Abstract
Purpose of Review
Chronic inflammation, adipokines, and hepatokines have been identified as basis of insulin resistance and β cell failure in animal models. We present our current knowledge concerning the potential relationship between these cytokines, inflammation, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM) in the pediatric population.
Recent Findings
Pro-inflammatory cytokines related to insulin resistance and MetS in children are tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, interferon gamma, pigment epithelium-derived factor, chemerin, vaspin, and fetuin A. Anti-inflammatory cytokines associated with insulin resistance and MetS in children are leptin, adiponectin, omentin, fibroblast growth factor (FGF)-21, osteocalcin, and irisin. These anti-inflammatory cytokines are decreased (adiponectin, omentin, and osteocalcin) or increased (leptin, FGF-21, and irisin) in obesity suggesting a resistance state. TNF-α, fetuin A, and FGF-21 are altered in obese children with T2DM suggesting an involvement in β cell failure.
Summary
These cytokines, adipokines, and hepatokines may be able to predict development of MetS and T2DM and have a potential therapeutic target ameliorating insulin resistance.
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Introduction
The metabolic syndrome (MetS) is defined as a clustering of obesity, hypertension, dyslipidemia, and impaired glucose tolerance [1, 2]. The MetS is diagnosed with increased frequency in children [3, 4]. The MetS leads to cardiovascular diseases and therefore to increased mortality [1, 2]. Even though the exact definition of the MetS in children is still under debate [5, 6], it is clear that the basis of MetS in childhood is insulin resistance [1, 5, 6]. When insulin resistance is associated with reduced β cell function and loss of β cell mass, then type 2 diabetes mellitus (T2DM) develops [7, 8].
It is now widely accepted that chronic inflammation plays an important role both in the development of insulin resistance and insulin secretion deficiency even if the mechanisms are not fully understood [9••, 10]. For example, high-sensitivity C-reactive protein (hsCRP) as an unspecific parameter of chronic inflammation is increased in obese insulin-resistant adults [11, 12], in obese children with MetS [13•, 14], and in obese adolescents with T2DM [15]. In addition to a direct link between chronic inflammation and insulin resistance, the involvement of adipokines, hepatokines, and cytokines of other tissues in the pathogenesis of MetS and T2DM is discussed [9••, 10, 16••, 17•].
The aim of this review is to demonstrate our current knowledge of inflammation markers in MetS and T2DM, which may offer important insights for future treatment strategies. This review focuses on the pediatric population since adverse patterns of MetS itself begin in childhood. Studies in children have also the advantage of not being influenced by other diseases, medications, or active tobacco smoking.
Inflammation as Trigger of Insulin Resistance and Insulin Secretion Deficiency
Adipose tissue produces a variety of pro- and anti-inflammatory cytokines. Proinflammatory cytokines promote insulin resistance by inducing uncontrolled insulin receptor substrates and anti-inflammatory cytokines have the opposite effect [18,19,20] (Fig. 1). Importantly, some pro-inflammatory cytokines also lead to β cell failure explaining at least in part the development of T2DM [10, 21,22,23,24,25,26]. Visceral adipose tissue produces more pro-inflammatory cytokines, whereas subcutaneous adipose tissue secretes larger quantities of anti-inflammatory and insulin-sensitizing cytokines [18, 27, 28]. Whether anti-inflammatory or pro-inflammatory cytokines are produced depends also on the regulation of a subset of T cells called CD4-positive T helper (Th) cells, which can be further differentiated into Th1 and Th2 cells [29]. Th1 cells promote a pro-inflammatory cytokine profile while Th2 cells promote an anti-inflammatory response.
Furthermore, insulin resistance in muscle and liver tissue is increased by the release of free fatty acids (FFA) from adipose tissue, since FFA activate the innate immune system to release pro-inflammatory cytokines [28]. On the other hand, the increase of FFA is stimulated by proinflammatory cytokines, which enhances activity of hormone sensitive lipase in adipose tissue resulting in a vicious repetitive cycle [18, 28].
Inflammatory Markers Produced Generally
The following inflammatory markers are expressed in the adipose tissue but also generally.
Tumor Necrosis Factor-Alpha (TNF-α)
TNF-α is a pro-inflammatory cytokine synthesized as a 26-kDa transmembrane protein that undergoes cleavage by a metalloproteinase [19]. TNF-α induces phosphorylation of the insulin receptor substrate 1 (IRS-1) and thus prevents the interaction of insulin with an insulin receptor [18] (Fig. 1). Additionally, TNF-α enhances activity of hormone sensitive lipase in adipose tissue and thus increases the release of FFA into circulation [18]. Animal studies suggest that TNF-α is also related to β cell failure [10, 21,22,23,24,25,26].
