oa let7 as a potential mediator of insulin resistance in normal weight subjects

Background and objectives: A high prevalence of insulin resistance (IR) amongst normal weight Qatari individuals may contribute to progression of type II diabetes and account for the current epidemic. Factors contributing to this increased risk of IR and its associated co-morbidities, especially in the absence of obesity, are still under investigation. Therefore the objectives of this pilot study were to characterize components of IR in normal weight Qatari individuals and to investigate the potential molecular mechanisms underlying this phenotype. Methods: Non-diabetic lean/overweight Qatari subjects were recruited and anthropometric measures including body weight (kg), height (m) and blood pressure recorded, along with determination of systemic lipids, glucose, insulin and adipokines. Subjects were dichotomized into IR and IS groups based on their HOMA index (fasting plasma glucose < 6.8 mmol/l and insulin levels < 6.5 miU/ml). The expression of 84 most abundantly expressed and characterized miRNA species was profiled in peripheral blood samples. Target genes of miRNA let7 were determined using Human let-7a Targets PCR Array. Results: When subjects (29+/-6.8 years old, BMI of 23+/-4.9 kg/m-2) were stratified into two groups based on their HOMA index (IS 1.3 (1-1.6) and IR 2.2 (1.6-2.7), IR (66%) was only associated with higher insulin levels {(IS 5.3 (5.2-5.5) vs IR 9.5 (7.7-12.1) u/ml, p <0.01)} with no significant differences in blood pressure, lipids profile or adipokines levels. Among 84 profiled miRNA species, the expression of 7 miRNA varied significantly between the two groups; among these were four members of let7 family (g/b/c/f). Three potential target genes of let7 exhibited significant variable expression between the two groups, including dual specificity protein phosphatase 1 (DUSP1). Conclusions: Prevalence of IR among young, lean/overweight Qatari individuals is alarmingly high (66%). This study has revealed let7 miRNA as a potential target mediating this phenotype. This miRNA has been shown previously to play an essential role in adipogenesis. The targets of let7 with an ability to regulate adipogenesis is currently being investigated to confer functionality.