oa Role(s) of microRNAs as markers and mediators of insulin resistance

Background: Early and rapid onset of obesity in the Qatari population, consequent to expansion primarily of abdominal adipose tissue, is closely associated with inflammation and insulin resistance. Recent interest has focused on microRNA (miRNA), both as biomarkers and mediators, of disease and therefore potentially therapeutic targets. MiRNAs are stable, non-coding species involved in the post-transcriptional regulation of gene expression. Aims: This study investigated the expression of a panel of miRNAs associated with inflammation and insulin resistance in peripheral blood cells of subjects with a range of adiposities and insulin sensitivities. The effect of surgical weight loss on these miRNAs was also investigated in a subset of patients. Method: Non-diabetic Qatari subjects were recruited from patients awaiting weight reduction surgery and from a normal population. Anthropometric measures were recorded. Fasting blood samples were obtained from all subjects, and in a subset after surgical weight loss, for determination of lipids, glucose, insulin and adipokines. miRNA from peripheral blood cells was used to assess their expression using an inflammatory array. Subjects were grouped by body mass index and insulin sensitivity. Results: Three comparisons were carried out: 1. Normal/over-weight (N/OW) versus obese (Ob), 2. Insulin Sensitive (IS) versus Insulin Resistant (IR), and, 3. Before (BWL) and after weight loss (AWL). Despite being matched for age (M 29.5±9.8 vs F 30.1±6.5 years), and BMI (M:36.1±12.9 vs 36.6±10.0 kg/m2) the males had higher systolic and diastolic blood pressure and mean arterial pressure, while levels of both leptin and adiponectin were higher in females. The N/OW, compared to the Ob group, had lower levels of systolic blood pressure, higher HDL-cholesterol, lower leptin, interleukin-6 and higher adiponectin levels. The IS group compared to the IR, matched for BMI, age and plasma glucose, had lower insulin and HOMA index of insulin resistance, as well as leptin and adiponectin. Weight loss was accompanied by a significant reduction in BMI (BWL:41.6±8.6 vs AWL 34.7±8.7 kg/m2), leptin, insulin and HOMA-IR. Three miRNA were significantly different between the different body weight groups. Conversely, 12 miRNA changed significantly when IS were compared to the IR. Weight loss also produced changes in the expression of ten miR species. Conclusion: It is apparent that significant differences in expression of the miR species occur along with changes in metabolic and inflammatory parameters in the different body weight groups, which are further enhanced both synergistically and independently by insulin resistance. Some, but not all, of the metabolic and inflammatory lesions that accompany obesity and insulin resistance appear to be ameliorated by weight loss. The target genes of these miRNAs are currently being investigated to assign possible functionality.