Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi


CiteScore 2018: 2.43

SCImago Journal Rank (SJR) 2018: 0.947
Source Normalized Impact per Paper (SNIP) 2018: 0.837

Online
ISSN
1868-1891
See all formats and pricing
More options …
Volume 18, Issue 1

Issues

The role of leptin/adiponectin ratio in metabolic syndrome and diabetes

Patricio López-Jaramillo
  • Corresponding author
  • Dirección de Investigaciones, Fundación Oftalmológica de Santander, FOSCAL, Floridablanca, Colombia
  • Escuela de Medicina, Universidad de Santander, UDES, Bucaramanga, Colombia
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Diego Gómez-Arbeláez
  • Dirección de Investigaciones, Fundación Oftalmológica de Santander, FOSCAL, Floridablanca, Colombia
  • Escuela de Medicina, Universidad de Santander, UDES, Bucaramanga, Colombia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jose López-López / Cristina López-López / Javier Martínez-Ortega / Andrea Gómez-Rodríguez / Stefany Triana-Cubillos
Published Online: 2013-12-13 | DOI: https://doi.org/10.1515/hmbci-2013-0053

Abstract

The metabolic syndrome comprises a cluster of cardiometabolic risk factors, with insulin resistance and adiposity as its central features. Identifying individuals with metabolic syndrome is important due to its association with an increased risk of coronary heart disease and type 2 diabetes mellitus. Attention has focused on the visceral adipose tissue production of cytokines (adipokines) in metabolic syndrome and type 2 diabetes mellitus, as the levels of the anti-inflammatory adipokine adiponectin are decreased, while proinflammatory cytokines are elevated, creating a proinflammatory state associated with insulin resistance and endothelial dysfunction. In this review, we will give special attention to the role of the leptin/adiponectin ratio. We have previously demonstrated that in individuals with severe coronary artery disease, abdominal obesity was uniquely related to decreased plasma concentrations of adiponectin and increased leptin levels. Leptin/adiponectin imbalance was associated with increased waist circumference and a decreased vascular response to acetylcholine and increased vasoconstriction due to angiotensin II. Leptin and adiponectin have opposite effects on subclinical inflammation and insulin resistance. Leptin upregulates proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6; these are associated with insulin resistance and type 2 diabetes mellitus. In contrast, adiponectin has anti-inflammatory properties and downregulates the expression and release of a number of proinflammatory immune mediators. Therefore, it appears that interactions between angiotensin II and leptin/adiponectin imbalance may be important mediators of the elevated risk of developing type 2 diabetes mellitus and cardiovascular diseases associated with abdominal obesity.

Keywords: adiponectin; angiotensin II; leptin; metabolic syndrome; type 2 diabetes

Introduction

Metabolic syndrome (MetS) is one of the leading global public health concerns [1]. Its prevalence varies between 15% and 40% internationally [2] and is higher in the populations of developing countries [2, 3]. MetS comprises a cluster of cardiometabolic risk factors, its central features being insulin resistance (IR) and adiposity [1, 4]. The Adult Treatment Panel III (ATPIII) criteria of the National Cholesterol and Education Program (NCEP) for MetS are the presence of three of the following characteristics: dysglycemia, low plasma high-density lipoprotein cholesterol (HDL-C), increased triglycerides (TG), elevated blood pressure, and abdominal obesity (AO) [5]. The diagnosis of MetS has been harmonized internationally using the NCEP ATPIII criteria with the notable exception of cutoffs for AO for waist circumference, which differ by ethnicity, country [5], and region [6]. MetS is of concern due to its association with an increased risk of coronary heart disease (CHD), type 2 diabetes mellitus (DM2), and other cardiometabolic diseases [7, 8]. The concept of MetS is controversial, but the higher prevalence of this cluster of metabolic alterations in Latin America suggests that it is a useful nosographic entity in the context of Latin American medicine. Therefore, it is important that physicians recognize this syndrome in order to identify a particularly high-risk population, often underestimated and undertreated [9]. We will review the possible mechanisms involved in the development of the MetS and DM2, with a particular emphasis on the role of leptin/adiponectin (L/A) ratio and its association with IR and low-degree inflammation.

Abdominal obesity and adipokine imbalance

It is well recognized that AO plays a central role in the development of MetS and contributes significantly to the progression of cardiovascular and metabolic diseases [10]. In a meta-analysis of studies assessing the impact of bodyweight on CHD, a five-unit increase in body mass index (BMI) was associated with a 29% increase in CHD risk [11]. However, it is still uncertain how much of this elevated risk is directly attributable to obesity alone and what the specific mechanisms are by which obesity (particularly AO) causes or accelerates atherogenesis.

There are a number of physiological and metabolic changes associated with obesity that may contribute to an increased risk of cardiovascular diseases (CVD). In recent years, attention has focused on the role of visceral adipose tissue due to the synthesis and release of a number of adipokines from adipocytes [12–14]. In MetS, increased visceral adipose tissue disturbs adipokine secretion and leads to a low-grade chronic inflammatory state mediated by the infiltration of macrophages into adipose tissue [14]. This inflammatory state is found to be associated with IR [15–17] and with atherosclerosis [14]. Visceral adipose tissue functions as a paracrine and an endocrine organ, secreting a number of adipokines, some of which are proinflammatory and atherogenic, such as leptin, tumor necrosis factor-α (TNF-α), resistin, interleukin-6 (IL-6), and fatty acid-binding protein 4, and others, which have anti-inflammatory, protective effects such as adiponectin [12, 13]. In MetS patients, serum adiponectin levels are decreased, while proinflammatory cytokines are elevated [18]. This imbalance in the inflammatory state leads to dysfunction of the endothelial cells, promoting the loss of their vasodilatory, antithrombotic, and antiatherogenic properties [19, 20], apparently a widespread biological response in humans [21]. The relationship between inflammation and MetS is supported by several studies [1, 18, 22], as is the association between increased visceral fat mass and MetS [23].