In adults, an increased production of TNF-α in visceral adipose tissue correlates positively with the degree of obesity and insulin resistance [12, 30, 31]. In both cross-sectional and longitudinal pediatric studies, TNF-α is associated with parameters of insulin resistance, MetS, and degree of overweight [13•, 14, 15, 32,33,34]. Furthermore, TNF-α is higher in obese adolescents with T2DM compared to BMI-, age-, and gender- matched adolescents without T2DM [15]. These findings support the hypotheses that TNF-α is associated with insulin resistance and β cell failure.
Interleukin-6 (IL-6)
IL-6 is an interleukin circulating in multiple glycosylated forms ranging from 22 to 27 kDa [18, 27]. It acts as a pro-inflammatory cytokine inhibiting the insulin-signaling cascade by an impairment of insulin-induced insulin receptor and IRS-1 phosphorylation [18] (Fig. 1). Infusion of recombinant IL-6 in adults leads to an increase in hepatic glucose output and hyperglycemia [18]. Furthermore, IL-6 has a lipolytic effect with a consequent increase of FFA levels in circulation [18]. IL-6 concentrations are elevated in obese insulin-resistant adults [11, 35] as well as in obese insulin-resistant children [36, 37]. There is no difference of IL-6 levels between children with and without T2DM [38]. These findings support the role of IL-6 in the genesis of insulin resistance but do not confirm the hypothesis that IL-6 is involved in β cell failure.
Interleukin 1 Beta (IL-1β)
The pro-inflammatory cytokine IL-1β increases not only insulin resistance but also inhibits the function and promotes apoptosis of β cells in mouse models [21, 22, 39]. The blockade of IL-1 improves glycemia and β cell function and reduces inflammation in animal models of T2DM [40] and in humans with T2DM [21]. IL-1β concentrations are increased in adults with T2DM [11, 12, 30]. Obese children with MetS demonstrate higher concentrations of IL-1β than their lean counterparts [13•, 14]. IL-1β concentrations do not differ between obese adolescents with or without T2DM [15]. These findings do not support the hypothesis that IL-1β is involved in β cell failure but confirm the role of IL-1β in the genesis of insulin resistance and MetS in children.
Interferon Gamma (IFNγ)
Another pro-inflammatory cytokine suggested that to lead to β cell dysfunction is IFNγ. It is secreted by Th1 cells [22]. IFNγ is an important immune-activating cytokine that can prime macrophages for activation and induce inflammatory responses [41]. Obese adults with T2DM have higher concentrations of IFNγ [11, 12, 30, 31]. However, obese adolescents with T2DM do not have increased IFNγ levels [15]. Obese children have increased concentrations of IFNγ related to insulin resistance and other parameters of the MetS [42]. These findings do not support the hypothesis that IFNγ is involved in β cell failure but confirm the role of IFNγ in the genesis of insulin resistance and MetS in children.
Progranulin (PGRN)
PGRN is a widely expressed 593–amino acid glycoprotein, which has pro-inflammatory properties [43,44,45,46]. Full-length progranulin has anti-inflammatory activity [47], while proteolytic cleavage of progranulin generates granulin peptides, some of which promote inflammation [48]. Progranulin remarkably attenuate insulin sensitivity by inhibiting the insulin-signaling cascade by binding to the TNF-α receptor in cultured human adipocytes [45, 49]. PGRN promotes insulin resistance by increasing levels of IL-6 [45].
Data in humans are conflicting. Some studies report increased progranulin concentrations in obese adults with MetS or humans with T2DM, while others demonstrate no association between PGRN and MetS or T2DM [50,51,52]. Studies in obese children report no difference in respect to PGRN concentrations compared to their normal-weight counterparts as well as no relationship to parameters of the MetS or insulin resistance [53, 54]. Data in children with T2DM are lacking so far. Therefore, PGRN seems not to be related to insulin resistance or MetS in the pediatric population and the relationship to β cell failure is unclear.
Additional Inflammatory Cytokines
Besides the inflammatory cytokines mentioned above, several other widely expressed cytokines have been suggested to be related to insulin resistance. For example, obese insulin-resistant adults have significantly higher concentrations of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) concentrations [11, 12, 30, 31]. Obese children with parameters of the MetS demonstrate higher concentrations of MCP-1 and IL-8 than their lean counterparts [13•, 14, 32,33,34]. However, data concerning concentrations of these cytokines in adolescents with T2DM or MetS are not available so far. Therefore, it is unclear whether they play a role in insulin resistance, MetS, or T2DM in the pediatric population.
