**2. Adiponectin and atherosclerosis**

Human adiponectin is a protein containing 244 amino acids. It is produced by apM1 cDNA transcripts. Adiponectin consists of two structurally distinct domains and the C-terminal part is likely to be involved in protection against atherosclerosis (Figure 1).

As a member of the soluble collagen superfamily, adiponectin has a structural homology with collagen type VIII, X, complement C1q and tumor necrosis factor alpha family [2]. In

© 2012 Novotný, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

human plasma, adiponectin is present in a variety of heterogeneous isoforms, from large multimeric structures of high molecular weight to trimeric isoform. Monomeric one is present only in adipose tissue. The biological activity of various multimeric isoforms are not fully known yet, but it appears different isoforms have varying effects in different diseases. Although some studies have proposed that the ratio of high molecular weight (HMW) form to the other forms may serve as a better indicator of metabolic disorders, the majority of studies that have linked adiponectin to metabolic diseases have used assays for total adiponectin.


**Figure 1.** Schematic presentation of adiponectin structure (adapted from [2]).

Adiponectin gene is located on chromosome 3q27 and contains 3 exons and 2 introns. In 2003, DNA sequences encoding two receptors for adiponectin Adipo R1 and Adipo R2 were identified [3]. They are localized on chromosome 1 (1p36.13-q41) and 12 (12p13.31), respectively, with expression in most organs (AdipoR1 in skeletal muscle, AdipoR2 in the liver, in particular). Adiponectin gene is polymorphic, located in the region that contains susceptible loci for type 2 diabetes mellitus and metabolic syndrome. A number of single nucleotide polymorphisms (SNPs) and missense mutations were observed, especially in exons 2, 3 and the gene promoter.

Figure 2 schematically depicts some of the antiatherogenic properties of adiponectin towards different types of cells that have been established in experimental models. Adiponectin negatively regulates the expression of TNF alpha and C-reactive protein (CRP) in adipose tissue. On the contrary, its expression is negatively regulated by TNF alpha and interleukin 6 (IL 6). Adiponectin reduces expression of vascular and intracellular adhesion molecules (VCAM 1, ICAM 1), E-selectin, interleukin 8, and monocyte adhesion to human aortal endothelial cells after their stimulation with TNF alpha [4]. The proliferation and migration of smooth muscle cells induced by platelet growth factor (PDGF) is abolished or diminished by adiponectin action as inhibition of activation of nuclear factor kappa B in endothelial cells. This effect is partially mediated by its ability to support the action of cyclic adenosine monophosphate - proteinkinase A system (cAMP-PKA).

In endothelial cells, adiponectin inhibits the production of reactive oxygen species (ROS) induced by high levels of glucose via above mentioned the cAMP-PKA system. Adiponectin inhibits macrophage transformation to foam cells and reduces the intracellular content of cholesterol esters via suppression of expression of scavenger receptors, class A (SR-A). In these cells, adiponectin reduces lipopolysaccharides stimulated TNF alpha production. Recent clinical trials show a positive correlation of plasma levels of adiponectin and IL 10 [5]. In accordance with these findings, adiponectin has an antiatherogenic properties in mice models. Adenovirus-mediated supplementation of adiponectin inhibits the formation of atherosclerotic lesions and reduces the levels of mRNA of SR-A, TNF alpha and VCAM 1 in the vascular wall [6]. It is interesting that in these models, adiponectin has no effect on glucose and lipid parameters. The authors conclude that adiponectin affects atherogenesis through a series of antiinflammatory effects on macrophages and vascular endothelium.

**Figure 2.** Some of protective actions of adiponectin (adapted from [2]).

678 Lipoproteins – Role in Health and Diseases

exons 2, 3 and the gene promoter.

adiponectin.

human plasma, adiponectin is present in a variety of heterogeneous isoforms, from large multimeric structures of high molecular weight to trimeric isoform. Monomeric one is present only in adipose tissue. The biological activity of various multimeric isoforms are not fully known yet, but it appears different isoforms have varying effects in different diseases. Although some studies have proposed that the ratio of high molecular weight (HMW) form to the other forms may serve as a better indicator of metabolic disorders, the majority of studies that have linked adiponectin to metabolic diseases have used assays for total

