Altered levels of circulating cytokines and microRNAs in lean and obese individuals with prediabetes and type 2 diabetes

Abstract

Today obesity and type 2 diabetes (T2D) have both reached epidemic proportions. However, our current understanding of the primary mechanisms leading to these diseases is still limited due to the complex multifactorial nature of the underlying phenomena. We hypothesize that the levels of specific cytokines and miRNAs vary across the diabetes spectrum and unique signatures associated with them may serve as early biomarkers of the disease and provide insights into respective pathogenetic mechanisms. In this study, we measured the circulating levels of cytokines and microRNAs (miRNAs) in lean and obese humans with prediabetes (n = 21), T2D (n = 17), and healthy controls (n = 20) (ORIGINS trial, NCT02226640). Data were analyzed by fitting linear models adjusted for confounding variables (BMI, age, and gender in the diabetes context and age, gender, and diabetes status in the obesity context) and implementing nonparametric randomization-based tests for statistical inference. Group differences and correlations (r > 0.3) between variables with P < 0.05 were considered significant. False discovery rates (FDR) correcting for multiple testing were calculated using the Benjamini-Hochberg correction. We found a number of circulating cytokines and miRNAs deregulated in subjects with obesity, prediabetes, and T2D. Specifically, cytokines IL-6, IL-8, IL-10, IL-12, and SFRP4, as well as miRNAs miR-21, miR-24.1, miR-27a, miR-28-3p, miR-29b, miR-30d, miR-34a, miR-93, miR-126, miR-146a, miR-148, miR-150, miR-155, and miR-223, significantly changed across the diabetes spectrum, and were associated with measures of pancreatic islet β cell function and glycemic control, among others. Notably, SFRP4 was the only studied cytokine that was significantly associated with obesity, prediabetes, and T2D, which underscores the important role of this molecule during disease development and progression. Our data suggest that changes in circulating miRNAs and cytokines may have clinical utility as biomarkers of prediabetes.

Circulating microRNAs and endothelial cell migration rate are associated with metabolic syndrome and fitness level in postmenopausal African American women

“…Additionally, all but five participants had a waist circumference greater than 88 cm (risk criteria for MetS). In a study of lean and obese individuals with and without diabetes, Nunez Lopez et al () found positive correlations between percent body fat and both ci‐miR‐126 and ci‐miR‐146a, although we did not observe significant correlations with any ci‐miRs. Thus, a future study in a similar cohort to ours including a greater range of body fat levels may be needed to explore the relationship between body fat and cardiovascular ci‐miRs.…”

Circulating miR‐146a, miR‐34a and miR‐375 in type 2 diabetes patients, pre‐diabetic and normal‐glycaemic individuals in relation to β‐cell function, insulin resistance and metabolic parameters

“…Thus, in order to determinate the physiological stressors that could be affecting the relative expression of miR‐146a, miR‐34a, and miR‐375, we performed a detailed univariate analysis. We observed that the expression of miR‐146a was diminished in pre‐diabetic individuals, which is consistent with previous studies . Also, miR‐146a relative expression was associated with C‐reactive protein (an inflammatory marker) only in the T2D patients’ group.…”

Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation

“…Previous studies have uncovered that loss of myeloid-miR-223 enhances diet-induced obesity and T2D utilizing mouse models (14,15). In addition, altered miR-223 levels in humans are associated with the advancement of obesity and T2D (16)(17)(18). Our current studies have established that KLF6 directly represses miR-223 expression to advance macrophage proinflammatory gene expression and attendant functions.…”

“…Deficiency of miR-223 is known to enhance proinflammatory macrophage activation and pathogenic functions (13)(14)(15). Recent human studies have uncovered that obesity and T2D status significantly altered miR-223 expression (16)(17)(18)(19). More importantly, macrophage miR-223 deficiency significantly elevated high-fat diet (HFD)-induced metabolic tissue inflammation, obesity, and T2D (14,15).…”