Adipokines
Cytokines secreted predominately from adipose tissue are called adipokines. Some of them also regulate the inflammation processes [55].
Leptin
Leptin is a 16-kDa peptide hormone mainly secreted by white adipose tissue [55]. It acts on the hypothalamus, leading to decreased appetite and increased energy expenditure, thereby regulating body weight [55]. Additionally, leptin acts on immune cells to stimulate the production of a spectrum anti-inflammatory cytokines [18]. Furthermore, binding of leptin to its receptor activates Janus kinase (JAK)2 which leads to activation of signal transducer and activator of transcription (STAT)3, IRS and also mitogen-activated-protein kinase (MAPK) (Fig. 1) [56]. These pathways and inflammatory molecules can induce the activation of suppressors of cytokine signaling 3 (SOCS3), which is an anti-inflammatory cytokine that suppresses cellular responses to inflammatory cytokines and also exerts an inhibitory feedback loop to leptin and insulin signaling [57]. This overlap between both signaling pathways via SOCS3 is suggested as a concomitant development of insulin and leptin resistance, potentially contributing to glucose intolerance and excess weight gain [56, 57]. On the other side, leptin improves directly insulin resistance in mouse models of T2DM through an increased oxidation of FFA [58].
Some studies report reduced leptin concentrations in adults with T2DM, while others show increased leptin levels or no difference of leptin levels between obese adults with and without T2DM [12, 59,60,61]. Two recent clinical trials show that leptin therapy is ineffective in improving diabetes and insulin resistance in obese people affected by T2DM [62, 63]. This might be explained at least in part by the observation that common obesity in humans is as a leptin resistant state [64, 65]. The potential mechanisms for leptin resistance include defective transport of leptin across the blood-brain barrier and defects in leptin receptor/post-receptor signaling cascade [64]. An increased pro-inflammatory response is reported in leptin resistance during obesity [66].
In children, hsCRP serum levels are related to leptin concentrations [67]. However, in contrast to the hypothesis of leptin resistance as a trigger of insulin resistance, serum leptin concentrations were lower in adolescents with T2DM compared to adolescents without T2DM [68]. Studies in adults [30] or children [59] reporting increased leptin levels in T2DM have not adjusted their control group to weight status, which is an important confounder since leptin is strongly associated to fat mass. Therefore, it is not proven that leptin resistance is a relevant mechanism in the development of insulin resistance, MetS, or T2DM in adolescents.
Adiponectin
Adiponectin exists as a full-length protein of 30 kDa and as a number of multimeric complexes [18]. Especially high molecular weight adiponectin are related to insulin sensitivity and T2DM [69, 70]. Adiponectin acts as a hormone with insulin-sensitizing properties in vitro and in animal models and may also promote β cell survival [71]. Even though adiponectin is secreted predominantly by adipose tissue, adiponectin concentrations are negatively correlated with fat mass in humans [70, 72]. Adiponectin levels are inversely correlated to insulin resistance and parameters of MetS in adults [70, 73, 74] and children [61, 75]. The reason for hypoadiponectinemia in obesity and insulin resistance is unclear. IL-6 and TNF-α decrease adiponectin mRNA in vitro [76]. Furthermore, prolonged exposure to insulin leads to a decrease in levels of adiponectin gene expression in adipocytes in vitro [76]. Therefore, hyperinsulinemia in insulin resistance might contribute to low adiponectin levels.
Hypoadiponectinemia correlates with the development of T2DM in adults [12, 77, 78], but the causal directions of this association is unclear. In manifest adult T2DM, some studies report reduced adiponectin concentrations, while others show no alteration of adiponectin levels [12, 30, 34, 61, 79]. In children with T2DM, reduced concentrations of adiponectin are reported [10, 59]. After adjusting for weight status however, adiponectin concentrations do not differ between obese adolescents with and without T2DM, but between obese children with and without MetS [68]. These findings suggest that adiponectin is associated with insulin resistance but not with T2DM. Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in T2DM [80].