Adiponectin gene is located on chromosome 3q27 and contains 3 exons and 2 introns. In 2003, DNA sequences encoding two receptors for adiponectin Adipo R1 and Adipo R2 were identified [3]. They are localized on chromosome 1 (1p36.13-q41) and 12 (12p13.31), respectively, with expression in most organs (AdipoR1 in skeletal muscle, AdipoR2 in the liver, in particular). Adiponectin gene is polymorphic, located in the region that contains susceptible loci for type 2 diabetes mellitus and metabolic syndrome. A number of single nucleotide polymorphisms (SNPs) and missense mutations were observed, especially in

Figure 2 schematically depicts some of the antiatherogenic properties of adiponectin towards different types of cells that have been established in experimental models. Adiponectin negatively regulates the expression of TNF alpha and C-reactive protein (CRP) in adipose tissue. On the contrary, its expression is negatively regulated by TNF alpha and interleukin 6 (IL 6). Adiponectin reduces expression of vascular and intracellular adhesion molecules (VCAM 1, ICAM 1), E-selectin, interleukin 8, and monocyte adhesion to human aortal endothelial cells after their stimulation with TNF alpha [4]. The proliferation and migration of smooth muscle cells induced by platelet growth factor (PDGF) is abolished or diminished by adiponectin action as inhibition of activation of nuclear factor kappa B in endothelial cells. This effect is partially mediated by its ability to support the action of cyclic

In endothelial cells, adiponectin inhibits the production of reactive oxygen species (ROS) induced by high levels of glucose via above mentioned the cAMP-PKA system. Adiponectin inhibits macrophage transformation to foam cells and reduces the intracellular content of cholesterol esters via suppression of expression of scavenger receptors, class A (SR-A). In these cells, adiponectin reduces lipopolysaccharides stimulated TNF alpha production. Recent clinical trials show a positive correlation of plasma levels of adiponectin and IL 10 [5]. In accordance with these findings, adiponectin has an antiatherogenic properties in mice

**Figure 1.** Schematic presentation of adiponectin structure (adapted from [2]).

adenosine monophosphate - proteinkinase A system (cAMP-PKA).

A very important finding was observed in recent work describing the relationship of adiponectin-immune system. Adiponectin is able to bind to a number of target molecules, including the damaged endothelium and the surface of apoptotic cells. The significance of this phenomenon is not entirely clear. The study describes in vitro binding of purified C1q complement to recombinant adiponectin and dependence on calcium and magnesium ions. It was found that this binding stimulates the classical pathway of complement activation. Adiponectin does serve as an antiinflammatory factor, but may also induce biological activity through activation of complement. The authors hypotesize the binding of C1q leads to conformational changes in the adiponectin molecule, which induces the classical pathway of complement activation. Adiponectin may play an important role in immunity by its direct biological effect [7]. There is also evidence of adiponection accumulation on injured vascular arterial wall (but not in healthy one). This may lead to the hypothesis of the "consumption" of circulating adiponectin in patients with ischemic heart disease.

In some recent studies, adiponectin has a positive effect in endothelial homeostasis. It acts as a regulator of the enzyme endothelial nitric oxide synthase (eNOS), which is a key determinant of endothelial function and angiogenesis (the production of NO inhibits the inflammatory response in the arteries), and also promotes phosphorylation of eNOS in endothelial cells, increases its expression and induces NO production after suppression of its activity caused by the effect of oxidized low-density lipoproteins (oxLDL) [8].

Adiponectin promotes cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) synthesis in cardiac cells. It also has an antiapoptotic properties in vitro, as in endothelial cells. In the heart tissue adiponectin thus acts as a regulator of cardiac damage through its antiinflammatory effect and as a factor preventing the reconstruction of cardiac tissue. In order to become a useful biomarker of cardiovascular risk, it is necessary to determine which of its isoforms exhibit cardioprotectivity, and to clarify mechanism of their action in various pathophysiological conditions [7].

There is an increasing number of papers on experimental models point to the fact that adiponectin plays an important protective role in the development of insulin resistance and diabetes. Severe insulin resistance was seen in adiponectin-deficient knockout mice (KO-AD) after administration of high fat and/or carbohydrates diets. Administration of adiponectin led to reduced hyperglycemia in the diabetic mice without affecting insulin levels. In another study, increased muscle fatty acid oxidation and reduction of plasma glucose, free fatty acids and triglycerides were observed. Studies on experimental animal models revealed the administration of adiponectin has a beneficial action against the development of obesity and atherosclerosis. It seems that adiponectin acts not only as a factor increasing insulin sensitivity, and the protective effect may result from its ability to suppress production of proinflammatory cytokine [4].

