Abstract
Proinflammatory cytokines and the novel myokine irisin, a cleavage product of FNDC5, have been found to play a role in obesity and type 2 diabetes mellitus (T2DM). Irisin has been shown to increase browning of adipose tissue, thermogenesis, energy expenditure, and insulin sensitivity, yet its association with inflammatory markers is still limited. Circulating irisin has been found to be increased in obesity, while in adult subjects with T2DM decreased levels have been found. However, data establishing the association of circulating irisin in children and adolescents with T2DM has not been described in the literature. The objective of this study was to determine irisin plasma concentration and its association with metabolic and adiposity markers and with hs-CRP, a surrogate marker of inflammation used in clinical practice, in a pediatric population with T2DM. A cross-sample of 40 Mexican children and adolescents aged 7-17 were recruited, 20 diagnosed with T2DM and 20 healthy controls. Plasma irisin levels were found to be lower in the T2DM group compared with controls, which could be attributed to a reduced PGC-1α activity in muscle tissue with a consequent decrease in FNDC5 and irisin expression. Irisin concentration was found to be positively correlated with HDL-c, LDL-c, and total cholesterol, while negatively correlated with BMI, waist circumference, and triglycerides. However, after multiple regression analysis, only HDL-c correlation remained significant. hs-CRP was higher in the T2DM group and positively associated with adiposity markers, unfavorable lipid profile, insulin levels, and HOMA-IR, but no association with irisin was found. Given the favorable metabolic effects attributed to irisin, the low plasma levels found in children and adolescents with T2DM could exacerbate the inflammatory and metabolic imbalances and the intrinsic cardiovascular risk of this disease. We propose an “irisin-proinflammatory/anti-inflammatory axis” to explain the role of irisin as a metabolic regulator in obesity and T2DM.
Highlights
Overweight and obesity are well established risk factors for the development of hypertension, atherogenic dyslipidemia, insulin resistance, and glucose intolerance, all of which carry an increased risk of developing cardiovascular disease and type 2 diabetes mellitus (T2DM) [1, 2] with subsequent increased morbidity and premature mortality
In hepatocytes, irisin has been shown to reduce oxidative stress [49, 50], to promote glycogenesis, to inhibit gluconeogenesis [51], and to reduce lipogenesis and lipid accumulation [49]. Overall, considering these favorable metabolic effects, the decreased levels of irisin observed in our T2DM pediatric population could potentially exacerbate the decreased glucose uptake in muscle and other metabolic derangements observed in peripheral tissues of T2DM subjects
Our results show high-sensitivity C-reactive protein (hs-C-reactive protein (CRP)) levels to be higher in the T2DM group compared with the normal weight group. hs-CRP levels were found to be positively associated with waist circumference (WC), W/ht ratio, and triglycerides, while a negative association with HDL-c was found, all markers of central adiposity and the metabolic imbalance characteristic of both obesity and T2DM
Summary
Overweight and obesity are well established risk factors for the development of hypertension, atherogenic dyslipidemia, insulin resistance, and glucose intolerance, all of which carry an increased risk of developing cardiovascular disease and type 2 diabetes mellitus (T2DM) [1, 2] with subsequent increased morbidity and premature mortality. Over the last three decades, overweight and obesity in children and adolescents have become increasingly prevalent worldwide [3]. Both Mexico and the United States present the highest obesity rates in the world [4]. Research has focused on circulating factors involved in the metabolic and inflammatory derangements observed in obesity but in T2DM including inflammatory markers [13,14,15,16] and novel myokines, such as irisin, among others [17]. Some researchers have found increased inflammatory markers in the serum of T2DM children [19] and adolescents [20], which suggests that this inflammatory phenomenon occurs at all ages and justifies further investigation in the less studied pediatric population
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