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.

PROJECT NARRATIVE Development of new strategies to slow or prevent the progression of prediabetes to type 2 diabetes would have a significant health benefit to millions of individuals worldwide and would reduce related economic burden on healthcare systems. Zinc supplementation may represent an efficacious, safe, and inexpensive way to improve insulin action and reduce fasting glucose, hemoglobin A1c, and lipid levels in subjects with prediabetes. The proposed research will provide novel insights regarding the utility of zinc supplementation in those with prediabetes, prospectively characterize genetic variation that impacts zinc transport, and ultimately provide justification for future mechanistic studies and larger clinical trials of zinc supplementation to prevent or delay onset of type 2 diabetes.