#### **2.1. Adiponectin and its relationship to obesity and metabolic syndrome**

There has been a growing evidence of significantly reduced levels of adiponectin in obese individuals compared to subjects with normal body mass index (BMI) [9]. An inverse relationship with BMI was observed in both men and women, as well as negative correlation of adiponectin with visceral fat accumulation. It is obvious that hypoadiponectinemia (levels typically less than 4 mg/l) is associated with the development of insulin resistance and type 2 diabetes mellitus, independently of BMI and metabolic syndrome. Low adiponectinemia are considered the independent risk factor for developing hypertension. Kern et al. measured adiponectin plasma concentrations and mRNA levels in adipose tissue in nondiabetic subjects with varying degree of obesity and IR. They found a strong correlation of these two parameters. The obese individuals had significantly lower plasma adiponectin. When BMI was less than 30 kg/m2, women had twice more the body fat than men, but adiponectin levels were higher on average of 65% than in men (14.2 mg/l vs. 8.6 mg/l). Individuals with the highest levels of mRNA secreted the lowest levels of TNF alpha in adipose tissue. The authors conclude that adiponectin expression in adipose tissue is highest in lean subjects and women, and correlates with higher index of insulin sensitivity and lower TNF alpha expression [9]. Another study found that expression of adiponectin mRNA in adipose tissue may reflect short-term energy changes in some obese subjects. Expression of adiponectin and insulin sensitivity may be influenced by genetic variations in the adiponectin gene in response to acute energy fluctuations [10].

Metabolic syndrome characterized by abdominal obesity, dyslipidemia, hypertension and hyperglycemia, is a general risk for the development of atherosclerotic vascular disease. The study with 661 Japanese individuals investigated possible application of adiponectin as a biomarker of the metabolic syndrome [11]. Its plasma levels negatively correlated with waist circumference, visceral fat, TGL concentration, glucose and fasting insulinemia, systolic and diastolic blood pressure, and positively with HDL cholesterol. With decreasing levels of adiponectin, on the contrary, the number of components of metabolic syndrome increased. Total of 52% men and of 38% women with levels below 4.0 mg/l met criteria for MS. The authors suppose hypoadiponectinemia is closely associated with the clinical phenotype and its measurement could be useful in the MS treatment. Saely et al. observed a group of patients undergoing coronary angiography. Low adiponectin levels were independently associated with both metabolic syndrome and angiographically confirmed coronary atherosclerosis [12]. The highest levels of adiponectin were seen in subjects without MS and heart disease (12.1 ± 8.3 mg/l), whereas the lowest levels in patients with MS and presence of heart disease (6.7 ± 3.8 mg/l). Another study then identified a link between serum adipokines and cholesterol metabolism in individuals with MS. In 58 subjects with impaired glucose tolerance or elevated fasting glucose and signs of MS the markers of cholesterol synthesis were measured (determined by the ratio of non-cholesterol sterols to cholesterol and dietary cholesterol portion), in relation to adipokines and ultrasensitive CRP (hsCRP). It was found that adiponectin, leptin and CRP were associated with cholesterol metabolites (variations) and the high ratio of cholesterol synthesis to its absorption is characterized by high levels of serum leptin and low adiponectin [13].

#### **2.2. Adiponectin and its relationship to heart disease**

680 Lipoproteins – Role in Health and Diseases

various pathophysiological conditions [7].

suppress production of proinflammatory cytokine [4].

the adiponectin gene in response to acute energy fluctuations [10].

inflammatory response in the arteries), and also promotes phosphorylation of eNOS in endothelial cells, increases its expression and induces NO production after suppression of

Adiponectin promotes cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) synthesis in cardiac cells. It also has an antiapoptotic properties in vitro, as in endothelial cells. In the heart tissue adiponectin thus acts as a regulator of cardiac damage through its antiinflammatory effect and as a factor preventing the reconstruction of cardiac tissue. In order to become a useful biomarker of cardiovascular risk, it is necessary to determine which of its isoforms exhibit cardioprotectivity, and to clarify mechanism of their action in

There is an increasing number of papers on experimental models point to the fact that adiponectin plays an important protective role in the development of insulin resistance and diabetes. Severe insulin resistance was seen in adiponectin-deficient knockout mice (KO-AD) after administration of high fat and/or carbohydrates diets. Administration of adiponectin led to reduced hyperglycemia in the diabetic mice without affecting insulin levels. In another study, increased muscle fatty acid oxidation and reduction of plasma glucose, free fatty acids and triglycerides were observed. Studies on experimental animal models revealed the administration of adiponectin has a beneficial action against the development of obesity and atherosclerosis. It seems that adiponectin acts not only as a factor increasing insulin sensitivity, and the protective effect may result from its ability to

