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1.  Metabolic syndrome, insulin resistance, fibrinogen, homocysteine, leptin, and C-reactive protein in obese patients with obstructive sleep apnea syndrome 
Annals of Thoracic Medicine  2011;6(3):120-125.
The prevalence of obstructive sleep apnea syndrome (OSAS) and metabolic syndrome is increasing worldwide, in part linked to epidemic of obesity. The purposes of this study were to establish the rate of metabolic syndrome and to compare fibrinogen, homocysteine, high-sensitivity C-reactive protein (hsCRP), leptin levels, and homeostasis model assessment insulin resistance (HOMA-IR) in the obese patients with and without OSAS.
The study population included 36 consecutive obese patients with OSAS (23 males; mean age, 50.0 ±19.7 years), and 34 obese patients without OSAS (17 males; mean age, 49.7±11.1 years) were enrolled as control group. Metabolic syndrome was investigated; fibrinogen, homocysteine, CRP, and leptin levels were measured, and IR was assessed.
Metabolic syndrome was found in 17 (47.2%) obese OSAS patients, whereas only 29.4% of obese subjects had metabolic syndrome (P > 0.05). Obese patients with OSAS had significantly higher mean levels of triglyceride (P < 0.001), total-cholesterol (P = 0.003), low-density lipoprotein-cholesterol (P = 0.001), fasting glucose (P = 0.01), HOMA-IR (P <0.001), thyroid-stimulating hormone (P = 0.03), fibrinogen (P < 0.003), hsCRP (P <0.001), and leptin (P = 0.03) than control group . Besides, leptin level was positively correlated with waist (r = 0.512, P = 0.03) and neck circumferences (r = 0.547, P = 0.03), and fasting glucose (r = 0.471, P = 0.04) in OSAS patients, but not in obese subjects.
This study demonstrated that obese OSAS patients may have an increased rate of metabolic syndrome and higher levels of serum lipids, fasting glucose, IR, leptin, fibrinogen, and hsCRP than obese subjects without sleep apnea. Thus, clinicians should be encouraged to systematically evaluate the presence of metabolic abnormalities in OSAS and vice versa.
PMCID: PMC3131753  PMID: 21760842
C-reactive protein; fibrinogen; homocysteine; insulin resistance; leptin; metabolic syndrome; obesity; obstructive sleep apnea syndrome
2.  The association of inflammatory and fibrinolytic proteins with 5-year change in insulin clearance - the Insulin Resistance Atherosclerosis Study (IRAS) 
Diabetologia  2012;56(1):112-120.
Insulin clearance may decline as an early compensatory mechanism to deteriorating insulin sensitivity. However, no previous studies have investigated the association of subclinical inflammation or impaired fibrinolysis with insulin clearance. We examined the association between plasminogen activator inhibitor (PAI)-1, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, leptin and fibrinogen and the progression of metabolic clearance rate of insulin (MCRI) over time.
We studied 784 non-diabetic Caucasians, Hispanics and African-Americans in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity (SI), acute insulin response (AIR) and MCRI were determined from frequently sampled intravenous glucose tolerance tests at baseline and at 5-year follow-up. Inflammatory and fibrinolytic proteins were measured in fasting plasma at baseline.
MCRI declined significantly by 29% in 5-year follow-up. We observed a significant association between higher plasma PAI-1 and the decline in MCRI in multivariable-adjusted regression models (β= −0.045 [−0.081, −0.0091]). Higher plasma CRP and leptin were associated with a decline in MCRI in unadjusted models, however, these associations were non-significant after adjusting for body mass index and waist circumference (β= −0.016 [−0.041, 0.0083] for CRP, β= −0.044 [−0.10, 0.011] for leptin). Higher plasma TNF-α was associated with a decline in MCRI in unadjusted (β= −0.071 [−0.14, −0.00087]), but not in multivariable-adjusted (β= −0.056 [−0.13, 0.017]) models. Plasma fibrinogen was not associated with the change in MCRI.
We identified that higher plasma PAI-1 (but not CRP, TNF-α, leptin or fibrinogen) independently predicts the progressive decline of insulin clearance in the multi-ethnic cohort of the IRAS.
PMCID: PMC4010386  PMID: 23052060
C-reactive protein; fibrinogen; leptin; metabolic clearance of insulin; plasminogen activator inhibitor-1; tumor necrosis factor-α
3.  Adipokines, Insulin Resistance and Coronary Artery Calcification 
We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, the metabolic syndrome and plasma C-reactive protein (CRP).
Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.
We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA).
Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjusting for age, gender, traditional risk factors and Framingham Risk Scores (FRS) [tobit regression ratio 2.42 (95% CI 1.48–3.95, p=0.002)] and further adjusting for metabolic syndrome and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
In SIRCA, while both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.
Condensed Abstract
Adipokines are fat-secreted biomolecules with pleiotropic actions and represent novel markers for cardiovascular risk. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic Caucasians. Leptin was positively (top vs. bottom quartile) associated with higher CAC even after adjustment for age, gender, traditional risk factors, Framingham Risk Score, metabolic syndrome, and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. Adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
PMCID: PMC2853595  PMID: 18617073
Adiponectin; Leptin; Coronary Artery Calcification; Atherosclerosis; Inflammation
4.  Young adult obese subjects with and without insulin resistance: what is the role of chronic inflammation and how to weigh it non-invasively? 
