leptin and Diabetic-Angiopathies

The adipocytokines leptin and adiponectin have been variously associated with diabetic microvascular complications. No comprehensive clinical data exist examining the association between adipocytokines and the presence of these complications.. This is a systematic review of cross-sectional studies comparing circulating adipocytokines in patients with type 2 diabetes mellitus (T2DM), with and without microvascular complications. Studies were retrieved from MEDLINE, EMBASE, Scopus and Cochrane databases. Study quality was evaluated using a modified Newcastle-Ottawa Scale. Meta-analysis was performed using an inverse-variance model, providing standardised mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity was determined by I(2) statistic.. Amongst 554 identified studies, 28 were included in the review. Study quality range was 3.5-9 (maximum 11). Higher leptin levels were associated with microalbuminuria (SMD=0.41; 95% CI=0.14-0.67; n=901; p=0.0003), macroalbuminuria (SMD=0.68; 95% CI=0.30-1.06; n=406; p=0.0004), and neuropathy (SMD=0.26; 95% CI=0.07-0.44; n=609; p=0.008). Higher adiponectin levels were associated with microalbuminuria (SMD=0.55; 95% CI=0.29-0.81, n=274; p<0.001), macroalbuminuria (SMD=1.37; 95% CI=0.78-1.97, n=246; p<0.00001), neuropathy (SMD=0.25; 95% CI=0.14-0.36; n=1516; p<0.00001), and retinopathy (SMD=0.38; 95% CI=0.25-0.51; n=1306; p<0.00001). Meta-regression suggested no influence of body mass index and duration of diabetes on effect size, and a weak trend in terms of age on effect size.. Our meta-analysis suggests leptin and adiponectin levels are higher in T2DM patients with microvascular complications. Studies were limited by cross-sectional design. Large prospective analyses are required to validate these findings.

Topics: Adipokines; Adiponectin; Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Leptin; Male; Middle Aged

Topics: Allylamine; Animals; Blood Glucose; Bromocriptine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Metformin; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; United States

The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.

Topics: Adipocytes; Adipose Tissue; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Energy Metabolism; Female; Humans; Intra-Abdominal Fat; Leptin; Male; Metabolic Syndrome; Obesity; Risk Reduction Behavior; Subcutaneous Fat, Abdominal; Transcription Factors

Stroke is an important cause of morbidity and mortality, and is an economic burden. Diabetes and obesity are two important modifiable risk factors for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke. Risk-factor modification is the most important aspect of prevention of stroke in diabetes and obesity. This includes lifestyle modifications and different therapeutic modalities to control conditions, such as diabetes, hypertension, dyslipidemia and arrhythmia. Recent landmark studies have shown the beneficial effects of statins in diabetic patients even with close to normal or normal low-density lipoprotein cholesterol. Obesity, which is a risk factor for diabetes, hypertension and hyperlipidemia has been shown to be an independent risk factor for stroke. Increased leptin, dysregulation of adipocyte proteins, increased insulin resistance and C-reactive protein may be factors involved in the increased incidence of cardiovascular morbidity and mortality directly related to obesity. Visceral fat is a much bigger health risk than subcutaneous fat. Lifestyle interventions and pharmacotherapeutic agents have been used to manage obesity. In morbidly obese patients, surgical intervention seems to be the best method of treatment with a long-lasting favorable metabolic outcome. In the 21st Century, with the advanced medical knowledge and the therapeutic modalities available, it should be possible to reduce the incidence of stroke associated with diabetes and obesity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atrial Fibrillation; Blood Glucose; Cardiovascular Agents; Carotid Stenosis; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Dyslipidemias; Humans; Hypertension; Insulin Resistance; Ischemic Attack, Transient; Leptin; Life Style; Lipoproteins; Obesity; Plasminogen Activator Inhibitor 1; Risk Factors; Smoking; Stroke

Topics: Amyloid; Animals; Biomarkers; Bone and Bones; Bone Density; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Humans; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Leptin; Osteoblasts; Osteoporosis; Rats

It has been increasingly recognised in recent years that type 2 (non-insulin-dependent) diabetes is part of a cluster of cardiovascular risk factors known as the metabolic syndrome, but also endorsed with such names as the deadly quartet, syndrome X and the insulin resistance syndrome. Atherosclerosis is the most common complication of type 2 diabetes among Europeans, and coronary artery, cerebrovascular and peripheral vascular disease are 2 to 5 times more common in people with this condition than in those without diabetes. These observations indicate that the treatment of type 2 diabetes requires agents that do more than simply lower blood glucose levels, and a therapy with both antihyperglycaemic effects and beneficial effects on dyslipidaemia, hypertension, obesity, hyperinsulinaemia and insulin resistance is likely to be most useful. In this respect, metformin has an important and established role: this drug has been shown to lower blood glucose and triglyceride levels, and to assist with weight reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin resistance to be the initial and underlying metabolic disorder in obesity and type 2 diabetes. Thus, the well established effect of metformin in reducing insulin resistance makes this drug an excellent candidate for the prevention of progression of impaired glucose tolerance to type 2 diabetes, and for the reduction of mortality associated with cardiovascular disease.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Chromans; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Rats; Risk Factors; Thiazoles; Thiazolidinediones; Troglitazone

