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; 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（T2D）是全球发病率和死亡率的主要原因，导致几种衰弱 慢性病，包括肾衰竭，视网膜病，神经病和心血管疾病，并导致 美国医疗保健系统的重大负担。除了具有T2D的人，大约90 百万美国人患有糖尿病前期，这种情况与几种类似的健康风险相关，并且很大 增加了未来开发T2D的可能性。考虑到显着的临床后果 相关的经济影响，有主要未满足的医疗需求来设计缓慢或 防止糖尿病前期到T2D。目前，没有药物批准用于治疗 糖尿病前；因此，患有这种疾病的人主要仅限于行为生活方式的变化（例如，增加 运动，体重减轻和饮食修饰）。最近的调查主要是在T2D患者中进行的 补充锌的饮食赋予有利的代谢作用，包括减少空腹葡萄糖 和血红蛋白A1C（HGBA1C）。确实，锌在生物合成，加工和 除了提高外周组织中胰岛素敏感性外，胰岛素的分泌。此外，最近 基因组研究令人信服地表明，负责胰岛转运的基因的变异（即 SLC30A8）是T2D风险中最强的遗传决定因素之一。鉴于这些数据，主要 本应用的目标是1）评估糖尿病患者中补充锌的效用 为了改善血糖指数和胰岛素作用，2）更好地表征了遗传变异对 响应锌处理的葡萄糖控制的SLC30A8。为了实现这些目标，我们将执行 对200名糖尿病患者的前瞻性，双盲安慰剂对照试验，评估了锌的作用 在HGBA1C，空腹血糖，2H口服葡萄糖耐受性测试上补充（25 mg/day，持续12个月） 0、6和12个月的度量和脂质水平。我们还将执行前瞻性基因型定向 基于SLC30A8基因型的回调研究，以评估该基因遗传变异对血糖的影响 与补充锌的控制有关。胰岛素作用的度量包括加工（即 促硫素：胰岛素比），清除率（即C肽：胰岛素比）和耐药性（即Matsuda指数）为 通过SLC30A8基因型进行了评估的Pre-pre and-Zinc补充。发现新的，可扩展的， 和便宜的策略，这些策略有助于改善血糖控制 糖尿病前期最终将有助于减少与T2D相关的慢性并发症，并降低相关的相关并发症 医疗保健费用。此外，我们预计该应用程序中概述的研究将为 糖尿病前期基因型指导的方法更有效，并为将来的机械提供了理由 SLC30A8基因型定向治疗以及可能预防T2D的研究和较大的临床试验。