Obesity is a leading risk factor for metabolic syndrome whose further expression is non-alcoholic fatty liver disease. Metabolic syndrome is associated with a proinflammatory state that contributes to insulin resistance. Finally, a "metabolically benign obesity" that is not accompanied by insulin resistance has recently been postulated to exist.
To find whether any inflammation markers were independently associated with the presence of insulin resistance, evaluating specific anthropometric, ultrasonographic and laboratory parameters in a population of young adult obese subjects.
Of forty two young individuals, divided into two groups (with or without insulin resistance), were studied serum C-reactive protein and fibrinogen as indexes of chronic pro-inflammatory status. Body mass index, waist circumference and metabolic syndrome presence were assessed as part of the metabolic evaluation. Ultrasonography weighted visceral and subcutaneous abdominal fat thickness, spleen size as longitudinal diameter and liver hyperechogenicity.
Results and Discussion
Serum C-reactive protein and fibrinogen as well as spleen longitudinal diameter were significantly increased in the obese young with insulin resistance compared to non-insulin resistance group. Insulin resistance was significantly associated with hepatic steatosis score at sonography (r = 0.33, P = 0.03), spleen longitudinal diameter (r = 0.35, P = 0.02) and C-reactive protein (r = 0.38, P = 0.01), but not with body mass index, visceral or subcutaneous abdominal adipose tissue, waist circumference and fibrinogen (P = 0.18, 0.46, 0.33, 0.37 and 0.4, respectively). Steatosis score at sonography was well associated with spleen volume (rho = 0.40, P = 0.01) and C-reactive protein levels (rho = 0.49, P = 0.002). Metabolic syndrome was much more frequent in obese patients with insulin resistance. These findings show that in young adults the only abdominal adiposity without insulin resistance, plays a scarce role in determining hepatic steatosis as well as metabolic syndrome.
Increases in spleen size and CRP levels represent a reliable tool in diagnosing insulin resistance.
PMCID: PMC2663560  PMID: 19291292
5.  CRP Is Related to Higher Leptin Levels in Minority Peripubertal Females Regardless of Adiposity Levels 
Obesity (Silver Spring, Md.)  2011;20(3):512-516.
Overweight is related to higher levels of C-reactive protein (CRP) and leptin, which have been independently associated with increased risk for diabetes, cardiovascular disease, and the metabolic syndrome. Elevated CRP may trigger leptin resistance by inhibiting the binding of leptin to its receptors. We cross-sectionally examined the relationship between CRP, leptin, BMI z-score, percent body fat (%BF) assessed by air plethysmography (BodPod), and insulin sensitivity (SI) and acute insulin response (AIRg) measured by intravenous glucose tolerance test in 51 Latina and African-American females (77% Latina), mean age 9.2 (±0.9) years, at either Tanner Pubertal Stage (TPS) 1 (n = 25) or TPS 2 (n = 26). Females at TPS 2 had higher BMI z-scores, %BF (23% ± 10.1 vs. 30% ± 10.0, P = 0.02), AIRg (976.7 ± 735.2 vs. 1555.3 ± 1,223 µIU/ml, P = 0.05), fasting insulin (11.0 ± 10.8 vs. 17.2 ± 13.6 µlU/ml, P = 0.00) and leptin levels (11.0 ± 7.1 vs. 19.6 ± 10.9 ng/ml, P < 0.001) than those at TPS 1. There were no ethnic differences in any of the measured variables. CRP was positively correlated with BMI z-score (P = 0.001), %BF (P = 0.006), fasting insulin and AIRg (P = 0.02), and fasting leptin (P = 0.00), and negatively correlated with SI (P = 0.05). A linear regression model showed that CRP independently explained 10% (P = 0.00) of the variance in leptin after adjusting %BF, TPS, ethnicity, habitual physical activity and SI. Hence, low-grade inflammation may contribute to prolonged leptin exposure and leptin resistance, even in healthy children.
PMCID: PMC3200494  PMID: 21436796
The Journal of rheumatology  2013;40(11):10.3899/jrheum.130394.
Hypertension, a common modifiable cardiovascular risk factor, is more common in patients with rheumatoid arthritis (RA), but the underlying mechanisms are unclear. We examined the hypothesis that mediators of inflammation and markers of cardiovascular risk are associated with hypertension in RA.
We compared measures of inflammation (serum C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), homocysteine and leptin concentrations) and insulin resistance (homeostasis model assessment index (HOMA)) in RA patients with (n=90) and without hypertension (n=79). Hypertension was defined as blood pressure ≥140/90 mmHg or treatment with antihypertensive therapy. The independent association of markers of interest with hypertension was examined using multivariable logistic regression.
Hypertensive patients were significantly older and had longer disease duration than those without hypertension (both P<0.001). Concentrations of homocysteine (11.1[8.5–13.5] μmol/L vs. 9.3[7.8–11.0] μmol/L were significantly higher in hypertensive patients (P<0.001). After adjustment for age, sex, race, smoking, body mass index, and corticosteroid and NSAID use, increased concentrations of homocysteine (OR 2.9, 95%CI: 1.5–5.5, P=0.001), and leptin (OR 2.0, 95%CI: 1.0–3.8, P=0.046) were significantly associated with hypertension, but the 28-joint Disease Activity Score, IL-6, CRP, TNF-α and HOMA index were not (all P values >0.05).
