Latino youth are disproportionately impacted by obesity, prediabetes and type 2 diabetes (T2D). Pediatric obesity is characterized by abnormal increases in pro-inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) and reductions in anti-inflammatory markers, high molecular weight adiponectin (HMW Adpn) and interleukin-10 (IL-10). Interleukin-1 receptor antagonist (IL-1ra) is an anti-inflammatory that is positively associated with obesity. IL-6, TNF-α, MCP-1 and IL-1ra have been associated with reduced insulin sensitivity and β-cell dysfunction, two central pathophysiologic mediators of glucose intolerance, while HMW Adpn and IL-10 have been associated with increased insulin sensitivity and β-cell function. The United States Diabetes Prevention Program (DPP) supported lifestyle intervention as the cornerstone approach for preventing T2D among adults with prediabetes, yet no studies to date have assessed the efficacy of an adapted DPP among Latino youth with prediabetes. In this dissertation, three studies were conducted. The first cross-sectional study among Latino youth with prediabetes and obesity (n=65) demonstrated that MCP-1 (β=-0.001, p=0.027; β=0.03, p=0.033), HMW Adpn (β=0.2, p<0.001; β=-2.2, p=0.018), and IL-1ra (β=-0.03, p=0.006; β=0.09, p=0.009) significantly predicted insulin sensitivity (measured by whole body insulin sensitivity index, WBISI) and glucose tolerance (measured by 2-hr glucose concentrations from an oral glucose tolerance test), respectively. Only HMW Adpn significantly predicted β-cell function, measured by oral disposition index, or oDI (β=0.6, p<0.001). The second study was a randomized control trial that demonstrated the efficacy of lifestyle intervention (INT, n=79) for improving oDI among Latino youth with prediabetes and obesity, compared to a usual care control (UCC, n=38) group. No differences were found for changes in WBISI (Δ0.1, p=0.899) or 2-hr glucose (Δ-7.2, p=0.260) between groups. The third study was a secondary analysis (INT n=46, UCC n=29) that demonstrated no significant effects on IL-6, TNF-α, MCP-1, HMW Adpn, IL-10, or IL-1ra (all interactions, p>0.05).

Obesity and its underlying insulin resistance are caused by environmental and genetic factors. DNA methylation provides a mechanism by which environmental factors can regulate transcriptional activity. The overall goal of the work herein was to (1) identify alterations in DNA methylation in human skeletal muscle with obesity and its underlying insulin resistance, (2) to determine if these changes in methylation can be altered through weight-loss induced by bariatric surgery, and (3) to identify DNA methylation biomarkers in whole blood that can be used as a surrogate for skeletal muscle.

Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.

These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.

Latino youth have substantially higher rates of obesity and T2D than their white peers. The higher prevalence of obesity and T2D among Latino youth places them at greater risk for cognitive dysfunction, an urgent and serious health threat to the United States. Exercise has been the cornerstone to combat the negative effects of obesity, diabetes and recent research also supports this effects for preventing cognitive dysfunction. A wealth of evidence suggests that a mediating mechanism linking exercise with brain health is BDNF, a cognitive biomarker that increases in the brain with exercise. BDNF is the most abundant neurotrophic factor that supports growth, survival and synaptic plasticity of neurons, all vital for cognitive function and brain health. The present study sought to investigate the effects of a 12-week lifestyle intervention of physical activity and lifestyle education on serum BDNF, in obese pre diabetic Latino youth.

A total of twelve obese pre diabetic Latino youth were selected from a larger RCT sample to be the focus for this analysis. After an overnight fast, a serum concentration was collected from all youth to be used for the BDNF analysis. In addition, the following cardio metabolic measures were also at taken at baseline and post intervention: Submaximal VO2max, medical and family history questionnaire, anthropometric, fasting glucose and a 2-hour oral glucose tolerance test (OGTT). A 12-weeks Lifestyle Intervention that involved a progressive moderate to high intensity exercise component and lifestyle education program did not significantly change serum BDNF levels in obese pre diabetic Latino youth. In conclusion, the variation of our serum BDNF results are highly speculative at this time, therefore the need for future investigations is crucial.