**4. Interleukin-6**

In normal subjects, adiponectin has important physiological functions in maintaining the metabolic balance (**Figure 2**); therefore, in patients with MetS, adiponectin levels are decreased [43]. Numerous studies have demonstrated its positive effect on metabolic protection, mainly based on its potentially inhibitory activity on the atherogenic process [46]. Recent studies have shown that adiponectin is inversely correlated with MetS components and that it has benefic effects on metabolic disorders [47]. Hypoadiponectinemia induced by visceral obesity determines vascular changes and insulin resistance. Likewise, two clinical studies conducted by Gannage-Yared et al. and by Santaneimi et al. have demonstrated the correlation of adipo-

Various studies recommend using the leptin:adiponectin ratio (LAR) due to its increased predictive power, despite determining leptin and/or adiponectin alone. Recent data suggest the fact that leptin and adiponectin are two molecules that possess antagonistic effects. In addition, the study by Thorand et al. has been suggested that leptin and adiponectin interact with each other in order to modulate the risk of diabetes [3]. Therefore, Finucane et al. have demonstrated that LAR is a useful marker of insulin resistance in non-diabetic adults [48]. Lopez-Jaramillo et al. have emphasized the use of LAR in the evaluation of insulin resistance, and Kotani et al. have confirmed the predictive value of LAR in Japanese patients with MetS; other studies have

Ghrelin is a peptide hormone produced in the gastrointestinal tract, and it has an important role in regulating the use of energy in human organism. Ghrelin undergoes posttranslational changes resulting in two circulating forms: unacylated ghrelin (UAG) and acylated ghrelin (AG) [51].

also shown the correlation between LAR with all five MetS components [49–51].

nectin with MetS independent of BMI [7, 9].

**Figure 2.** Metabolic balance mediated by adiponectin.

92 Ultimate Guide to Insulin

**2.3. Leptin:adiponectin ratio**

**3. Ghrelin**

**3.1. Generalities**

#### **4.1. Interleukin-6 and inflammation response**

IL-6 is a human cytokine that plays important roles in acute and chronic inflammation, immune cell development, and the pathogenesis of autoimmune disease. It is known that the increased activity of IL-6 gene is associated with an elevated risk of developing diabetes mellitus [56]. Likewise, IL-6 is linked with all the components of the inner immunity and yields a pro-inflammatory effects explained by different pathways **(Figure 3)**. Nevertheless,

**Figure 3.** Inflammation pathways that involve IL-6.

studies confirmed that IL-6 also controls processes involved in the resolution of inflammation, emphasizing its anti-inflammatory function [57].

**5.2. Tumoral necrosis factor-alpha and metabolic syndrome**

variant and determine a 23% increased risk to develop MetS [20].

components.

with MetS.

**Figure 5.** TNF-α and insulin resistance.

TNF-α can be produced by inflammatory cells from the dysfunctional adipose tissue, similar to IL-6. TNF-α is involved in numerous MetS pathways and alterations, in insulin resistance through similar mechanism of mTOR and protein C kinase activation and systemic inflammation [62]. As many studies have shown, TNF-α is being associated with all MetS

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In the study by Moon et al. on obese adolescents, it was confirmed that TNF-α had higher levels in obese patients, even higher in male subjects, also, TNF-α positively correlated with BMI and waist circumference. Initially, TNF-α correlated positively with triglyceride levels and diastolic blood pressure, and inversely with HDL cholesterol, but after adjustment for BMI and waist circumference, only the association with triglyceride levels persisted [19].

In the meta-analysis of Sookoian et al. conducted on 16 homogeneous studies, it has been shown that obesity, systolic blood pressure, and serum insulin levels positively correlate with TNF-α -308A gene (genetic polymorphism that influences the plasmatic level of cytokine)

Obesity induces a systemic inflammatory status that determines dysfunctions of the macrophages and adipocytes and inappropriate cytokine production [21]. As a result, higher levels of TNF-α determine insulin resistance through various mechanisms and promote disease progression in patients with MetS **(Figure 5).** Studies emphasize that insulin resistance caused by TNF-α is based on abnormal insulin signaling, overexpression of tissular and plasmatic levels of TNF-α in subjects with insulin resistance, and administration of TNF-α determines and TNF-α neutralization improves insulin resistance [22–25]. Therefore, TNF-α is involved in MetS pathogenesis and progression and could be used in determining patients