Hypertension in patients with RA is not associated with generalized systemic inflammation or insulin resistance, but is associated with increasing concentrations of homocysteine and leptin. The pathogenesis of hypertension in RA may involve pathways more likely usually associated with fat and vascular homeostasis.
PMCID: PMC3818311  PMID: 23996293
rheumatoid arthritis; inflammation; hypertension; blood pressure; homocysteine; leptin; insulin resistance
7.  r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans 
Leptin is an adipocyte secreted hormone and an important regulator of neuroendocrine, metabolic, and immune function. Both r-metHuLeptin and IGF1 administration result in reduced central adipose tissue in subjects with highly active antiretroviral therapy-induced metabolic syndrome (HAART-MS) but whether the effects of leptin are mediated through increasing IGF levels remains unknown.
To assess whether r-metHuLeptin improves the HAART-MS by regulating circulating IGF and IGFBPs, we first conducted a cross-sectional study of 118 men and women with HIV infection and less than 6 months of exposure to antiretroviral medications to examine any association between circulating IGF1 and leptin levels. We also performed a randomized, double-blinded, placebo-controlled, crossover trial of recombinant human leptin (r-metHuLeptin) administration to seven HIV positive men with lipoatrophy and leptin deficiency (leptin !3 ng/ml) related to antiretroviral medication use.
In the observational study, leptin levels were inversely associated with circulating IGF1 levels after adjusting for age and gender (rZ0.27 PZ0.002), but this inverse association became nonsignificant after adjustment for % body fat and exercise. In the interventional leptin study, leptin levels increased significantly during r-metHuLeptin treatment (from 1.34G0.20 ng/ml at baseline to17G5.05 ng/ml after 8 weeks PZ0.046) and metabolic parameters improved including reduced fasting insulin levels and reduced homeostasis model assessment-insulin resistance (HOMA-IR). Despite the increase in circulating leptin levels, there was no change in IGF1, IGF2, free IGF1, or IGFbinding proteins during the 2-month treatment period.
The effects of r-metHuLeptin in patients with HAART-MS are not mediated through increasing IGF or IGFBP levels.
PMCID: PMC2760959  PMID: 19029226
leptin; lipoatrophy; IGF-I; IGF binding proteins
8.  Preliminary evidence for obesity-associated insulin resistance in adolescents without elevations of inflammatory cytokines 
To ascertain whether the associations between obesity, inflammation, and insulin resistance established in human adult studies are found among adolescents.
We contrasted 36 obese and 24 lean youth on fasting glucose, insulin levels, lipid profile, hemoglobin A1C, markers of hepatic function, white blood cell count, C-reactive protein (CRP) and fibrinogen levels. The cytokines IL-6, TNF-α, IFN-γ, IL-10 and IL-4 and the adipokines leptin, resistin, and adiponectin were also compared between the two groups. The fasting glucose and insulin values were used to estimate the degree of insulin resistance with the homeostatic model assessment of insulin resistance (HOMA-IR). T-tests and correlations were run to examine group differences and associations between groups. In addition, regression analyses were used to ascertain whether the markers of inflammation were predictive of the degree of insulin resistance.
Although obese adolescents had clear evidence of insulin resistance, only CRP, fibrinogen and leptin were elevated; there were no group differences in pro- or anti-inflammatory cytokines nor adiponectin and resistin. Anthropometric measures of obesity and level of insulin resistance were highly correlated to the acute phase reactants CRP and fibrinogen; however, the degree of insulin resistance was not predicted by the pro- or anti-inflammatory cytokine markers. Obese adolescents had higher white blood cell counts. In addition they had higher circulating alanine aminotransferase concentrations and lower circulating albumin and total protein than lean adolescents, possibly as a result of hepatocyte damage from fatty liver.
Unlike rodent or adult studies, we found that wide-spread systemic inflammation is not necessarily associated with insulin resistance among adolescents. This finding does not support the current paradigm that the associations between obesity and insulin resistance are, to a significant degree, mediated by low grade systemic inflammation. These data support the need for further adolescent studies to explore these associations.
PMCID: PMC3509401  PMID: 22682228
Insulin resistance; Cytokines; Adipokines; Adolescents; Obesity
9.  Genetic Variation Within a Metabolic Motif in the Chromogranin A Promoter: Pleiotropic Influence on Cardiometabolic Risk Traits in Twins 
The cardiometabolic syndrome comprised of multiple correlated traits, but its origin is incompletely understood. Chromogranin A (CHGA) is required for formation of the catecholamine secretory pathway in sympathochromaffin cells. In twin pair studies, we found that CHGA traits aggregated with body mass index (BMI), as well as its biochemical determinant leptin.
Here we used the twin method to probe the role of heredity in generating such risk traits, and then investigated the role of risk-trait-associated CHGA promoter genetic variation in transfected chromaffin cells. Trait heritability (h2) and shared genetic determination among traits (pleiotropy, genetic covariance, ρG) were estimated by variance components in twin pairs.