**2.1. Adiponectin and its relationship to obesity and metabolic syndrome** 

There has been a growing evidence of significantly reduced levels of adiponectin in obese individuals compared to subjects with normal body mass index (BMI) [9]. An inverse relationship with BMI was observed in both men and women, as well as negative correlation of adiponectin with visceral fat accumulation. It is obvious that hypoadiponectinemia (levels typically less than 4 mg/l) is associated with the development of insulin resistance and type 2 diabetes mellitus, independently of BMI and metabolic syndrome. Low adiponectinemia are considered the independent risk factor for developing hypertension. Kern et al. measured adiponectin plasma concentrations and mRNA levels in adipose tissue in nondiabetic subjects with varying degree of obesity and IR. They found a strong correlation of these two parameters. The obese individuals had significantly lower plasma adiponectin. When BMI was less than 30 kg/m2, women had twice more the body fat than men, but adiponectin levels were higher on average of 65% than in men (14.2 mg/l vs. 8.6 mg/l). Individuals with the highest levels of mRNA secreted the lowest levels of TNF alpha in adipose tissue. The authors conclude that adiponectin expression in adipose tissue is highest in lean subjects and women, and correlates with higher index of insulin sensitivity and lower TNF alpha expression [9]. Another study found that expression of adiponectin mRNA in adipose tissue may reflect short-term energy changes in some obese subjects. Expression of adiponectin and insulin sensitivity may be influenced by genetic variations in

its activity caused by the effect of oxidized low-density lipoproteins (oxLDL) [8].

The hypoadiponectinemia was also found in patients with angiographically documented coronary atherosclerosis or acute coronary syndrome. In men, plasma adiponectin significantly predicted the extent of coronary atherosclerosis [14]. A prospective study of patients with end-stage renal disease showed an inverse relationship between cardiovascular events and adiponectinemia. Higher adiponectin levels represent a low risk of myocardial infarction in healthy men individuals and moderately reduced risk of coronary heart artery disease in diabetic men patients [4]. In contrast, adiponectin concentrations did not correlate significantly with the risk of heart disease in American Indians or the British women. A large prospective study involving British men with heart disease combined with a meta-analysis of seven previously published studies found only a weak association of adiponectin with the disease [4]. This inconsistent data could be due to differences in study populations (ethnicity, gender, type of disease etc.). In any cases, it remains unclear whether hypoadiponectinemia is a reliable indicator of heart disease.

#### **2.3. Adiponection and inflammation**

CRP is known to be an independent predictor of future risk for cardiovascular events and risk factor for developing MS. Its positive association with BMI is considered as a useful biomarker for chronic inflammation linked to obesity. Plasma levels of CRP correlated negatively with adiponectin levels [15] which was confirmed by various studies. Since CRP mRNA in humans is expressed in adipose tissue, adiponectin can apparently participate in influencing CRP levels in plasma by regulation of its expression. The regulation of CRP synthesis in the liver is also influenced by proinflammatory adipokines IL 6 and TNF alpha. On the one side, adiponectin expression is regulated by proinflammatory cytokines, on the other side, adiponectin modulates the activity and the production of TNF alpha in different tissues. Several studies have found links between hypoadiponectinemia and elevated serum IL 6. So far, there is no evidence of a link between adiponectin and TNF alpha in plasma in humans. Nishida et al. describe the action of IL 6, adiponectin, CRP and metabolic syndrome in subclinical atherosclerosis [16]. The relative influence of these parameters on a group of healthy subjects was observed. In 714 men and 364 women aged 40 to 59 years, thickness of the intima-media complex (IMT), pulse blood flow velocity and components of MS were measured. IL 6 levels correlated with IMT parameter, while adiponectin correlated negatively with IMT only in men. Individuals with either high IL 6 or CRP, or low levels of adiponectin, had increased IMT in the presence of MS. Increasing number of MS components was expressed more strongly in women than in men. The authors speculate IL 6 and adiponectin are important risk factors for premature arterial alterations in men.