In this review, we pay particular attention to the interactions between AO and L/A ratio in CHD patients. We have examined these associations using an ex vivo model in which segments of internal mammary arteries were obtained from individuals with severe coronary artery disease (CAD) who subsequently underwent coronary artery bypass grafts. Patients were divided according to the presence of AO and matched by age, sex, glucose and insulin plasma levels, homeostatic model assessment (HOMA) index, lipid profile, tobacco and alcohol consumption, physical activity, and arterial blood pressure. We found that the presence of AO was uniquely related to decreased plasma concentrations of adiponectin and increased leptin levels (Figure 1) and was associated with a decreased vascular response to acetylcholine and an increased vasoconstriction in response to angiotensin II (Ang II). However, in these patients, plasma levels of other inflammatory markers evaluated, such as C-reactive protein (CRP), IL-6, and TNF-α, did not differ according to the presence or absence of AO [24]. Ang II is produced in adipocytes [25], and plasma levels of angiotensinogen and Ang II are positively associated with BMI [26]. Several studies in obese, insulin-resistant, or hypertensive animals and humans show that treatment with Ang II AT1 receptor antagonists reduces IR [27, 28]. Moreover, blocking the intracellular signals elicited by Ang II produces these effects that oppose the action of insulin on its target organs [29]. It is also proposed that the beneficial effects of AT1 receptor blockers on adipose tissue mass and IR in obesity could be related to the enhancement of adiponectin expression, the reduction of leptin expression, and the concomitant correction of the L/A imbalance [30].

Adiponectin, leptin and leptin/adiponectin ratio in patients with severe coronary artery disease divided by the presence of abdominal obesity. -AO: Patients without abdominal obesity; +AO: Patients with abdominal obesity. Data presented as mean. Adiponectin: μg/dL; Leptin: ng/dL. Mann-Whitney-Wilcoxon test p<0.05.
Figure 1

Adiponectin, leptin and leptin/adiponectin ratio in patients with severe coronary artery disease divided by the presence of abdominal obesity.

-AO: Patients without abdominal obesity; +AO: Patients with abdominal obesity. Data presented as mean. Adiponectin: μg/dL; Leptin: ng/dL. Mann-Whitney-Wilcoxon test p<0.05.

The role of leptin in metabolic syndrome and diabetes

Leptin has an important role in the long-term regulation of body weight. It has also been proposed as an independent risk factor for CVD and as an important link between obesity and cardiovascular risk [31, 32]. Paradoxically, markedly increased plasma leptin levels were found in obese individuals, suggesting a resistance to its effects on target organs when produced excessively [33]. Increased leptin levels were correlated both with BMI and IR in DM2 patients [34–36]. IR was found to indirectly contribute to hyperleptinemia [37], and it has been reported that the hyperinsulinemia that frequently accompanies obesity is likely to result in increased obesogenic gene expression and higher plasma leptin levels [31]. Therefore, the association between leptin and insulin may simply reflect the size of adipose tissue stores [31]. The higher leptin levels generally observed in individuals with increased plasma insulin could be partially explained by a resistance to leptin. Chronically elevated leptin levels in obesity may result in decreased responsiveness of pancreatic β-cell receptors, leading to increased insulin secretion. In turn, the resulting hyperinsulinemia may exacerbate obesity and further increase leptin levels, resulting in a diabetogenic positive feedback loop [36, 37]. In support of this proposal, Uslu et al. [35] found a close relationship between insulin and leptin levels in DM2 patients. Moreover, this group observed that leptin levels were positively correlated with TG, lipoprotein (a) [Lp (a)], Apo-A1, glucose, systolic blood pressure and diastolic blood pressure levels, and negatively with HDL-C levels in DM2 patients. Also, it has been proposed that the increased levels of leptin observed in obesity deregulates blood pressure control and results in hypertension, suggesting that leptin may also be a potential promoter of hypertension [38].

Leptin may also have a role in the immune response via the stimulation of T-helper cell proliferation and production of proinflammatory cytokines as IL-6, which induce liver CRP synthesis. In addition, leptin produced in adipocytes may directly induce IL-6 production, resulting in further upregulation of hepatic CRP production [31]. Thus, serum leptin levels may be used as an integrated marker of adiposity, IR, and vascular dysfunction useful for cardiovascular risk stratification in clinical practice.

The role of adiponectin in metabolic syndrome and cardiometabolic diseases

Adiponectin, also referred to as ACRP30 and AdipoQ [39, 40], is an adipocyte-derived hormone abundantly present in human plasma, ranging between 3 and 30 µg/mL [39]. Adiponectin levels in plasma are negatively regulated by accumulation of visceral fat [41] and are, therefore, lower in more obese individuals [42]. Adiponectin has anti-atherogenic, antidiabetic, and anti-inflammatory properties that are directly involved in obesity-related disorders. Moreover, clinical studies implicate hypoadiponectinemia in the pathogenesis of DM2 [43], CAD [44], and hypertension [45]. Hypoadiponectinemia has also been associated with left ventricular hypertrophy, which is accompanied by diastolic dysfunction [46].

