Clinical and Nutrigenetic Assessment of Zinc in Patients with Prediabetes

糖尿病前期患者锌的临床和营养遗传学评估

• 批准号: 10713103
• 负责人: JOSHUA PATRICK LEWIS
• 金额: $ 77.07万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713103
• 关键词: Alleles; American; Anabolism; Behavioral; Blood Glucose; Body Weight decreased; C-Peptide; Callback; Cardiovascular Diseases; Cholesterol; Chronic; Clinical; Clinical Trials; Data; Development; Diet Modification; Dietary Supplementation; Disease; Double-Blind Method; Dropout; Economic Burden; Exercise; FDA approved; Family; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glucose; Glucose tolerance test; Glycemic Index; Glycosylated hemoglobin A; Health; Health Benefit; Health Care Costs; Healthcare Systems; Homozygote; Hour; Individual; Insulin; Insulin Resistance; Intervention; Investigation; Islet Cell; Kidney Failure; LDL Cholesterol Lipoproteins; Life Style; Lipids; Measures; Medical; Metabolic; Minor; Morbidity - disease rate; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Participant; Patients; Peripheral; Pharmaceutical Preparations; Placebos; Play; Prediabetes syndrome; Prevention; Probability; Proinsulin; Randomized; Research; Resistance; Retinal Diseases; Risk; Role; Sampling; Structure of beta Cell of islet; Tissues; Triglycerides; United States; Variant; Zinc; Zinc Acetate; Zinc supplementation; adverse outcome; blood glucose regulation; design; diabetes risk; double-blind placebo controlled trial; economic impact; fasting glucose; fasting plasma glucose; genome wide association study; global health; glycemic control; impaired glucose tolerance; improved; indexing; insight; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; islet; member; mortality; novel; nutrition related genetics; placebo group; prevent; prospective; randomized, clinical trials; recruit; response; side effect; solute; therapeutic development; trial comparing; zinc-binding protein

PROJECT SUMMARY Type 2 diabetes (T2D) is a major cause of morbidity and mortality worldwide, leads to several debilitating chronic conditions including kidney failure, retinopathy, neuropathy, and cardiovascular disease, and results in a substantial burden to the United States healthcare system. In addition to those with T2D, approximately 90 million Americans have prediabetes, a condition that is associated with several similar health risks and greatly increases the probability of developing T2D in the future. Given the significant clinical consequences and associated economic impact, there is a major unmet medical need to design new strategies that slow or prevent the progression of prediabetes to T2D. Currently, no medications are FDA-approved for the treatment of prediabetes; thus, those with this disorder are mainly limited to behavioral lifestyle changes (e.g. increased exercise, weight loss, and diet modification). Recent investigations, mostly conducted in T2D patients, show that dietary supplementation with zinc confers favorable metabolic effects including reduction in fasting glucose and hemoglobin A1c (HgbA1c). Indeed, zinc is known to be critical in the biosynthesis, processing, and secretion of insulin in addition to improving insulin sensitivity in peripheral tissues. Furthermore, recent genomic studies have convincingly shown that variants in genes responsible for islet zinc transport (i.e. SLC30A8) are amongst the strongest genetic determinants of T2D risk. Given these data, the primary objectives of this application are to 1) assess the utility of zinc supplementation in individuals with prediabetes to improve glycemic indices and insulin action and 2) better characterize the impact of genetic variation in SLC30A8 on glucose control in response to zinc treatment. To accomplish these objectives, we will conduct a prospective, double-blind placebo-controlled trial of 200 prediabetic subjects that evaluates the effect of zinc supplementation (25 mg/day for 12 months) on HgbA1c, fasting plasma glucose, 2h oral glucose tolerance test measures, and lipid levels at 0, 6, and 12 months. We will also perform a prospective genotype-directed callback study based on SLC30A8 genotype to assess the effect of genetic variation in this gene on glycemic control in relation to zinc supplementation. Measures of insulin action including processing (i.e. proinsulin:insulin ratio), clearance (i.e. C-peptide:insulin ratio), and resistance (i.e. Matsuda Index) will be evaluated pre- vs. post-zinc supplementation as well as by SLC30A8 genotype. Discovering new, scalable, and inexpensive strategies that help improve glycemic control with little to no side effects in subjects with prediabetes would ultimately help in reducing chronic complications associated with T2D and lower related healthcare costs. In addition, we anticipate that the studies outlined in this application will set the stage for more effective genotype-directed approaches in prediabetics and provide justification for future mechanistic studies and larger clinical trials of SLC30A8 genotype-directed treatment and possibly prevention of T2D.

项目摘要 2型糖尿病（T2 D）是世界范围内发病率和死亡率的主要原因，导致多种衰弱性疾病， 慢性疾病，包括肾衰竭、视网膜病变、神经病变和心血管疾病，并导致 这对美国的医疗保健系统来说是一个沉重的负担。除了T2 D患者，大约90 100万美国人患有前驱糖尿病，这种疾病与几种类似的健康风险有关， 增加了未来发展为T2 D的可能性。考虑到严重的临床后果， 与此相关的经济影响，有一个主要的未满足的医疗需求，设计新的战略，减缓或 预防前驱糖尿病发展为T2 D。目前，没有药物是FDA批准的治疗 糖尿病前期;因此，患有这种疾病的人主要限于行为生活方式的改变（例如增加 运动、减肥和饮食调整）。最近的研究，主要是在T2 D患者中进行的，显示 饮食中补充锌可产生有利的代谢作用，包括降低空腹血糖， 和血红蛋白A1 c（HgbA 1c）。事实上，已知锌在生物合成、加工和代谢中是关键的。 除了改善外周组织中的胰岛素敏感性之外，还促进胰岛素分泌。此外，最近 基因组研究已经令人信服地表明，负责胰岛锌转运的基因中的变体（即， SLC 30 A8）是T2 D风险最强的遗传决定因素之一。根据这些数据，主要 本申请的目的是1）评估锌补充剂在患有前驱糖尿病的个体中的效用 改善血糖指数和胰岛素作用，2）更好地表征遗传变异对 SLC 30 A8对响应于锌处理的葡萄糖控制的影响。为达致这些目标，我们会 200例糖尿病前期受试者的前瞻性、双盲、安慰剂对照试验，评估锌的作用 补充（25 mg/天，持续12个月）对HgbA 1c、空腹血糖、2小时口服葡萄糖耐量试验的影响 测量和0、6和12个月时的脂质水平。我们还将进行前瞻性基因型导向 基于SLC 30 A8基因型的回调研究，以评估该基因的遗传变异对血糖的影响 与锌补充有关的控制。胰岛素作用的测量，包括加工（即 胰岛素原：胰岛素比率）、清除率（即C肽：胰岛素比率）和抵抗（即Matsuda指数）将被测量。 评价锌补充前后以及SLC 30 A8基因型。发现新的、可扩展的、 和廉价的策略，有助于改善血糖控制，几乎没有副作用， 糖尿病前期最终将有助于减少与T2 D相关的慢性并发症， 医疗费用。此外，我们预计，本申请中概述的研究将为以下方面奠定基础： 更有效的基因型导向的方法在糖尿病前期，并提供理由，为未来的机制 SLC 30 A8基因型导向治疗和可能预防T2 D的研究和更大的临床试验。