In another study, the relationship of adiponectin to markers of inflammation, atherogenic dyslipidemia and heart disease was investigated in patients with coronary artery disease [17]. Study participants were in a rehabilitation program to reduce the cardiovascular risk factors. After adjusting for age and sex, adiponectin was associated positively with HDL cholesterol and N- terminal propeptide of B natriuretic peptide (NT-proBNP), while the association was negative for triglycerides. In this study, no relationship was found with markers of inflammation. The same results were obtained after next adjustment for other parameters; BMI, alcohol intake, smoking, presence of diabetes and/or hypertension and lipid-lowering therapy, and fasting glucose. The authors conclude serum adiponectin is associated with the presence of the atherogenic dyslipidemia and NT-proBNP levels, but not with markers of systemic inflammation (IL 6, CRP) in patients with manifest coronary heart disease. Atherogenic dyslipidemia may be a link between adiponectin and progression of atherosclerosis. The role of systemic inflammation as part of the adiponectin-atherosclerosis relationship may decrease during the course of the disease, and could be more amplified in the earlier stage of disease development.

#### **3. Adiponectin and gene polymorphisms**

As mentioned above, the adiponectin gene is located on chromosome 3q27, containing 3 exons and 2 introns. This region also encopasses the susceptibile loci for type 2 diabetes and metabolic syndrome. The sequence polymorphism was found in the form of several single nucleotide polymorphisms (SNPs) and a number of missense mutations. Sequence analysis of the gene for adiponectin in Japanese and Caucasian populations found more than 10 SNPs, some of which are associated with BMI, metabolic syndrome, insulin sensitivity, hyperglycemia, type 2 diabetes, levels of plasma adiponectin, etc. The results of studies, however, are inconsistent, providing conflicting results. In many cases, the haplotype analysis was performed from a combination of alleles of individual SNPs.

682 Lipoproteins – Role in Health and Diseases

the earlier stage of disease development.

**3. Adiponectin and gene polymorphisms** 

biomarker for chronic inflammation linked to obesity. Plasma levels of CRP correlated negatively with adiponectin levels [15] which was confirmed by various studies. Since CRP mRNA in humans is expressed in adipose tissue, adiponectin can apparently participate in influencing CRP levels in plasma by regulation of its expression. The regulation of CRP synthesis in the liver is also influenced by proinflammatory adipokines IL 6 and TNF alpha. On the one side, adiponectin expression is regulated by proinflammatory cytokines, on the other side, adiponectin modulates the activity and the production of TNF alpha in different tissues. Several studies have found links between hypoadiponectinemia and elevated serum IL 6. So far, there is no evidence of a link between adiponectin and TNF alpha in plasma in humans. Nishida et al. describe the action of IL 6, adiponectin, CRP and metabolic syndrome in subclinical atherosclerosis [16]. The relative influence of these parameters on a group of healthy subjects was observed. In 714 men and 364 women aged 40 to 59 years, thickness of the intima-media complex (IMT), pulse blood flow velocity and components of MS were measured. IL 6 levels correlated with IMT parameter, while adiponectin correlated negatively with IMT only in men. Individuals with either high IL 6 or CRP, or low levels of adiponectin, had increased IMT in the presence of MS. Increasing number of MS components was expressed more strongly in women than in men. The authors speculate IL

6 and adiponectin are important risk factors for premature arterial alterations in men.

In another study, the relationship of adiponectin to markers of inflammation, atherogenic dyslipidemia and heart disease was investigated in patients with coronary artery disease [17]. Study participants were in a rehabilitation program to reduce the cardiovascular risk factors. After adjusting for age and sex, adiponectin was associated positively with HDL cholesterol and N- terminal propeptide of B natriuretic peptide (NT-proBNP), while the association was negative for triglycerides. In this study, no relationship was found with markers of inflammation. The same results were obtained after next adjustment for other parameters; BMI, alcohol intake, smoking, presence of diabetes and/or hypertension and lipid-lowering therapy, and fasting glucose. The authors conclude serum adiponectin is associated with the presence of the atherogenic dyslipidemia and NT-proBNP levels, but not with markers of systemic inflammation (IL 6, CRP) in patients with manifest coronary heart disease. Atherogenic dyslipidemia may be a link between adiponectin and progression of atherosclerosis. The role of systemic inflammation as part of the adiponectin-atherosclerosis relationship may decrease during the course of the disease, and could be more amplified in

