Clinical and Nutrigenetic Assessment of Zinc in Patients with Prediabetes - 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.