Furthermore, adiponectin values may have good prognostic value in terms of CVD. High levels of adiponectin were associated with a decreased risk of CAD in male diabetic patients [47] and with cardiovascular outcomes in patients with end-stage renal failure [48]. A prospective study showed that high plasma adiponectin levels were associated with a lower risk of myocardial infarction in healthy men, independent of CRP level or glycemic status [49]. In addition, in patients with peripheral arterial disease, serum adiponectin was positively correlated with the ankle-brachial pressure index, maximum walking distance, and initial claudication distance [50], and in another study, serum levels were negatively correlated with the Fontaine stage [51].

Different pathophysiological mechanisms are implicated in the protective role of adiponectin against the genesis of cardiometabolic diseases. Adiponectin exerts an anti-inflammatory effect through the activation of its three receptors (AdipoR1, AdipoR2, and T-cadherin) [52]. The activation of AdipoR1 and R2 results in increased hepatic and skeletal muscle fatty acid oxidation, increased skeletal muscle lactate production, reduced hepatic gluconeogenesis, increased cellular glucose uptake, and inhibition of inflammation and oxidative stress [53]. In vascular endothelial cells, activation of T-cadherin is protective against oxidative stress-induced apoptosis [54]. Several mechanisms have been suggested to explain the anti-inflammatory effects of adiponectin, including direct actions on inflammatory cells, actions on NF-κB, and interactions with TNF-α [52]. It has been demonstrated that adiponectin inhibits the expression of adhesion molecules in endothelial cells and inhibits smooth muscle cell proliferation. It also inhibits the differentiation of monocytes into macrophages and the formation of foam cells and secretion of TNF-α by macrophages [55–57]. Increased adiponectin levels are related to improvement in the differentiation of preadipocytes into adipocytes, a process that is usually impaired in obese subjects [58]. In addition, adiponectin increases endothelial nitric oxide secretion [59, 60]. Therefore, adiponectin appears to be an important molecule involved in limiting the pathogenesis of obesity-linked disorders and may have potential benefits in the treatment and prevention of cardiovascular diseases. However, due to the problematic nature of supplementation of adiponectin, increasing adiponectin production may be a useful approach. The thiazolidinediones, for example, promote an increased secretion of adiponectin by activating PPAR-γ in adipocytes [61, 62]. Caloric restriction has also been shown to increase adiponectin levels and, in turn, confer resistance to myocardial ischemia-reperfusion injury [63]. Recently, a novel nonpharmacological therapeutic intervention, aged garlic extract, was found to increase adiponectin levels in individuals with MetS [64]. However, additional studies are needed to evaluate the potential benefits of increasing adiponectin in the treatment and prevention of cardiovascular and metabolic diseases.

Leptin/adiponectin ratio in metabolic syndrome and diabetes

As reviewed above, leptin and adiponectin have opposing effects on subclinical inflammation. Leptin upregulates cytokines such as TNF-α and IL-6 that are associated with IR in DM2 and is therefore considered as a proinflammatory cytokine. In contrast, adiponectin downregulates the expression and release of many proinflammatory immune mediators and exerts anti-inflammatory properties. Thorand et al. [37] suggested that leptin and adiponectin interact with each other in the modulation of DM2 risk, but that adiponectin is likely to have a stronger association with DM2 risk. Other groups also found an inverse relationship between leptin and adiponectin in DM2 patients [36] and in patients with obesity and CAD [24]. Although leptin or adiponectin were separately associated with the risk of MetS, DM2, and CAD, the association of DM2 risk with the L/A ratio was stronger than with leptin or adiponectin alone [24, 65]. These results suggest that the L/A ratio may be a useful index for IR in clinical practice and a good indicator for assessing the effectiveness of antidiabetic therapy. Indeed, it has been reported that both the calculated HOMA-IR index and the L/A ratio can be used to identify IR.

Regional differences in plasma adiponectin levels in subjects with metabolic syndrome

While in the developed world the incidence of CVD is stabilizing or decreasing [3, 66, 67] and prognosis is improving [3, 68], incidence is increasing in the developing world. These differences in the global epidemiological profile of CVD may be due to diverse geographical, environmental, demographic, socioeconomic, and ethnic characteristics [3]. We suggest that one of the explanations for these differences is that the populations of developing countries are more prone to develop cardiovascular and metabolic diseases at lower levels of AO as a result of shorter exposure times to the new lifestyles associated with modernization [69]. The shorter the exposure time, the less adapted the population and the greater the risk of an inflammatory imbalance at lower levels of AO. We propose that this phenomenon may produce epigenetic modifications in the visceral adipose tissue and, in consequence, a larger reduction in adiponectin levels in individuals in developing countries, in turn, increasing their risk of DM2 and CVD.

To evaluate this hypothesis, we reviewed studies that assessed adiponectin plasma values in subjects with MetS and then examined potential regional differences. We reviewed only English and Spanish language articles related to the association between adiponectin and MetS published since January 2002 in the Medline database. Our initial search terms were metabolic syndrome and adiponectin; we then conducted the same search as MESH terms.

We included cross sectional and cohort studies that reported adiponectin values in adults (≥18 years) with MetS. We included abstracts only when they presented unique data not already included in our review from published studies. We only included studies in which adiponectin levels were determined by ELISA and RIA. Studies were excluded from our review if they were clinical trials or case-control studies, as these types of research studies did not account for representative samples of the general population. Moreover, if the studies included postpartum women or patients with any additional condition, such as bipolar affective disorder, rheumatoid arthritis, chronic hepatitis, and chronic obstructive pulmonary disease, they were also excluded. Articles that we could not get access to were also excluded. One hundred fifty-eight articles were identified with the general search and 195 using the MESH terms, 23 of which met our inclusion criteria. Two investigators independently reviewed titles, abstracts, and full articles to determine whether studies met the inclusion criteria. Moreover, the two investigators independently abstracted data on study design; numbers of patients assessed, evaluated population, method of adiponectin quantification, and reported levels of plasma adiponectin (Table 1). Conflicting assessment between reviewers were resolved through discussion and review.