As mentioned above, the adiponectin gene is located on chromosome 3q27, containing 3 exons and 2 introns. This region also encopasses the susceptibile loci for type 2 diabetes and metabolic syndrome. The sequence polymorphism was found in the form of several single nucleotide polymorphisms (SNPs) and a number of missense mutations. Sequence analysis of the gene for adiponectin in Japanese and Caucasian populations found more than 10 SNPs, some of which are associated with BMI, metabolic syndrome, insulin sensitivity, Kondo et al. analyzed a cohort of Japanese patients with type 2 diabetes and nondiabetic controls to detect mutations in the gene for adiponectin [18]. Four missense mutations in the globular domain (I+164T, R+112 C, H+241P, R+221S) were identified. The frequency of one mutation, the substitution of I+164T, was significantly higher in patients than in controls of comparable age and body weight. Mutation carriers had lower adiponectin concentrations in plasma and also showed the presence of a feature characteristic of the metabolic syndrome (hypertension, hyperlipidemia, diabetes, atherosclerosis). Hypoadiponectinemia was already evident at the same time in heterozygotes I+164 T mutation carriers and also in R +112 C, but this was the case of only 3 patients. The authors suggest I+164 T variant is associated with low adiponectin levels in plasma and type 2 diabetes mellitus.

Another study has examined the adiponectin gene locus as a candidate site for coronary artery disease [19]. 383 Japanese patients with angiographically confirmed disease and 318 individuals adjusted for age and BMI were the subjects of this study. Analyses of SNPs were performed using real time polymerase chain reaction (rtPCR) and restriction fragment length polymorphism (RFLP). In patients, the higher incidence of T+164 mutation and lower adiponectin levels in plasma were seen, independently of BMI. Subjects with the mutation showed a clinical phenotype of metabolic syndrome. According to the authors, the I+164T polymorphism is associated with metabolic syndrome and coronary artery disease in Japanese population.

Hara et al. examined the relationship between two SNPs located at exon 2 of adiponectin gene (T+45G and G+276T) and type 2 diabetes in the Japanese population [20]. Subjects with the GG genotype at position +45 or +276 had an increased risk of DM compared to TT genotypes. GG +276 homozygotes showed higher insulin resistance index and the presence of G allele at position 276 was characterized by lower levels of plasma adiponectin in subjects with higher BMI (GG: 10.4 mg/l, TT: 16.6 mg/l). The different results showed the study focused on the relationship between haplotypes of the adiponectin gene with obesity and other signs of metabolic syndrome in nondiabetic Caucasian population [21]. Both polymorphisms, T+45G and G+276T, separately significantly correlated with IR. The common haplotype was also closely associated with a number of components of metabolic syndrome. Homozygotes for middle-risk haplotype TG (i.e. individuals with +45 TT variant and +276 GG variant) had higher body weight, waist circumference, blood pressure, fasting glucose, insulin, cholesterol/ HDLcholesterol ratio and lower adiponectin levels, after adjustment for age, sex and body weight. However, in the second group (614 Caucasian individuals with type 2 DM) the risk haplotype was associated with increased body weight, not with DM. It is hypothesized the variability of the adiponectin gene is connected with obesity and other features of insulin resistance, but the risk haplotype is probably a marker of linkage disequilibrium with a polymorphism yet unidentified that directly affects the plasma levels of adiponectin and insulin sensitivity. Moreover, Fillipi et al. found no

association of SNP T+45G with insulin resistance [22]. The T+276 G polymorphism was associated with higher BMI, lower insulin and adiponectin, but, unlike previous study, in the TT genotype. In discussion the authors analyzed possible causes of these results and conclude the same mentioned above. There is the high probability of the existence of further SNPs or gene mutations, which is in linkage disequilibrium with SNP +276 and which determines its effect. Variations in the adiponectin gene and risk for subsequent type 2 diabetes in women has been of interest in the study of Hu et al. [23].

A prospective study focused on the determination of SNPs participation in the development of IR in French population found that variations in the adiponectin gene affects weight gain, body fat distribution and the development and the onset of hyperglycemia, as well as serum adiponectin [24]. At the start of a three-year study, the normoglycemic individuals with no signs of diabetes or impaired glucose tolerance were influenced mainly by two SNPs: G-11391A and T+45G.

An interesting work was published in 2006 in Clinical Chemistry by Hegener et al. [24]; the prospective study monitoring the risk of atherothrombotic disease in individuals with no signs of diabetes. Five SNPs in the gene for adiponectin were investigated in 600 Caucasian men with subsequent aterotrombotic events (myocardial infarction or stroke) and 600 controls. After adjustment for potential risk factors, regression analysis then revealed two variants with a decreased risk of stroke (C-11377G and G-11066A). This study has provided evidence of links of specific adiponectin gene variants with reduced risk of stroke.