CHGA, BMI, and leptin each displayed substantial h2, and the traits also aggregated with several features of the metabolic syndrome (e.g., insulin resistance, blood pressure (BP), hypertension, catecholamines, and C-reactive protein (CRP)). Twin studies demonstrated genetic covariance (pleiotropy, ρG) for CHGA, BMI, and leptin with other metabolic traits (insulin resistance, BP, and CRP). We therefore investigated the CHGA locus for mechanisms of codetermination with such metabolic traits. A common functional variant in the human CHGA promoter (G-462A, rs9658634, minor allele frequency ~21%) was associated with leptin and CRP secretion, as well as BMI, especially in women; marker-on-trait effects on BMI were replicated across twin populations on two continents. In CHGA promoter/luciferase reporter plasmids transfected into chromaffin cells, G-462A alleles differed markedly in reporter expression. The G-462A variant disrupted predicted transcriptional control by a PPARγ/RXRα motif and costimulation by PPARγ/RXRα and their cognate ligands, differentially activated the two alleles. During chromatin immunoprecipitation, endogenous PPARγ bound the motif.
Multiple features of the metabolic syndrome are thus under joint (pleiotropic) genetic determination, with CHGA as one such contributory locus: a common polymorphism in the promoter (G-462A) of CHGA predicts such heritable metabolic traits as BMI and leptin. CHGA promoter variant G-462A was not only associated with such metabolic traits but also disrupted a PPARγ/RXRα motif and responded differentially to characteristic trans-activators of that motif. The results suggest novel links between the catecholaminergic system and risk for the metabolic syndrome as well as systemic hypertension.
PMCID: PMC3664223  PMID: 21918574
adrenal; blood pressure; BMI; C-reactive protein; catecholamine; chromaffin; chromogranin; hypertension; leptin; metabolic syndrome; twin study
10.  Cardiovascular disease markers in women with polycystic ovary syndrome with emphasis on asymmetric dimethylarginine and homocysteine 
Annals of Saudi Medicine  2010;30(4):278-283.
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Little is known about cardiovascular risk factors in patients with PCOS. We investigated plasma markers of cardiovascular disease in Saudi women with PCOS, with an emphasis on asymmetric dimethylarginine (ADMA) and total homocysteine (tHcy).
Fifty Saudi women with PCOS diagnosed by the Rotterdam criteria (mean age [SD] 30.2 [3.0] years) and 40 controls without PCOS (mean age 29.3 [2.5] years) had measyrements taken of clinical, metabolic, and hormonal parameters, including plasma ADMA, tHcy, lipoprotein (a) ([Lp(a)], and serum high sensitivity C-reactive protein (hs-CRP), nitric oxid, and fibrinogen. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR).
Women with PCOS had significantly higher fasting insulin, HOMA-IR, and luteinizing hormone (LH) levels than healthy controls (P<.001). Lipid profile, free androgen index (FAI), ADMA, tHcy, hsCRP, and Lp(a) were significantly higher in women with PCOS compared with healthy controls (P<.001). The women with PCOS had significantly lower nitric oxide and high-density lipoprotein cholesterol (HDL-C) levels compared with healthy controls (P<.001).
Our study revealed that Saudi women with PCOS had a significantly different levels of plasma markers of cardiovascular disease compared with normal controls. Therefore, clinicians who manage women with PCOS should follow up on these markers to reduce the risk of cardiovascular disease.
PMCID: PMC2931778  PMID: 20622344
11.  Temporal Relationship between Diet-Induced Steatosis and Onset of Insulin/Leptin Resistance in Male Wistar Rats 
PLoS ONE  2015;10(2):e0117008.
Rats fed with high-fat-high-sucrose (HFHS) diet are known to manifest metabolic syndrome including hyperinsulinemia, hyperleptinemia, hyperglycemia, diabetic dyslipidemia, and hepatic steatosis. The aim of the current study is to determine the temporal relationships between the development of hepatic steatosis and the onset of insulin and leptin resistance in hypothalamus and liver in male Wistar rats (six weeks of age) fed chow or HFHS diet for up to 8 weeks. Fasting plasma glucose, lipids/lipoproteins, insulin and leptin levels were quantified, histopathologic score of hepatic steatosis and inflammation were assessed, and the responses of common checkpoints of insulin and leptin signalling responsible for lipogenesis and gluconeogenesis were analyzed. In addition, acute insulin or leptin administration was performed at different stages of HFHS dieting to determine the responsiveness of the respective signalling pathways. Hyperinsulinemia, hyperglycemia, dyslipidemia, and increased homeostasis model assessment of basal insulin resistance occurred 1-week after HFHS dieting, coinciding with upregulation of suppressor of cytokine signalling 3 in both hypothalamus and liver. However, hepatosteatosis, accompanied with increased expression of sterol regulatory element binding protein 1c and phosphoenolpyruvate carboxykinase, did not manifest until 4- to 8-week after HFHS dieting. Lowered insulin sensitivity (shown by decreased insulin receptor substrate 1 and protein kinase B phosphorylation) occurred approximately 2 weeks prior to leptin resistance (shown by impaired signal transducer and activator of transcription 3 activation) in both the liver and hypothalamus. Acute insulin/leptin administration also demonstrated the impaired insulin or leptin signalling transduction. These data suggest that lowered insulin sensitivity and leptin resistance occurred at least 2–3 weeks earlier than the manifestation of hepatosteatosis in rats fed HFHS diet.