Table 1

Worldwide adiponectin levels in subjects with metabolic syndrome.

We found evidence of worldwide differences in adiponectin levels in subjects with MetS. While it is difficult to establish consistent regional differences (Table 1), there appears to be considerable differences between developed and developing countries within the same region. In Latin America, a Brazilian study reported adiponectin values of 7.11 µg/mL [70], and we observed levels of 5.93 µg/mL in Colombia [64], but in Australian women with MetS, the values were 13.7 µg/mL [71], while in Indonesian MetS women, the values were much lower, 4.9 µg/mL [72]. Moreover, important differences between genders were found: women showing higher levels of adiponectin than men when compared within the same country.

In the United States, a higher incidence of IR and DM2 has been reported in Latinos, compared to non-Latino whites [73, 74]. Although this observation has been attributed, at least in part, to a higher rate of obesity in Latinos [73], IR and DM2 are more prevalent in Latinos compared to whites even after controlling for weight differences [74, 75]. Moreover, decreased adiponectin levels were found in Latino compared to non-Latino White patients with CVD risk. Lower adiponectin levels in the Latino group were independent of BMI and other factors known to affect adiponectin and seemed to account for the increased IR observed in this group [76]. These findings in Latinos are similar to those from studies of adiponectin in other minority ethnic/racial groups, in that adiponectin is lower in minority groups than White populations [77]. Ethnic and racial minority groups (including Latinos) participating in the Diabetes Prevention Program study were also reported to have lower baseline adiponectin levels than non-Latino White participants [75].

In this review, we are not able to neither establish a causative association between low adiponectin and the progression of cardiovascular and metabolic diseases nor conclusively demonstrate regional differences in adiponectin levels. Our review, however, does appear to suggest a developed vs. developing country patterning of adiponectin levels. We are not able to ascertain whether the lower adiponectin values observed in subjects with MetS from developing countries were related to genetic and or environmental factors. Moreover, it is noteworthy that values of different parameters can differ from one laboratory to another; therefore, a possible bias can be present. Furthermore, the contribution of adiponectin to regional differences in cardiometabolic disease incidence has not been evaluated.

Expert opinion

The MetS, with IR and adiposity as its central features, is associated with an increased risk of CHD, DM2, and other cardiometabolic diseases. While there are a number of adipokines involved in the proinflammatory state caused by AO, interactions between Ang II and L/A imbalance, in particular, appear to have an important role in the metabolic alterations related to visceral adiposity and in the increased risk of developing DM2 and CVD associated with AO. Leptin and adiponectin have opposing effects on subclinical inflammation and IR. Leptin upregulates proinflammatory cytokines, while adiponectin has anti-inflammatory properties. Moreover, L/A imbalance is associated with increased vasoconstriction due to Ang II. To date, there are few therapeutic options to improve the L/A imbalance, and more research is warranted.

Outlook

We anticipate an increasing interest in producing epigenetic modifications of visceral adipose tissue, either by pharmacological therapy or dietary interventions, with the purpose of improving the L/A imbalance in patients at elevated cardiometabolic risk. Moreover, pharmacological interventions using adiponectin supplements or analogs to examine the potential benefits of this adipokine in the treatment and prevention of cardiovascular and metabolic diseases may be conducted. The increasing burden of noncommunicable diseases in the developing world, such as in Latin America and South Asian countries and the higher sensitivity of these populations to CVD at lower levels of AO, will stimulate a particular interest in studying interactions and interventions in these populations.

Highlights

  • In patients with CAD, AO is associated with decreased plasma concentrations of adiponectin and increased leptin levels and with a decreased vascular response to acetylcholine and an increased vasoconstriction in response to Ang II.

  • The regional differences in adiponectin values may have an important role in the susceptibility of certain populations to CVD. However, there is a paucity of data, and more research is required.

  • Future research should investigate potential pathways to improve the L/A ratio, especially by increasing adiponectin levels in subjects at elevated cardiometabolic risk.

  • Epigenetic modifications of the visceral adipose tissue could become an important mechanism for improving the L/A ratio.

References

  • 1.

    Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–28.Google Scholar

  • 2.

    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002;287:356–9.Google Scholar

  • 3.

    López-Jaramillo P, Pradilla LP, Castillo VR, Lahera V. Socioeconomic pathology as a cause of regional differences in the prevalence of metabolic syndrome and pregnancy-induced hypertension. Rev Esp Cardiol 2007;60:168–78.CrossrefGoogle Scholar

  • 4.

    Reaven GM. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr 2005;25:391–406.CrossrefGoogle Scholar

  • 5.

    Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–5.Google Scholar

  • 6.

    O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S; INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376:112–23.Google Scholar

  • 7.

    Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006;119:812–9.CrossrefGoogle Scholar

  • 8.

    Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403–14.CrossrefGoogle Scholar

  • 9.

