Intervention; Streptozocin; Supplementation; Testing; Time; Tobacco use; United States National Institutes of Health; Vulnerable Populations; Withdrawal; Withdrawal Symptom; Woman; Work; addiction; anxiety-like behavior; base; behavior measurement; clinical effect; clinical efficacy; cohort; diabetic; diabetic rat; exenatide; experience; feeding; glucagon-like peptide 1; glucophage; improved; indexing; insulin signaling; male; men; negative affect; nicotine cessation; nicotine exposure; nicotine use; pre-clinical; preference; programs; sex; smoking cessation; varenicline

ABSTRACT Diabetes and nicotine use are significant public health problems that produce compounded health consequences, particularly in women. The proposed team of neuroscientists employ rodent models to provide a better understanding of the underlying factors that promote nicotine use in persons with metabolic disorders, such as diabetes. Our prior pre-clinical work has established that the rewarding effects of nicotine are greater in rodents that display a disruption in insulin signaling, the primary mediator of diabetes. This work has raised important additional questions regarding whether the development of insulin resistance (IR) or other indices of metabolic syndrome coincide with or predict greater nicotine dependence in females versus males. Also, the effects of nicotine exposure on the emergence of various biomarkers of metabolic syndrome are unclear. Importantly, there is also a lack of information on the efficacy of medications that reduce IR or serve as nicotine cessation agents on the development of nicotine dependence in rodent models of Type 1 or Type 2 diabetes. To address these issues, Aim 1 will assess sex- and time-dependent changes in IR, plasma biomarkers of metabolic syndrome, and behavioral indices of nicotine dependence that include escalation of nicotine self-administration and withdrawal severity. Aim 1 will use a procedure that will examine the natural emergence of IR following chronic access to a high fat diet (HFD). We will also include HFD-fed rats that receive a pharmacological intervention that accelerates the induction of IR. Aim 2 will assess the efficacy of various pharmacotherapies for diabetes (insulin, exenatide, glucophage, and bromocriptine) or smoking cessation (bupropion and varenicline) on the same measures collected in Aim 1 using rodent models of Type 1 and Type 2 diabetes. The scientific premise is that the development of IR will coincide with the escalation of nicotine intake and greater withdrawal severity in both types of diabetic rats. We anticipate that diabetic females will display the greatest escalation of nicotine intake and more intense withdrawal symptoms than males. Also, pharmacological interventions that treat IR will suppress the development of nicotine dependence in diabetic rats. These studies are rigorous because they incorporate rodent models of Type 1 and Type 2 diabetes and will assess time-dependent changes in nicotine dependence and various biomarkers of metabolic syndrome. The proposed work is significant because the results will advance our understanding of the relationship between various biomarkers of metabolic syndrome and the development of nicotine dependence. Our work will also inform how nicotine exposure alters various biomarkers of metabolic syndrome that lead to diabetes. Lastly, our results will inform the effectiveness of clinically approved pharmacotherapies in reducing the risk of nicotine use in persons with diabetes. This is in line with the mission of NIH to improve the lives of persons suffering from debilitating diseases, particularly in patients inflicted by compounded health consequences produced by diabetes and nicotine use.

抽象的 糖尿病和尼古丁的使用是造成复合健康的重大公共卫生问题 后果，特别是对女性而言。拟议的神经科学家团队采用啮齿动物模型来提供 更好地了解促进代谢紊乱患者使用尼古丁的潜在因素， 例如糖尿病。我们之前的临床前工作已经证实，尼古丁的奖励作用在以下方面更大： 啮齿类动物的胰岛素信号传导受到干扰，胰岛素信号传导是糖尿病的主要介质。这项工作提出了 关于是否会出现胰岛素抵抗（IR）或其他指标的重要附加问题 代谢综合征与女性比男性对尼古丁的依赖性相一致或预示着女性对尼古丁的依赖性更大。另外， 尼古丁暴露对代谢综合征各种生物标志物出现的影响尚不清楚。 重要的是，还缺乏关于减少 IR 或充当尼古丁药物的功效的信息 戒烟剂对 1 型或 2 型糖尿病啮齿动物模型尼古丁依赖的影响。到 为了解决这些问题，目标 1 将评估 IR、代谢的血浆生物标志物的性别和时间依赖性变化 综合症和尼古丁依赖的行为指标，包括尼古丁自我给药的升级 和戒断严重程度。目标 1 将使用一个程序来检查 IR 的自然出现，如下 长期接受高脂肪饮食（HFD）。我们还将包括接受药理治疗的 HFD 喂养大鼠 加速 IR 诱导的干预。目标 2 将评估各种药物疗法的功效 糖尿病（胰岛素、艾塞那肽、噬菌体和溴隐亭）或戒烟（安非他酮和伐尼克兰） 使用 1 型和 2 型糖尿病啮齿动物模型，采用目标 1 中收集的相同测量值。科学的 前提是IR的发展将与尼古丁摄入量的增加和戒断的增加同时发生 两种类型糖尿病大鼠的严重程度。我们预计，患有糖尿病的女性将表现出最大的升高 尼古丁摄入量和戒断症状比男性更严重。此外，药物干预 治疗 IR 将抑制糖尿病大鼠尼古丁依赖的发展。这些研究很严谨 因为它们结合了 1 型和 2 型糖尿病的啮齿动物模型，并将评估随时间变化的变化 尼古丁依赖和代谢综合征的各种生物标志物。拟议的工作意义重大 因为这些结果将促进我们对代谢的各种生物标志物之间关系的理解 综合征和尼古丁依赖的发展。我们的工作还将揭示尼古丁暴露如何改变 导致糖尿病的代谢综合征的各种生物标志物。最后，我们的结果将告知有效性 临床批准的药物疗法可降低糖尿病患者使用尼古丁的风险。这是在 符合 NIH 的使命，即改善患有衰弱性疾病的人们的生活，特别是在 因糖尿病和尼古丁使用造成的复合健康后果所造成的患者。