Telmisartan, a new angiotensin II type 1 receptor blocker (ARB), was recently reported to stimulate PPARgamma, and stronger effects of Telmisartan on insulin sensitivity has been expected than the class effect of ARB. In the present study, we examined the effects of Telmisartan on insulin sensitivity and adipokine levels in hypertensive and type 2 diabetic patients. Outpatients with both hypertension and type 2 diabetes mellitus (n=36; male 23, female 13), received 20-40mg Telmisartan orally once daily for 6 months. Physical examinations and blood or urine tests were performed before and 3 or 6 months after starting Telmisartan treatment. Results were statistically compared using Wilcoxon analysis. Telmisartan treatment for 3 or 6 months reduced systolic and diastolic blood pressure and urinary albumin excretion. Fasting plasma glucose, HbA1c, total and HDL-cholesterol, triglyceride, body weight, BMI and waist length were not changed. Fasting IRI and HOMA-IR were significantly decreased after Telmisartan treatment, suggesting the improved insulin sensitivity. Total and high molecular adiponectin were not changed. Interestingly, serum leptin was significantly increased by 3 months Telmisartan treatment, suggesting a possible involvement of leptin in improved insulin sensitivity. In conclusion, Telmisartan improved insulin resistance with increased serum leptin level in hypertensive and type 2 diabetic patients.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Female; Humans; Hypertension; Hypoglycemic Agents; Leptin; Lipids; Male; Middle Aged; Telmisartan

Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients.. A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone.. The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA(1c) levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA(1c) (n = 30) and responders showing >1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism.. This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect.

Topics: Adiponectin; Arteriosclerosis; Blood Pressure; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycolipids; Humans; Hyperglycemia; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Japan; Leptin; Male; Middle Aged; Pioglitazone; Proteins; Thiazolidinediones

To evaluate adipokine serum values of irisin, retinol-binding protein 4, and leptin in Saudi cases with type 2 diabetes mellitus (T2DM) for providing markers of T2DM macrovascular complications. Methods: This case-control research was carried out at Erfan Hospital, Jeddah, Saudi Arabia. The study included 138 subjects, classified into 3 groups: 46 T2DM patients with macrovascular complications, 46 T2DM without macrovascular complications, and 46 controls. Participants evaluated clinically and some biochemical parameters were measured. Results: Diabetic with and without macrovascular complications showed elevation of retinol-binding protein 4 (RBP4) and leptin; decreased irisin serum levels versus controls. Serum irisin was lower (p=0.007), while RBP4 was higher (p less than 0.0001) in T2DM patients with macrovascular complications versus without. Irisin showed negative correlations with fasting blood glucose (FBG), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), RBP4, hemoglobin A1C (HbA1C), triglyceride, cholesterol, and low-density lipoprotein cholesterol. While RBP4 showed positive correlations with fasting blood glucose, insulin, HOMA-IR, leptin, and HbA1c; but a negative association with high-density lipoprotein cholesterol. Conclusion: Type 2 DM patients had raised RBP4 and leptin, but lower irisin levels versus controls. Irisin was lower, but RBP4 was higher in T2DM patients with macrovascular complications versus without, suggesting T2DM patients in pro-inflammatory conditions. These results suggested that irisin is protective, while RBP4 is a risk factor for T2DM macrovascular complications.

Topics: Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibronectins; Humans; Leptin; Male; Middle Aged; Retinol-Binding Proteins, Plasma; Risk Factors; Saudi Arabia

Oxidative stress (OS) plays an important role in type 2 diabetes (T2D) pathogenesis and its complications. New therapies target natural antioxidants as an alternative and/or supplemental strategy to prevent and control them. Our previous chemical and biological studies highlighted the important antioxidant activities of cherries, among other fruits and vegetables, thus we aimed to determine in vivo effects of 2-month long cherry consumption using a high-fat/high-fructose (HFHF) model of diabetic-rats (Lozano et al. in Nutr Metab 13:15, 2016).. After 2 months of HFHF, male Wistar rats were divided into: HFHF and HFHF enriched in cherry (nutritional approach) or standard diet ND (lifestyle measures) and ND plus cherry during 2 months. Metabolic, lipidic, oxidative parameters were quantified. Tissues (liver, pancreas and vessels) OS were assessed and hepatic (steatosis, fibrosis, inflammation) and vascular (endothelial dysfunction) complications were characterized.. T2D was induced after 2 months of HFHF diet, characterized by systemic hyperglycaemia, hyperinsulinemia, glucose intolerance, dyslipidaemia, hyperleptinemia, and oxidative stress associated with endothelial dysfunction and hepatic complications. Cherry consumption for 2 months, in addition to lifestyle measures, in T2D-rats decreased and normalized the systemic disturbances, including oxidative stress complications. Moreover, in the vessel, cherry consumption decreased oxidative stress and increased endothelial nitric oxide (NO) synthase levels, thus increasing NO bioavailability, ensuring vascular homeostasis. In the liver, cherry consumption decreased oxidative stress by inhibiting NADPH oxidase subunit p22phox expression, nuclear factor erythroid-2 related factor 2 (Nrf2) degradation and the formation of reactive oxygen species. It inhibited the activation of sterol regulatory element-binding proteins (1c and 2) and carbohydrate-responsive element-binding protein, and thus decreased steatosis as observed in T2D rats. This led to the improvement of metabolic profiles, together with endothelial and hepatic function improvements.. Cherry consumption normalized vascular function and controlled hepatic complications, thus reduced the risk of diabetic metabolic disorders. These results demonstrate that a nutritional intervention with a focus on OS could prevent and/or delay the onset of vascular and hepatic complications related to T2D.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, High-Fat; Endothelium, Vascular; Energy Metabolism; Fructose; Fruit; Insulin; Leptin; Lipids; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pancreas; Prunus avium; Rats, Wistar; Signal Transduction; Time Factors