    Lopez-Jaramillo P, Sanchez R, Diaz M, Cobos L, Bryce A, Parra-Carrillo JZ, Lizcano F, Lanas F, Sinay I, Sierra IV, Peñaherrera E, Bendersky M, Schmid H, Botero R, Urina M, Lara J, Foss MC, Marquez G, Harrap S, Ramirez AJ, Zanchetti A, on behalf of the Latin America expert Group. Latin American consensus on hypertension in patients with diabetes type 2 and metabolic syndrome. J Hypertens 2013;31:223–38.CrossrefGoogle Scholar

  • 10.

    Türkoglu C, Duman BS, Günay D, Cagatay P, Ozcan R, Büyükdevrim AS. Effect of abdominal obesity on insulin resistance and the components of the metabolic syndrome: evidence supporting obesity as the central feature. Obes Surg 2003;13:699–705.CrossrefGoogle Scholar

  • 11.

    Bogers RP, Bemelmans WJ, Hoogenveen RT, Boshuizen HC, Woodward M, Knekt P, van Dam RM, Hu FB, Visscher TL, Menotti A, Thorpe RJ Jr, Jamrozik K, Calling S, Strand BH, Shipley MJ, for the BMI-CHD Collaboration Investigators. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300,000 persons. Arch Intern Med 2007;167:1720–8.Google Scholar

  • 12.

    Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000;11:327–32.CrossrefGoogle Scholar

  • 13.

    Iacobellis G, Pistilli D, Gucciardo M, Leonetti F, Miraldi F, Brancaccio G, Gallo P, di Gioia CR. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine 2005;29:251–5.Google Scholar

  • 14.

    Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol 2010;316:129–39.Google Scholar

  • 15.

    DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173–94.CrossrefGoogle Scholar

  • 16.

    Friedman JE, Dohm GL, Leggett-Frazier N, Elton CW, Tapscott EB, Pories WP, Caro JF. Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4. J Clin Invest 1992;89:701–5.CrossrefGoogle Scholar

  • 17.

    Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1985;61:917–25.CrossrefGoogle Scholar

  • 18.

    Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH. The metabolic syndrome. Endocr Rev 2008;29:777–822.CrossrefGoogle Scholar

  • 19.

    López-Jaramillo P, Casas JP. Endothelial dysfunction, angiotensin-converting enzyme inhibitors and calcium antagonists. J Hum Hypertens 2002;16(Suppl 1):34–7.Google Scholar

  • 20.

    López-Jaramillo P, Casas JP. Blockade of endothelial enzymes: new therapeutic targets. J Hum Hypertens 2002;16(Suppl 1): 100–3.CrossrefGoogle Scholar

  • 21.

    Okosun IS, Liao Y, Rotimi CN, Prewitt TE, Cooper RS. Abdominal adiposity and clustering of multiple metabolic syndrome in White, Black and Hispanic Americans. Ann Epidemiol 2000;10:263–70.CrossrefGoogle Scholar

  • 22.

    Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010;2010. doi:pii: 289645. 10.1155/2010/289645.CrossrefGoogle Scholar

  • 23.

    Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881–7.Google Scholar

  • 24.

    Rueda-Clausen CF, Lahera V, Calderón J, Bolivar IC, Castillo VR, Gutiérrez M, Carreño M, Oubiña Mdel P, Cachofeiro V, López-Jaramillo P. The presence of abdominal obesity is associated with changes in vascular function independently of other cardiovascular risk factors. Int J Cardiol 2010;139:32–41.Google Scholar

  • 25.

    Karlsson C, Lindell K, Ottosson M, Sjöström L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 1998;83:3925–9.Google Scholar

  • 26.

    Harte A, McTernan P, Chetty R, Coppack S, Katz J, Smith S, Kumar S. Insulin-mediated up regulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by rosiglitazone. Circulation 2005;111:1954–61.CrossrefGoogle Scholar

  • 27.

    de las Heras N, Martín-Fernández B, Miana M, Ballesteros S, Oubiña MP, López-Farré AJ, Cachofeiro V, Lahera V. The protective effect of irbesartan in rats fed a high fat diet is associated with modification of leptin-adiponectin imbalance. J Hypertens Suppl 2009;27:37–41.CrossrefGoogle Scholar

  • 28.

    Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens 2005;23:463–73.CrossrefGoogle Scholar

  • 29.

    Strazzullo P, Galletti F. Impact of the renin-angiotensin system on lipid and carbohydrate metabolism. Curr Opin Nephrol Hypertens 2004;13:325–32.CrossrefGoogle Scholar

  • 30.

    Fasshauer M, Paschke R, Stumvoll M. Adiponectin, obesity, and cardiovascular disease. Biochimie 2004;86:779–84.CrossrefGoogle Scholar

  • 31.

    Wannamethee SG, Tchernova J, Whincup P, Lowe GD, Kelly A, Rumley A, Wallace AM, Sattar N. Plasma leptin: associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis 2007;191:418–26.Google Scholar

  • 32.

    Reilly MP, Iqbal N, Schutta M, Wolfe ML, Scally M, Localio AR, Rader DJ, Kimmel SE. Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. J Clin Endocrinol Metab 2004;89:3872–8.CrossrefGoogle Scholar

  • 33.

    Stefanović A, Kotur-Stevuljević J, Spasić S, Bogavac-Stanojević N, Bujisić N. The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2008;79:156–63.CrossrefGoogle Scholar

  • 34.

    Abdella NA, Mojiminiyi OA, Moussa MA, Zaki M, Al Mohammedi H, Al Ozairi ES, Al Jebely S. Plasma leptin concentration in patients with Type 2 diabetes: relationship to cardiovascular disease risk factors and insulin resistance. Diabet Med 2005;22:278–85.CrossrefGoogle Scholar

  • 35.