Adipocyte-Specific Fatty Acid-Binding Protein (A-FABP)
A-FABP belongs to the fatty acid-binding proteins and is present in adipocytes and macrophages [81]. Like most FABPs, A-FABP can bind with a variety of hydrophobic lipid ligands known to influence systemic inflammation [82]. Mice deficient in A-FABP is protected from development of hyperinsulinemia, hyperglycemia, and insulin resistance [81]. A-FABP concentrations are associated with insulin resistance and parameters of MetS in obese adults [81, 83]. In contrast, there is no relationship between A-FABP concentrations and insulin resistance or any parameters of the MetS in obese children [84]. Data concerning A-FABP in adolescents with T2DM are not available so far. Therefore, there are no data in the pediatric population supporting the hypothesis that A-FABP is related to insulin resistance, MetS, or T2DM.
Resistin
Resistin is a 12.5-kDa peptide produced by preadipocytes [18]. It was hypothesized that resistin has pro-inflammatory properties leading to insulin resistance [18]. Administration of resistin in healthy mice impairs glucose tolerance, whereas immunoneutralization of resistin in obese mice improves insulin sensitivity [85]. However, the role of resistin in human insulin resistance is less clear. Some studies documented that plasma resistin levels are elevated in obese adults with insulin resistance [86], whereas others reported that high-insulin-sensitive athletes have higher plasma resistin levels than obese subjects [87]. Data concerning resistin in adolescents with T2DM are not available so far. Resistin concentrations are not associated with parameters of the MetS or insulin resistance in obese children [88]. This is in line with the current hypothesis suggesting that the main significance of resistin in humans appears to regulate the inflammatory process rather than directly influencing insulin sensitivity [18].
Apelin
Apelin exists in at least three bioactive forms, consisting of 13, 17, or 36 amino acids, all originating from a common 77-amino acid precursor. Apelin is the endogenous ligand of the orphan G protein-coupled receptor [89]. Although synthesized in several tissues, apelin is expressed and secreted predominately by human adipocytes [90]. The most documented functions of apelin concern the regulation of fluid homeostasis and the modification of cardiac contractility and blood pressure [89, 91, 92]. Additionally, apelin inhibits insulin secretion in mice [89] suggesting a link between apelin and glucose homeostasis [93].
The situation in humans concerning apelin and its relation to insulin resistance is less clear. Some studies in adults demonstrate a positive correlation between apelin, insulin resistance, and parameters of MetS [94, 95], while other studies report the opposite [96, 97]. In children, no association between apelin and insulin resistance or parameters of MetS could be detected [98, 99]. Data concerning apelin in adolescents with T2DM are not available so far. Therefore, there are no data in the pediatric population supporting the hypothesis that apelin is related to insulin resistance, MetS, or T2DM.
Visfatin
Visfatin is a 52-kDa pre-B cell colony-enhancing factor expressed in peripheral blood lymphocytes [18] and visceral adipose tissue [100]. Similar to insulin, visfatin in vitro enhances glucose uptake by adipocytes and myocytes and inhibits hepatocyte glucose release [100]. Visfatin’s insulin-like effects are observed in the phosphorylation of insulin receptors IRS-1 and IRS-2. Interestingly, visfatin and insulin have the same affinity for the insulin receptor but interact with the insulin receptor at different site. Furthermore, visfatin regulates intracellular activity of the NAD/NADH dependent enzymes that are critical for glucose-stimulated insulin secretion in pancreatic β cells [101]. Clinical studies in adults provide controversial findings concerning the role of visfatin glucose metabolism with positive, negative, or no associations found [102,103,104]. In children, no association between visfatin and insulin resistance is reported [105]. Data concerning visfatin in adolescents with T2DM are not available so far. Therefore, there are no data in children supporting the hypothesis that visfatin is related to insulin resistance, MetS, or T2DM.
Omentin
Omentin is a 38–40-kDa adipokine preferentially produced by visceral adipose tissue [106]. Omentin enhances insulin-stimulated glucose uptake in human adipocytes [106, 107]. Expression of omentin in visceral adipose tissue is reduced in insulin resistance [106, 107]. Omentin leads to suppression of TNF-α-induced vascular inflammation in cell models [108]. Omentin upregulates adiponectin gene expression [109]. In children, serum omentin levels correlate negatively with insulin resistance [110]. Obese children with MetS have lower omentin serum levels compared to obese children without MetS [111, 112]. Data concerning omentin in adolescents with T2DM are not available so far. These findings support the role of omentin in the genesis of insulin resistance and MetS, while its protective effect on β cells is unclear in the pediatric population.
