The Role of Circulating miRNAs as Clinical Biomarkers of Insulin Sensitivity and Exercise Adaptation in Young Offpsring of Type 2 Diabetes Patients
Background: A family history of Type 2 Diabetes (FH) is considered a risk factor for development of type 2 diabetes (T2D). Exercise training is an effective strategy to improve insulin resistance. Recently, micro-RNAs (miRNAs) have emerged as mediators of various intracellular processes, including insulin signaling, and may act as signaling molecules when released into circulation. The miRNAs -29a, -133a and -155 have been implicated in the regulation of insulin sensitivity, however their roles in exercise training-induced improvements in insulin sensitivity are yet to be elucidated. The purpose of this study was to determine whether circulating miRNA-29a, miRNA-29b, miRNA-29c, miRNA-133a, miRNA-133b and miRNA-155 were altered by a FH in healthy, normoglycemic men. In addition, we examined the effects of eight weeks of combined exercise training on circulating expressions of miRNA-29a, miRNA-29b, miRNA-29c, miRNA-133a, miRNA-133b and miRNA-155. Methods: 19 sedentary, normoglycemic Mexican American men (mean ± SEM; age: 23.3 ± 0.6; BMI: 26.9 ± 0.9) with/without a family history of T2D (FH-/FH+) underwent eight weeks (3x/wk) of combined exercise training (endurance and resistance exercise). A five-day standardized diet was provided prior to test days. Insulin sensitivity was assessed via the gold-standard hyperinsulinemic euglycemic clamp and serum was collected for miRNA detection. Total RNA was extracted and reverse transcribed to cDNA followed by miRNA analysis via qRT-PCR. Differences in miRNA expression between FH- and FH+ at baseline were analyzed by independent t-tests. Group and time effects of the exercise training intervention were analyzed by two-way ANOVA. Relationships between miRNA expression and clinical outcome measures were determined using Pearson correlation analyses. Results: While insulin sensitivity was similar between groups at baseline (p > 0.05), exercise training significantly increased insulin sensitivity in FH- and FH+ (FH-: 3.01 ± 0.38 to 4.16 ± 0.35; FH+: 3.86 ± 0.61 to 4.16 ± 0.35 mg/kg EMBS/min; two-way ANOVA p = 0.0005). Baseline circulating miRNA expression levels were similar between FH- and FH+ (FH- vs. FH+; miRNA-29a: -3.82 ± 4.92 vs. 3.56 ± 1.48, p = 0.17; miRNA-133a: 0.89 ± 3.97 vs. 1.76 ± 3.85, p = 0.88; miRNA-133b: -1.73 ± 4.4 vs. -3.52 ± 5.44, p = 0.80; miRNA-155: 2.01 ± 5.06 vs. 3.31 ± 9.47, p = 0.89). Exercise training did not significantly alter circulating miRNA expression regardless of FH (two-way ANOVA; miRNA-29: p = 0.05; miRNA-133a: p = 0.19; miRNA-133b: p = 0.31; miRNA-155: p=0.37). There were significant negative associations between fasting blood glucose at baseline and miRNA-29a (r2 = 0.63, p = 0.01), miRNA-133a (r2 = 0.52; p = 0.001), miRNA-133b (r2 = 0.30, p = 0.02) and miRNA-155 (r2 = 0.80, p = 0.0002). The exercise training-induced reductions in fasting blood glucose were significantly associated with miRNA-29a (r 2 = 0.46, p = 0.003), miRNA-133a (r2 = 0.43; p = 0.004), miRNA-133b (r2 = 0.39, p = 0.008) and miRNA-155 (r2 = 0.50, p = 0.01). Conclusions: Insulin sensitivity was not impaired in young, sedentary men with a FH and eight weeks of combined exercise training improved insulin sensitivity, independent of FH. Circulating miRNAs (miRNA-29a, miRNA-133a, miRNA-133b and miRNA-155) were not altered by a FH or combined exercise training. Our findings suggest circulating miRNAs (miRNA-29a, miRNA-133a, miRNA-133b and miRNA-155) are unaltered between normoglycemic individuals with/without a FH or following eight weeks of combined exercise training. However, fasting glucose levels may be regulated by circulating miRNAs -29a, -133a, -133b and -155, despite normoglycemia.
Meza, Cesar Arturo, "The Role of Circulating miRNAs as Clinical Biomarkers of Insulin Sensitivity and Exercise Adaptation in Young Offpsring of Type 2 Diabetes Patients" (2018). ETD Collection for University of Texas, El Paso. AAI13422921.