PMCID: PMC4319780  PMID: 25658428
12.  Prothrombotic State, Cardiovascular, and Metabolic Syndrome Risk Factors in Prepubertal Children Born Large for Gestational Age 
Diabetes Care  2010;33(11):2468-2470.
To evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age (LGA) to nondiabetic, nonobese mothers.
At 6–7 years of age, the comparison of various factors was made between 31 LGA and 34 appropriate-for-gestational-age (AGA) children: fibrinogen, antithrombin III, protein C and S, fasting insulin, glucose, homeostasis assessment model of insulin resistance (HOMA-IR) index, adiponectin, leptin, visfatin, IGF-1, IGF-binding protein (IGFBP)-1, IGFBP-3, lipids, and the genetic factors V Leiden G1691A mutation, prothrombin 20210A/G polymorphism, and mutation in the enzyme 5,10-methylenetetrahydrofolate-reductase gene (MTHFR-C677T).
LGA children had higher levels of leptin (P < 0.01), fasting insulin (P < 0.01), and HOMA-IR (P < 0.01), but lower IGFBP-3 (P = 0.0001), fibrinogen (P = 0.0001), and lipoprotein(a) (P < 0.001) than AGA children. Significantly more LGA children were homozygous for the MTHFR-C677T mutation (P = 0.0016).
Being born LGA to nondiabetic, nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty.
PMCID: PMC2963515  PMID: 20724652
13.  Leptin and its association with Somatic Depressive Symptoms in Patients with the Metabolic Syndrome 
This study aimed to determine the association between circulating leptin levels and total depressive symptoms as well as depressive symptom dimensions (cognitive and somatic) after controlling for important confounding factors.
The study sample was comprised of 135 participants with the metabolic syndrome. Depressive symptoms were measured using the Beck Depression Inventory - II. Leptin was measured using a leptin-specific enzyme immunoassay. Inflammation was assessed using C-reactive protein and interleukin-6 levels.
Leptin was significantly associated with somatic depressive symptoms (β=0.33, P=0.018) but not total depressive symptoms (β=0.27, P=0.067), or cognitive depressive symptoms (β=0.21, P=0.182), after controlling for age, gender, body mass index and insulin resistance. Further adjustment for C-reactive protein and interleukin-6 levels did not alter the relationship (β=0.32, P=0.023) between circulating leptin levels and somatic depressive symptoms.
Leptin is independently associated with somatic depressive symptoms in patients with the metabolic syndrome.
PMCID: PMC3696025  PMID: 23436275
Depression; Leptin; Inflammation; Metabolic Syndrome; Blood Pressure; Body Weight; Insulin Resistance; Lipoproteins; Cardiovascular Disease
14.  Levels of homocysteine are increased in metabolic syndrome patients but are not associated with an increased cardiovascular risk, in contrast to patients without the metabolic syndrome 
Heart  2006;93(2):216-220.
The metabolic syndrome is associated with increased cardiovascular risk. Elevated plasma homocysteine may cause or result from insulin resistance, and may indicate vascular risk or be actively involved in atherogenesis. The aim of the study was to investigate the relationship between homocysteine, the metabolic syndrome and the incidence of cardiovascular events in patients with manifest vascular disease.
A cohort of 2169 patients with manifest vascular disease was followed for a mean period of 2.8 years. Plasma homocysteine was measured at baseline. Metabolic syndrome was defined by NCEP criteria.
Homocysteine levels were higher in metabolic syndrome patients compared to patients without the metabolic syndrome (14.9±0.2 v 14.1±0.2 μmol/l; p = 0.002) and increased with the presence of its components (from 0 to 5) (12.7 to 15.9 μmol/l; p<0.001). During follow‐up, 52 strokes, 67 myocardial infarctions, 5 fatal ruptures of aortic aneurysms and 53 vascular deaths occurred. Patients without the metabolic syndrome and homocysteine levels in the highest tertile had increased risk for events (HR 1.9; 95% CI 1.0 to 3.5) compared to patients without the metabolic syndrome and homocysteine levels in the lowest tertile. The presence of the metabolic syndrome increased the risk (HR 2.2; 95% CI 1.2 to 4.2), but elevated homocysteine levels further increased the risk only marginally (2.5; 95% CI 1.4 to 4.6).
Metabolic syndrome patients have elevated homocysteine levels, but these higher levels are not associated with an increased risk for new cardiovascular events. In contrast, elevated homocysteine levels confer increased risk in patients without the metabolic syndrome.
PMCID: PMC1861402  PMID: 16952974
cardiovascular disease; homocysteine; metabolic syndrome
15.  The Association of Cysteine with Obesity, Inflammatory Cytokines and Insulin Resistance in Hispanic Children and Adolescents 
PLoS ONE  2012;7(9):e44166.
Plasma total cysteine (tCys) independently relates to fat mass in adults. Dietary cyst(e)ine promotes adiposity and decreases glucose tolerance in some rodent models, but alleviates insulin resistance in others.
To investigate whether the association of tCys with body fat extends to children at particular risk of obesity, and whether tCys is associated with insulin resistance and obesity-associated inflammation.