Pigment Epithelium-Derived Factor (PEDF)
PEDF is a 50-kDa secreted glycoprotein belonging to the serine protease inhibitor (serpin) family [18]. Recombinant PEDF activates macrophages to release TNF-α and IL-1 [113]. Additionally, PEDF promotes lipolysis in an adipose triglyceride lipase-dependent manner and mobilizes FFA into systemic circulation leading to inflammation [18]. PEDF provokes kinase-mediated inhibitory phosphorylation cascade of IRS that attenuates insulin signaling and induces insulin resistance in peripheral tissues [18]. Furthermore, PEDF might be the link between insulin resistance and acanthosis nigricans [114].
Administration of recombinant PEDF reduces insulin sensitivity during hyperinsulinemic-euglycemic clamp in mice, whereas neutralization of PEDF restores insulin sensitivity [115]. PEDF expression in adipose tissue positively correlates with obesity and insulin resistance in mice [115]. In adults, PEDF correlates better to insulin resistance than to the degree of obesity [116]. In children, plasma PEDF is positively associated with insulin resistance [117]. However, PEDF concentrations are similar in obese children with and without T2DM [118]. These findings support the role of PEDF in the genesis of insulin resistance and MetS, but do not confirm the hypothesis that PEDF is involved in β cell failure.
Chemerin
Chemerin is an adipokine highly expressed in white adipose tissue and in the liver [119, 120]. It is unclear whether chemerin increases insulin resistance or if chemerin is an adaptive hormone to improve insulin resistance since conflicting data exist regarding the effect of chemerin on insulin signaling in adipocytes in vitro. Chemerin has been shown to downregulate insulin-stimulated glucose uptake in adipocytes [121], while another study reported the opposite [122]. Chemerin might also influence β cell function [123]. TNF-α stimulates mRNA levels of chemerin in visceral adipocytes from obese patients [124]. Injection of recombinant human chemerin exacerbates glucose intolerance, lowers serum insulin levels, and decreases tissue glucose uptake in obese mice [125].
Chemerin is associated with components of MetS in some studies of adults [126, 127], while another study does not find any relationship between parameters of MetS, insulin resistance, and chemerin [128]. In children, serum concentrations of chemerin are related both cross-sectionally and longitudinally to the degree of insulin resistance, amount of fat mass, and severity of MetS [54, 129,130,131,132,133]. Data concerning chemerin in adolescents with T2DM are not available so far. These findings support the role of chemerin in the genesis of insulin resistance and MetS, while the situation in T2DM is less clear in children.
Vaspin
Vaspin belongs to the serpin superfamily and is serine protease inhibitor with insulin-sensitizing effects [134]. It is produced predominately in the visceral adipose tissue [134]. Recombinant vaspin administration in obese mice improves insulin sensitivity [134]. In adults, vaspin correlates with fat mass and insulin resistance [135, 136]. Obese children with MetS have higher vaspin concentrations than obese children without MetS [111, 137]. T2DM seems to abrogate the correlation between increased circulating vaspin, higher body weight, and decreased insulin sensitivity in adults [138]. Data concerning vaspin in adolescents with T2DM are not available so far. These findings support the role of vaspin in the genesis of insulin resistance and MetS, while the situation in T2DM is unclear in children.
Other Adipokines
There are several other adipokines which have been proposed to be linked to insulin resistance, parameters of MetS, and T2DM such as adipolin [18, 139]. However, today, there are only few studies of these adipokines in insulin-resistant humans and studies in children are especially missing.
Hepatokines
Cytokine secreted by the liver, so-called hepatokines, have also been proposed to be related to chronic inflammation, insulin resistance, parameters of MetS, and T2DM [140,141,142,143,144,145,146,147,148]. For example, hepatocyte-secreted dipeptidyl peptidase 4 (DPP4) in obese mice promotes adipose inflammation and insulin resistance [149].
Fibroblast Growth Factor (FGF)-21
FGF-21 is an insulin-sensitizing hepatokine. It is mainly produced by the liver but also by other tissues including white adipose tissue, skeletal muscle, and pancreatic β cells [150]. FGF-21 induces glucose uptake and decreases glucose concentrations in obese animals [142, 151]. Adults with insulin resistance or T2DM have higher FGF-21 serum levels pointing to FGF-21 resistance [143, 152, 153]. FGF-21 resistance can be mediated through altered expression of both the FGF-21 receptor and the adapter molecule β-klotho [154]. Interestingly, TNF-α represses β-klotho expression and impairs FGF-21 action in adipose cells [148]. In concordance, FGF-21 concentrations are higher in obese adolescents with T2DM compared to obese adolescents without T2DM [155]. These findings suggest a FGF-21 resistance state in the genesis of insulin resistance and β cell failure in the pediatric population.
