All ETDs from UAB

Advisory Committee Chair

W Timothy Garvey

Advisory Committee Members

Jeffrey Engler

Barbara Gower

Suzanne Judd

Gang Liu

Daniel Smith Jr

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

Insulin resistance (IR) is central to the pathophysiology of Type 2 diabetes (T2DM), and is a risk factor for cardiovascular disease. The mechanisms behind IR are not clear, but microRNA (miR; short, non-coding RNA strands that base-pair with mRNA to modify gene expression) have garnered interest as potential contributors. miRs have recently been shown to be detectable in the circulation, and can be taken up and regulate target genes within recipient cells. Our primary objective was to identify circulating miRs (c-miRs) that play a role in regulating systemic metabolism and participate in the pathophysiology of IR and cardiometabolic disease. Three studies were performed to 1) ascertain the relationship between candidate c-miRs and IR in humans, 2) assess the association of these miRs with oxidative stress as a potential mechanism for the development of IR, and 3) evaluate the impact of an insulin-sensitizing intervention on c-miRs. We found that miR-16, -107, -33, -150, -222, -34a, -126, -320, and let-7a are related to measures of insulin sensitivity in cross-sectional analyses. miRs were also associated with related metabolic risk factors (e.g., lipids). While we made the novel observation that F2-isoprostanes may reflect oxidative stress relating to age (decreases in bone and lean mass), there was no association between F2-isoPs and insulin sensitivity, nor between miRs and F2-isoPs. In patients with obesity placed on weight-loss diets, c-miRs were not affected by the amount of weight loss or macronutrient diet composition. However, changes in miR-222 were correlated with enhanced insulin sensitivity and changes in miR-16 and miR-122a with decrements in HDL. The amount of weight loss affected the relationships between miR species and metabolic traits; after 15 weeks, miR-126, -34a, -320, and let-7a were correlated with insulin sensitivity in low responders and miR-16, and -223 with lipids in high responders. The data indicate that miRs could determine the metabolic response to dietary interventions in obesity. Taken together, our results suggest that circulating miRs may be involved with insulin resistance pathophysiology, and thus have potential as biomarkers and/or therapeutic agents for diabetes and cardiometabolic disease. Future studies are warranted to better elucidate the mechanisms through which circulating miRs regulate metabolism.

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