We explored the cross-sectional relations of fasting plasma tCys and related metabolites with body composition measured by dual-energy X-ray absorptiometry in 984 Hispanic children and adolescents aged 4–19 years from the Viva La Familia Study. Linear and logistic regression and dose-response curves were used to evaluate relations of tCys with obesity, insulin resistance and inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein (CRP).
tCys, methionine and total homocysteine (tHcy) increased with age. Upper tCys quartile was independently associated with a 5-fold increased risk of obesity (95% CI 3.5–8.0, P<0.001), and 2-fold risk of insulin resistance (95% CI: 1.6-5.0, P<0.001; adjusted for body fat%). Within the overweight/obese subgroup, but not in normal-weight children, tCys accounted for 9% of the variability in body fat% (partial r = 0.30, P<0.001; adjusted for age and gender). tCys correlated positively with serum non-esterified fatty acids and leptin, partly independent of body fat, but was not associated with serum IL-6, TNF-α or MCP-1. A positive correlation with CRP disappeared after adjustment for BMI.
tCys is independently associated with obesity and insulin resistance in Hispanic children and adolescents, highlighting a previously underappreciated link between the sulfur amino acid metabolic pathway and obesity and cardiometabolic risk.
PMCID: PMC3439485  PMID: 22984471
16.  Status of Homocysteine in Polycystic Ovary Syndrome (PCOS) 
Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of reproductive age and is estimated to affect 5-10 % of the population. Women with PCOS have a clustering of cardiovascular risk factors, such as obesity, dyslipidemia, impaired glucose tolerance and hypertension. Homocysteine has been recognized recently as a risk factor for cardiovascular diseases. Preliminary investigations suggest that high sensitivity C-reactive protein, homocysteine and adiponectin are abnormal in women with PCOS. The possible determinants of elevated homocysteine concentration are still debated among authors who found significant correlations between homocysteine and insulin resistance or hyperandrogenism.
Aim: The purpose of this study is to evaluate homocysteine levels in the PCOS population compared with controls.
Materials and Methods: Study group comprised of 142 women with PCOS and 65 healthy non-PCOS controls. Body mass index (BMI), Waist circumference and serum homocysteine were measured in PCOS subjects and age matched controls.
Statastical Analysis: All values are expressed as mean α SD. The results obtained are analysed statistically using the unpaired student t-test to evaluate the significance of differences between the mean values.
Results: The mean BMI, Waist circumference and serum homocysteine values are significantly increased in PCOS subjects when compared with non PCOS controls.
Conclusion: The present study has demonstrated increase in mean serum homocysteine concentrations in women with PCOS.
PMCID: PMC3972590  PMID: 24701474
Polycystic ovary syndrome; Homocysteine; Cardiovascular disease
17.  Comprehensive analysis of circulating adipokines and hsCRP association with cardiovascular disease risk factors and metabolic syndrome in Arabs 
Cardiovascular diseases (CVD) are a leading cause of death worldwide including the Middle East. This is caused in part by the dysregulation of adipose tissue leading to increased production of pro-inflammatory adipokines and reduction in cardio-protective adipokines such as adiponectin. Ethnicity has been recognized as a major factor in the association between CVD risk factors and the different circulating adipokines. In this study, for the first time, the relationship between traditional cardiovascular risk factors, Metabolic Syndrome (MetS) and circulating level of adipokines in Arab ethnicity was investigated.
We conducted a population-based cross-sectional survey on 379 adult Arab participants living in Kuwait. Traditional cardiovascular risk factors such as blood pressure (BP), low density lipoprotein (LDL) and triglyceride (TG) were measured. Plasma levels of circulating Leptin, Plasminogen Activator Inhibitor (PAI-1) visfatin, adiponectin, resistin and adipsin were assessed using the multiplexing immunobead-based assay.
Circulating levels of High sensitivity C-Reactive Protein (hsCRP), Leptin, PAI-1 and adiponectin were significantly higher in Arab women than men (p < 0.0001). In multi-variate analysis, the homeostasis model assessment-insulin resistance (HOMA-IR) and body mass index (BMI) showed strong association with most of the biomarkers (p < 0.05). HsCRP showed significant association with all risk factors (p < 0.05). Leptin, PAI-1 and adipsin showed significant positive correlation with BMI, unlike adiponectin which showed inverse correlation (p < 0.05). Subjects in the highest tertile of leptin, PAI-1 and hsCRP had higher odds of having Metabolic Syndrome (MetS) (odd ratio [OR] = 3.02, 95% confidence interval [CI] = 1.47 – 6.19) and (OR = 2.52, 95% CI = 1.45 – 4.35), (OR = 4.26, 95% CI = 2.39 – 7.59) respectively. On the other hand subjects with highest tertile of adiponectin had lower odds of having MetS (OR = 0.22, 95% CI = 0.12 – 0.40). Leptin, PAI-1 and hsCRP showed significant positive association with increased MetS components (P-trend <0.05), while adiponectin was negatively associated with increased MetS components (P-trend <0.0001).
Our results show positive association between hsCRP, leptin, PAI-1 with increased MetS components and increase the odds of having MetS. Adiponectin on the other hand showed inverse correlation with MetS components and associated with reduction in MetS. Overall, our data highlights the significant clinical value these markers have in MetS especially hsCRP which can be used as good marker of low grade inflammation in Arabs.