Fetuin A
Another protein secreted by the liver, fetuin A, is also proposed as a link between insulin resistance, MetS, and T2DM [156]. Fetuin A inhibits insulin receptor tyrosine kinase activity in muscles [157, 158] and induces cytokine expression and low-grade inflammation in animal models [147]. Additionally, fetuin A represses adiponectin production in animals [147]. Higher fetuin A concentrations are associated with the degree of insulin resistance, severity of MetS, and the presence of T2DM in adults [145, 159]. Furthermore, fetuin A is associated both cross-sectionally and longitudinally with insulin resistance and parameters of the MetS in obese children [15, 160]. Fetuin A serum levels are higher in obese adolescents with T2DM compared to age-, gender-, and BMI-matched adolescents without T2DM [155]. These findings support the role of fetuin A in the development of insulin resistance and β cell failure in the pediatric population.
Other Tissues
The skeleton and muscle tissue are now regarded as endocrine organs secreting cytokines that affect glucose metabolism.
Osteocalcin
Osteocalcin, a marker of bone formation specifically synthesized and secreted by osteoblasts, has also insulin-sensitizing properties [161]. Adults with T2DM have low circulating osteocalcin levels [162, 163]. Osteocalcin is associated negatively with insulin resistance and parameters of MetS in cross-sectional and longitudinal analyses of obese children [164]. Data concerning osteocalcin in adolescents with T2DM are not available so far. These findings support the role of osteocalcin in the genesis of insulin resistance and MetS in children, while the situation in T2DM is less clear.
Irisin
Irisin, a myokine induced by exercise, is another cytokine with insulin-sensitizing properties [165, 166]. Circulating irisin results from C-terminal cleavage of the fibronectin type III domain containing five transmembrane protein [167]. This process is induced by the peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α [168]. Irisin concentrations increase immediately after exercise and correlate with exercise intensity [169]. Since irisin induces glucose and fatty acid uptake in human muscle, the increase of irisin in insulin-resistant obese humans in most studies suggests a state of irisin resistance [170, 171]. Data concerning irisin in adolescents with T2DM are not available so far. Accordingly to most previous studies in adults [165, 166, 172], irisin is associated with insulin resistance and other parameters of the MetS both in cross-sectional and longitudinal analyses in obese children [173]. These findings support an irisin resistant state in the genesis of insulin resistance and MetS in children, while the situation in T2DM is unclear.
Conclusions
There are a growing number of discovered inflammatory markers, adipokines, and hepatokines, which have been hypothesized to be linked to inflammation and consequently insulin resistance, MetS, and development of T2DM. While for some of these parameters, this hypothesis could not be confirmed in the pediatric population (no impact of progranulin, A-FABP, resistin, apelin, or visfatin on MetS, insulin resistance, or T2DM), a significant association of other parameters to MetS, and T2DM were confirmed in the children (Fig. 2): Pro-inflammatory cytokines related to insulin resistance and MetS in children are TNF-α, IL-6, IL-1β, IFNγ, PEDF, leptin, chemerin, vaspin, and fetuin A. The serum concentrations of all of them are increased in obesity. Anti-inflammatory cytokines associated with insulin resistance and MetS in children are adiponectin, omentin, FGF-21, osteocalcin, and irisin. These anti-inflammatory are decreased (adiponectin, omentin, and osteocalcin) or increased (FGF-21 and irisin) in obesity, the latter suggesting a resistance state. The pro-inflammatory cytokines TNF-α and fetuin A, and the anti-inflammatory metabolic factor FGF-21 are altered in obese children with T2DM pointing toward an involvement in β cell failure.
The presented data in the pediatric population support the hypothesis that systemic inflammation is one causative link between obesity, insulin resistance, MetS, and T2DM. In the future, elucidating pathways of these cytokines, adipokines, and hepatokines may yield a potential therapeutic target in ameliorating insulin resistance and preventing T2DM.
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Thomas Reinehr and Christian Ludwig Roth declare that they have no conflict of interest.
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This article is part of the Topical Collection on Pediatric Type 2 and Monogenic Diabetes
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Reinehr, T., Roth, C.L. Inflammation Markers in Type 2 Diabetes and the Metabolic Syndrome in the Pediatric Population. Curr Diab Rep 18, 131 (2018). https://doi.org/10.1007/s11892-018-1110-5
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DOI: https://doi.org/10.1007/s11892-018-1110-5