    Uslu S, Kebapçi N, Kara M, Bal C. Relationship between adipocytokines and cardiovascular risk factors in patients with type 2 diabetes mellitus. Exp Ther Med 2012;4:113–20.Google Scholar

  • 36.

    Asakawa H, Tokunaga K, Kawakami F. Relationship of leptin level with metabolic disorders and hypertension in Japanese type 2 diabetes mellitus patients. J Diabetes Complications 2001;15:57–62.CrossrefGoogle Scholar

  • 37.

    Thorand B, Zierer A, Baumert J, Meisinger C, Herder C, Koenig W. Associations between leptin and the leptin/adiponectin ratio and incident Type 2 diabetes in middle-aged men and women: results from the MONICA/KORA Augsburg study 1984–2002. Diabet Med 2010;27:1004–11.Google Scholar

  • 38.

    Maenhaut N, Van de Voorde J. Regulation of vascular tone by adipocytes. BMC Med 2011;9:25.Google Scholar

  • 39.

    Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270:26746–9.CrossrefGoogle Scholar

  • 40.

    Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996;271:10697–703.Google Scholar

  • 41.

    Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T. Adiponectin as a biomarker of the metabolic syndrome. Circ J 2004;68:975–81.CrossrefGoogle Scholar

  • 42.

    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 2012;425:560–4.Google Scholar

  • 43.

    Spranger J, Kroke A, Möhlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Adiponectin and protection against type 2 diabetes mellitus. Lancet 2003;361:226–8.Google Scholar

  • 44.

    Laughlin GA, Barrett-Connor E, May S, Langenberg C. Association of adiponectin with coronary heart disease and mortality: the Rancho Bernardo study. Am J Epidemiol 2007;165:164–74.Google Scholar

  • 45.

    Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahashi T, Rakugi H, Matsuzawa Y, Ogihara T. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 2004;43:1318–23.CrossrefGoogle Scholar

  • 46.

    Hong SJ, Park CG, Seo HS, Oh DJ, Ro YM. Associations among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index. Blood Press 2004;13:236–42.CrossrefGoogle Scholar

  • 47.

    Schulze MB, Shai I, Rimm EB, Li T, Rifai N, Hu FB. Adiponectin and future coronary heart disease events among men with type 2 diabetes. Diabetes 2005;54:534–39.CrossrefGoogle Scholar

  • 48.

    Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002;13:134–41.Google Scholar

  • 49.

    Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. J Am Med Assoc 2004;291:1730–7.Google Scholar

  • 50.

    Golledge J, Leicht A, Crowther RG, Clancy P, Spinks WL, Quigley F. Association of obesity and metabolic syndrome with the severity and outcome of intermittent claudication. J Vasc Surg 2007;45:40–6.CrossrefGoogle Scholar

  • 51.

    Iwashima Y, Horio T, Suzuki Y, Kihara S, Rakugi H, Kangawa K, Funahashi T, Ogihara T, Kawano Y. Adiponectin and inflammatory markers in peripheral arterial occlusive disease. Atherosclerosis 2006;188:384–90.Google Scholar

  • 52.

    Robinson K, Prins J, Venkatesh B. Clinical review: adiponectin biology and its role in inflammation and critical illness. Crit Care 2011;15:221.CrossrefGoogle Scholar

  • 53.

    Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002;8:1288–95.CrossrefGoogle Scholar

  • 54.

    Joshi MB, Philippova M, Ivanov D, Allenspach R, Erne P, Resink TJ. T-cadherin protects endothelial cells from oxidative stress-induced apoptosis. FASEB J 2005;19:1737–9.Google Scholar

  • 55.

    Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 2002;105:2893–8.CrossrefGoogle Scholar

  • 56.

    Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347–55.CrossrefGoogle Scholar

  • 57.

    Lenz A, Diamond FB Jr. Obesity: the hormonal milieu. Curr Opin Endocrinol Diabetes Obes 2008;15:9–20.CrossrefGoogle Scholar

  • 58.

    Tian F, Luo R, Zhao Z, Wu Y, Ban Dj. Blockade of the RAS increases plasma adiponectin in subjects with metabolic syndrome and enhances differentiation and adiponectin expression of human preadipocytes. Exp Clin Endocrinol Diabetes 2010;118:258–65.CrossrefGoogle Scholar

  • 59.

    Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care 2003;26:2442–50.CrossrefGoogle Scholar

  • 60.

    Díez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003;148:293–300.Google Scholar

  • 61.

    Tiikkainen M, Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004;53:2169–76.CrossrefGoogle Scholar

  • 62.

    Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2004;89:4312–19.CrossrefGoogle Scholar

  • 63.

    Shinmura K, Tamaki K, Saito K, Nakano Y, Tobe T, Bolli R. Cardioprotective effects of short-term caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase. Circulation 2007;116:2809–17.CrossrefGoogle Scholar

  • 64.

    Gómez-Arbeláez D, Lahera V, Oubiña P, Valero-Muñoz M, de Las Heras N, Rodríguez Y, García RG, Camacho PA, López-Jaramillo P. Aged garlic extract improves adiponectin levels in subjects with metabolic syndrome: a double-blind, placebo-controlled, randomized, crossover study. Mediators Inflamm 2013;2013:285795. doi: 10.1155/2013/285795.CrossrefGoogle Scholar

  • 65.

    Oda N, Imamura S, Fujita T, Uchida Y, Inagaki K, Kakizawa H, Hayakawa N, Suzuki A, Takeda J, Horikawa Y, Itoh M. The ratio of leptin to adiponectin can be used as an index of insulin resistance. Metabolism 2008;57:268–73.CrossrefGoogle Scholar

  • 66.