PMCID: PMC3997236  PMID: 24716628
Adipokine; Arab; Metabolic syndrome; Cardiometabolic risk factors; Lipid profile; hsCRP; Leptin; Adiponectin; Visfatin; Resistin; Adipsin; Low grade inflammation
18.  Leptin and Its Relation to Obesity and Insulin in the SHR/N-corpulent Rat, A Model of Type II Diabetes Mellitus 
The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p<0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r=0.73, p<0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r=0.54, p<0.05). There was also a significant positive.correlation between plasma leptin and plasma insulin in the entire group (r=0.70, p<0.01). However, this relationship was significant only for lean rats but not for obese rats (r=0.59, p<0.05 for lean rats, and r=0.23, p=NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r=0.75, p<0.05), total cholesterol (r=0.63, p<0.05), and triglyceride (r=0.67, p <0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome.
PMCID: PMC2478551  PMID: 12369710
19.  The effects of exercise on C-reactive protein, insulin, leptin and some cardiometabolic risk factors in Egyptian children with or without metabolic syndrome 
The prevalence and magnitude of obesity in the children and the adolescents have increased dramatically in the developing countries over the last 20–30 years. The prevalence of metabolic syndrome (MS) in children is increasing. Aim: This study aimed to investigate the changes of C-reactive protein (CRP), leptin, insulin, and blood lipids before and after the exercise therapy in normal and obese children (with or without metabolic syndrome).
The study covered 49 normal children (control), 32 obese children without metabolic syndrome and 12 obese children with metabolic syndrome. We examined the influence of exercise (3 times/week) for 12 weeks on the levels of serum CRP, leptin, insulin, homeostatic model assessment insulin resistance (HOMA-IR), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in all groups.
There were significant correlations between HOMA-IR and the individual components of the metabolic syndrome. After 12 weeks of exercise, both of the obese children groups, with and without metabolic syndrome, showed reduced body weight, body mass index (BMI), and CRP level, and increased HDL-C level. The percentage of metabolic syndrome decreased from 12.9% before the exercise training to 7.5% after training. Also, there was a significant reduction in BMI (from 47.3 to 32.6%), in systolic blood pressure (from 18.3 to 15.1%) and in HDL-C level (from 18.3 to 9.7%).
Overweight children have multiple risk factors associated with the metabolic syndrome. 12-week exercise may have a positive effect on reducing risk factors for the metabolic syndrome.
PMCID: PMC3536685  PMID: 22691465
Metabolic syndrome; Exercise; Children; Cardiometabolic risk factor; C-reactive protein and insulin
20.  Effect Of G2706A and G1051A polymorphisms of the ABCA1 gene on the lipid, oxidative stress and homocystein levels in Turkish patients with polycystıc ovary syndrome 
Obesity, insulin resistance and hyperandrogenism, crucial parameters of Polycystic ovary syndrome (PCOS) play significant pathophysiological roles in lipidemic aberrations associated within the syndrome. Parts of the metabolic syndrome (low HDL and insulin resistance) appeared to facilitate the association between PCOS and coronary artery disease, independently of obesity. ABCA1 gene polymorphism may be altered this components in PCOS patients.
In this study, we studied 98 PCOS patients and 93 healthy controls. All subjects underwent venous blood drawing for complete hormonal assays, lipid profile, glucose, insulin, malondialdehyde, nitric oxide, disulfide levels and ABCA genetic study.
In PCOS group fasting glucose, DHEAS, 17-OHP, free testosterone, total-cholesterol, triglyceride, LDL-cholesterol and fibrinogen were significantly different compare to controls. The genotype ABCA G2706A distribution differed between the control group (GG 60.7%, GA 32.1%, AA 7.1%) and the PCOS patients (GG 8.7%, GA 8.7%, AA 76.8%). The frequency of the A allele (ABCAG2706A) was higher in PCOS patients than control group with 13,0% and 23,2%, respectively. In this study, the homocystein and insulin levels were significantly higher in PCOS patients with ABCA G1051A mutant genotype than those with heterozygote and wild genotypes.
We found higher percentage of AA genotype and A allele of ABCA G2706A in PCOS patients compare to controls. The fasting insulin and homocystein levels were significantly higher in PCOS patients with ABCA G1051A mutant genotype than those with heterozygote and wild genotypes.
PMCID: PMC3219737  PMID: 22035022
21.  Obesity and metabolic syndrome in 7-9 years-old Portuguese schoolchildren 
Body fat is related to changes in lipid profile, blood pressure and metabolism of insulin and glucose, known as the metabolic syndrome (MS). The aim of this study was to estimate the prevalence of metabolic syndrome (MS) and its components among overweight and obese Portuguese schoolchildren, and to identify associated clinical and biochemical characteristics.
A total of 82 children (14 overweight and 68 obese; 40 boys and 42 girls) aged 7-9 years, underwent anthropometric measurements. A blood sample was obtained to assess biochemical parameters. Insulin resistance (IR) was determined by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). MS was defined by the National Cholesterol Education Program Adult Treatment Panel III criteria modified by Cook.
The prevalence of MS was 15.8%. Abdominal obesity was present in all children. Frequency of elevated blood pressure, low HDL-cholesterol and elevated triglyceride concentrations were 62.6%, 13.4% and 11.0%, respectively. None of the children presented impaired fasting glucose, however hyperinsulinemia (7.3%) and IR (8.5%) were observed. The number of components of MS was higher in children with higher z-BMI (ρ = 0.411; p < 0.001). MS was associated with higher leptin concentrations. No association was found with adiponectin or ghrelin levels. Leptin correlated positively with obesity, glucose metabolism, lipid profile, hepatic function and C-reactive protein, and negatively with HDL and Apolipoprotein A-I/B ratio.