    Lawlor DA, Ebrahim S, Davey Smith G. Sex matters: secular and geographical trends in sex differences in coronary heart disease mortality. Br Med J 2001;323:541–5.Google Scholar

  • 67.

    Lawlor DA, Smith GD, Leon DA, Sterne JA, Ebrahim S. Secular trends in mortality by stroke subtype in the 20th century: a retrospective analysis. Lancet 2002;360:1818–23.Google Scholar

  • 68.

    Heras M, Marrugat J, Arós F, Bosch X, Enero J, Suárez MA, Pabón P, Ancillo P, Loma-Osorio A, Rodríguez JJ, Subirana I, Vila J; en representación de los investigadores del estudio PRIAMHO. Reduction in acute myocardial infarction mortality over a five-year period. Rev Esp Cardiol 2006;59:200–8.CrossrefGoogle Scholar

  • 69.

    López-Jaramillo P, Velandia-Carrillo C, Alvarez-Camacho J, Cohen DD, Sánchez-Solano T, Castillo-López G. Inflammation and hypertension: are there regional differences? Int J Hypertens 2013;2013:492094. doi: 10.1155/2013/492094.CrossrefGoogle Scholar

  • 70.

    Simão AN, Lozovoy MA, Bahls LD, Morimoto HK, Simão TN, Matsuo T, Dichi I. Blood pressure decrease with ingestion of a soya product (kinako) or fish oil in women with the metabolic syndrome: role of adiponectin and nitric oxide. Br J Nutr 2012;108:1435–42.CrossrefGoogle Scholar

  • 71.

    Hung J, McQuillan BM, Thompson PL, Beilby JP. Circulating adiponectin levels associate with inflammatory markers, insulin resistance and metabolic syndrome independent of obesity. Int J Obes (Lond) 2008;32:772–9.CrossrefGoogle Scholar

  • 72.

    Soebijanto N, Waspadji S. Adiponectin levels and its role in insulin resistance among adult women with metabolic syndrome. Acta Med Indones 2010;42:187–91.Google Scholar

  • 73.

    Stern MP, Gaskill SP, Hazuda HP, Gardner LI, Haffner SM. Does obesity explain excess prevalence of diabetes among Mexican Americans? Results of the San Antonio Heart Study. Diabetologia 1983;24:272–7.Google Scholar

  • 74.

    Gardner LI Jr, Stern MP, Haffner SM, Gaskill SP, Hazuda HP, Relethford JH, Eifler CW. Prevalence of diabetes in Mexican Americans. Relationship to percent of gene pool derived from native American sources. Diabetes 1984;33:86–92.CrossrefGoogle Scholar

  • 75.

    Mather KJ, Funahashi T, Matsuzawa Y, Edelstein S, Bray GA, Kahn SE, Crandall J, Marcovina S, Goldstein B, Goldberg R. Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program. Diabetes 2008;57:980–6.CrossrefGoogle Scholar

  • 76.

    Pereira RI, Wang CC, Hosokawa P, Dickinson LM, Chonchol M, Krantz MJ, Steiner JF, Bessesen DH, Havranek EP, Long CS. Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures. BMC Endocr Disord 2011;11:13.Google Scholar

  • 77.

    Hulver MW, Saleh O, MacDonald KG, Pories WJ, Barakat HA. Ethnic differences in adiponectin levels. Metabolism 2004;53:1–3.CrossrefGoogle Scholar

About the article

Corresponding author: Patricio López-Jaramillo, MD PhD FACP, Director de Investigaciones, Fundación Oftalmológica de Santander, FOSCAL, Torre Milton Salazar, Primer piso, Calle 155A N. 23-09, El Bosque, Floridablanca, Santander, Colombia, Phone: +57-3153068939/57-7-6386000 Ext. 4165-4166, Fax: +57-7-6388108, E-mail: ; ; and Escuela de Medicina, Universidad de Santander, UDES, Bucaramanga, Colombia


Received: 2013-09-26

Accepted: 2013-11-20

Published Online: 2013-12-13

Published in Print: 2014-04-01


Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 18, Issue 1, Pages 37–45, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2013-0053.