This study shows a significant prevalence of MS among obese schoolchildren. Abdominal obesity and elevated blood pressure were the most frequent components of this syndrome. Dyslipidemia, IR and high levels of leptin were also associated with MS in this young group.
PMCID: PMC2901245  PMID: 20537155
22.  Agrarian diet and diseases of affluence – Do evolutionary novel dietary lectins cause leptin resistance? 
The global pattern of varying prevalence of diseases of affluence, such as obesity, cardiovascular disease and diabetes, suggests that some environmental factor specific to agrarian societies could initiate these diseases.
Presentation of the hypothesis
We propose that a cereal-based diet could be such an environmental factor. Through previous studies in archaeology and molecular evolution we conclude that humans and the human leptin system are not specifically adapted to a cereal-based diet, and that leptin resistance associated with diseases of affluence could be a sign of insufficient adaptation to such a diet. We further propose lectins as a cereal constituent with sufficient properties to cause leptin resistance, either through effects on metabolism central to the proper functions of the leptin system, and/or directly through binding to human leptin or human leptin receptor, thereby affecting the function.
Testing the hypothesis
Dietary interventions should compare effects of agrarian and non-agrarian diets on incidence of diseases of affluence, related risk factors and leptin resistance. A non-significant (p = 0.10) increase of cardiovascular mortality was noted in patients advised to eat more whole-grain cereals. Our lab conducted a study on 24 domestic pigs in which a cereal-free hunter-gatherer diet promoted significantly higher insulin sensitivity, lower diastolic blood pressure and lower C-reactive protein as compared to a cereal-based swine feed. Testing should also evaluate the effects of grass lectins on the leptin system in vivo by diet interventions, and in vitro in various leptin and leptin receptor models. Our group currently conducts such studies.
Implications of the hypothesis
If an agrarian diet initiates diseases of affluence it should be possible to identify the responsible constituents and modify or remove them so as to make an agrarian diet healthier.
PMCID: PMC1326203  PMID: 16336696
23.  ENU Mutagenesis Identifies Mice with Morbid Obesity and Severe Hyperinsulinemia Caused by a Novel Mutation in Leptin 
PLoS ONE  2010;5(12):e15333.
Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals.
Methodology/Principal Findings
To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin145E/145E mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin145E/145E mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin145E/145E mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region.
Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.
PMCID: PMC3000341  PMID: 21151569
24.  Metabolic syndrome and risk factors for cardiovascular disease: are nonagenarians protected? 
Age  2009;31(1):67-75.
This study assessed cardiovascular disease risk factors in three groups of human subjects aged 20–34 [young, 20 male (M)/33 female (F)], 60–74 (aged, 29M/29F), and > 90 years (nonagenarian, 47M/50F). Components of the metabolic syndrome, cardiovascular disease, and markers of inflammation and oxidative stress were assessed. Nonagenarians weighed less than the two other groups (P < 0.001); however, there was no difference in percent fat among the three groups. Aged individuals had the highest prevalence of the metabolic syndrome (P < 0.001) according to the Adult Treatment Panel III classification. Both fibrinogen and homocysteine concentrations were significantly higher in the nonagenarians compared to younger groups. However, there were no significant differences between groups in fasting insulin, high sensitive C-reactive protein, and plasminogen activator inhibitor 1 concentrations. There were also no relationships between inflammation/ oxidative stress and the metabolic syndrome or cardiovascular disease although nonagenarians appear to be protected from oxidative damage to DNA.
PMCID: PMC2645995  PMID: 19234770
Aging; Cardiovascular disease; Inflammation; Metabolic syndrome; Oxidative stress
25.  Leptin in Relation to the Lipodystrophy-Associated Metabolic Syndrome 
Diabetes & Metabolism Journal  2012;36(3):181-189.
Leptin, an adipocyte-secreted hormone, regulates energy homeostasis as well as reproductive, neuroendocrine, immune and metabolic functions. Subjects with decreased amounts of fat in their adipose tissue, i.e., lipoatrophy, have low leptin levels. In the context of open-label, uncontrolled studies leptin administration, in physiological replacement doses, has been shown to have metabolically salutary effects in the rare patients with the syndrome of congenital lipodystrophy accompanied by leptin deficiency. Much more patients with lipodystrophy suffer from lipodystrophy and the metabolic syndrome associated with the use of highly active antiretroviral therapy. In this so called highly active antiretroviral therapy (HAART)-associated lipodystrophy and metabolic syndrome, patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Leptin administration has been shown to decrease central fat mass and to improve fasting insulin/glucose levels and insulin sensitivity in human immunodeficiency virus-infected hypoleptinemic patients with HAART induced lipodystrophy and the metabolic syndrome. By contrast, the results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. In this review, we present the emerging clinical applications and potential therapeutic uses of leptin in humans with lipodystrophy and the metabolic syndrome.
PMCID: PMC3380121  PMID: 22737657
Antiretroviral therapy, highly active; Glucose metabolism; HIV; Leptin; Lipodystrophy

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