Export Citation

©2014 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Camila Schultz Marcolla, Carla Sosa Alvarado, Benjamin Peter Willing, and Filippo Miglior
Canadian Journal of Animal Science, 2019, Page 1
[2]
Talita da Silva Mendes de Farias, Regislane Ino da Paixao, Maysa Mariana Cruz, Roberta Dourado Cavalcante da Cunha de Sa, Jussara de Jesus Simão, Vitor Jaco Antraco, and Maria Isabel Cardoso Alonso-Vale
Cells, 2019, Volume 8, Number 9, Page 1041
[3]
Mohammed El Hafidi, Mabel Buelna-Chontal, Fausto Sánchez-Muñoz, and Roxana Carbó
International Journal of Molecular Sciences, 2019, Volume 20, Number 15, Page 3657
[4]
Hannah K. Drescher, Ralf Weiskirchen, Annabelle Fülöp, Carsten Hopf, Estibaliz González de San Román, Pitter F. Huesgen, Alain de Bruin, Laura Bongiovanni, Annette Christ, René Tolba, Christian Trautwein, and Daniela C. Kroy
Frontiers in Physiology, 2019, Volume 10
[5]
Arrigo Francesco Giuseppe Cicero, Federica Fogacci, Marilisa Bove, Marina Giovannini, and Claudio Borghi
Phytotherapy Research, 2019, Volume 33, Number 8, Page 2094
[6]
Patricio López-Jaramillo and Diana Rueda-García
Revista Cuidarte, 2019, Volume 10, Number 2
[7]
Habib Yaribeygi, Luis E. Simental-Mendía, George E. Barreto, and Amirhossein Sahebkar
Journal of Cellular Physiology, 2019, Volume 234, Number 10, Page 16987
[8]
Yuvreet Kaur, Dominic X. Wang, Hsin‐Yen Liu, and David Meyre
Obesity Reviews, 2019, Volume 20, Number 3, Page 385
[9]
Patricio Lopez-Jaramillo, Juan Barajas, Sandra M. Rueda-Quijano, Cristina Lopez-Lopez, and Camilo Felix
Frontiers in Physiology, 2018, Volume 9
[11]
Amitabha Ray
World Journal of Clinical Cases, 2018, Volume 6, Number 12, Page 483
[12]
Belen Palomares, Francisco Ruiz-Pino, Carmen Navarrete, Inmaculada Velasco, Miguel A. Sánchez-Garrido, Carla Jimenez-Jimenez, Carolina Pavicic, Maria J. Vazquez, Giovanni Appendino, M. Luz Bellido, Marco A. Calzado, Manuel Tena-Sempere, and Eduardo Muñoz
Scientific Reports, 2018, Volume 8, Number 1
[13]
Youngmi Lee, Eun-Young Kwon, and Myung-Sook Choi
International Journal of Molecular Sciences, 2018, Volume 19, Number 10, Page 3281
[14]
Julie Dupas, Annie Feray, Anthony Guernec, Morgane Pengam, Manon Inizan, François Guerrero, Jacques Mansourati, and Christelle Goanvec
Nutrition & Metabolism, 2018, Volume 15, Number 1
[15]
EunSeok Cha, Molly Sarah Talman, Ann H. Massey, Fengxia Yan, and Ann E. Rogers
Biological Research For Nursing, 2018, Page 109980041879104
[16]
Guojing Luo, Yuedong He, and Xijie Yu
Frontiers in Endocrinology, 2018, Volume 9
[17]
Hua He, Anne Monique Nuyt, Zhong-Cheng Luo, Francois Audibert, Lise Dubois, Shu-Qin Wei, Haim A. Abenhaim, Emmanuel Bujold, Isabelle Marc, Pierre Julien, and William D. Fraser
Frontiers in Endocrinology, 2018, Volume 9
[18]
[19]
Simone Coghetto Acedo
World Journal of Hepatology, 2015, Volume 7, Number 24, Page 2551
[20]
Ge Li, Linxin Xu, Yanglu Zhao, Lujiao Li, Junling Fu, Qian Zhang, Naishi Li, Xinhua Xiao, Changhong Li, Jie Mi, Shan Gao, Ming Li, and Yang-Ching Chen
PLOS ONE, 2017, Volume 12, Number 10, Page e0186222
[21]
Ludovico Abenavoli, Natasa Milic, Laura Di Renzo, Tomislav Preveden, Milica Medić-Stojanoska, and Antonino De Lorenzo
World Journal of Gastroenterology, 2016, Volume 22, Number 31, Page 7006
[22]
César A. Agostinis-Sobrinho, Edmar Lacerda Mendes, Carla Moreira, Sandra Abreu, Luís Lopes, José Oliveira-Santos, Albertas Skurvydas, Jorge Mota, and Rute Santos
Annals of Nutrition and Metabolism, 2017, Volume 70, Number 4, Page 321
[23]
Emanuela Galliera, Monica Gioia Marazzi, Carmine Gazzaruso, Pietro Gallotti, Adriana Coppola, Tiziana Montalcini, Arturo Pujia, and Massimiliano M. Corsi Romanelli
Immunity & Ageing, 2017, Volume 14, Number 1
[24]
Munazza Murtaza, Gulnaz Khan, Meha Fatima Aftab, Shabbir Khan Afridi, Safina Ghaffar, Ayaz Ahmed, Rahman M. Hafizur, Rizwana Sanaullah Waraich, and Guillermo López Lluch
PLOS ONE, 2017, Volume 12, Number 6, Page e0178910
[25]
Eun-Young Kwon, Jeonghyeon Lee, Ye Kim, Ara Do, Ji-Young Choi, Su-Jung Cho, Un Jung, Mi-Kyung Lee, Yong Park, and Myung-Sook Choi
Nutrients, 2017, Volume 9, Number 6, Page 569
[26]
Giulia Maurizi, Lucio Della Guardia, Angela Maurizi, and Antonella Poloni
Journal of Cellular Physiology, 2017
[27]
Alberto Lana, Ana Valdés-Bécares, Antonio Buño, Fernando Rodríguez-Artalejo, and Esther Lopez-Garcia
Aging and Disease, 2017, Volume 8, Number 2, Page 240
[28]
Heath Gasier, Colin Young, Erin Gaffney-Stomberg, Douglas McAdams, Laura Lutz, and James McClung
Nutrients, 2016, Volume 8, Number 2, Page 85
[29]
Yu-Song Ding, Shu-Xia Guo, Ru-Lin Ma, Shu-Gang Li, Heng Guo, Jing-Yu Zhang, Mei Zhang, Jia-Ming Liu, Jia He, Yi-zhong Yan, Wen-Jie Zhang, and Lie-Gang Liu
Mediators of Inflammation, 2015, Volume 2015, Page 1

Comments (0)

Please log in or register to comment.
Log in