Diabetic patients often exhibit severe, asymptomatic coronary artery disease (CAD). The relationship between osteoprotegerin (OPG), inflammatory markers and silent myocardial ischemia remains to be elucidated.. We recruited 45 type 2 diabetic patients and 33 healthy controls and assessed them for silent myocardial ischemia (SMI) by myocardial perfusion imaging. Patient blood was tested for OPG, IL-6 and leptin concentrations.. OPG, leptin and IL-6 levels were found significantly elevated in diabetic patients (p < 0.001, p < 0.01, p < 0.05). Based on our classification of presence/absence of SMI in our diabetic group, we found that there was a significant association between SMI and the biomarkers IL-6 (p < 0.001), leptin (p < 0.001) and OPG (p < 0.05). In multivariate regression analyses, OPG was found to be significantly related to diabetes mellitus and to SMI. Age, sex and smoking increased the association between OPG and SMI.. High OPG, leptin and IL-6 levels are associated with the presence and severity of SMI in type 2 diabetic patients.

Topics: Adult; Biomarkers; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exercise Test; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Perfusion Imaging; Osteoprotegerin; Regression Analysis

Insulin clearance may decline as an early mechanism compensating for deteriorating insulin sensitivity. However, no previous studies have investigated the association between subclinical inflammation or impaired fibrinolysis and insulin clearance. We examined the association between plasminogen activator inhibitor (PAI)-1, C-reactive protein (CRP), TNF-α, leptin and fibrinogen and the progression of metabolic clearance rate of insulin (MCRI) over time.. We studied 784 non-diabetic white, Hispanic and African-American individuals in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity, acute insulin response 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 had declined significantly by 29% at the 5-year follow-up. We observed a significant association between higher plasma PAI-1 levels and the decline in MCRI in multivariable-adjusted regression models (β = -0.045 [95% CI -0.081, -0.0091]). Higher plasma CRP and leptin levels were associated with a decline in MCRI in unadjusted models, but these associations were non-significant after adjusting for BMI and waist circumference (β = -0.016 [95% CI -0.041, 0.0083] for CRP; β = -0.044 [95% CI -0.10, 0.011] for leptin). A higher plasma TNF-α concentration was associated with a decline in MCRI in unadjusted (β = -0.071 [95% CI -0.14, -0.00087]) but not in multivariable-adjusted (β = -0.056 [95% CI -0.13, 0.017]) models. Plasma fibrinogen level was not associated with the change in MCRI.. We identified that higher plasma PAI-1 (but not CRP, TNF-α, leptin or fibrinogen) levels independently predicted the progressive decline of insulin clearance in the multiethnic cohort of the IRAS.

Topics: Atherosclerosis; Body Mass Index; Cohort Studies; Diabetic Angiopathies; Female; Fibrinogen; Follow-Up Studies; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin Resistance; Leptin; Male; Metabolic Clearance Rate; Middle Aged; Overweight; Plasminogen Activator Inhibitor 1; Prediabetic State; Prospective Studies; Risk Factors; United States

Adipokines are markers of insulin resistance and play a role in the atherosclerotic process. The association of adipokines with the macrovascular complications of type 1 diabetes mellitus (DM) needs to be determined. The aim of this study was to measure serum adiponectin, leptin, and resistin levels in type 1 DM patients and investigate their relationship with carotid intima media thickness (CIMT), a clinical marker of atherosclerosis.. Seventy-five type 1 DM patients and 115 sex and age-matched healthy controls were included in the study. Serum adiponectin, leptin, and resistin levels were measured by the enzyme-linked immunosorbent assay (ELISA method). CIMT was assessed by Doppler ultrasonography.. Adiponectin levels in diabetics were higher (25.8±14.8 μg/mL vs. 5.5±7.3 μg/mL; P<0.0001) and leptin levels were lower than controls (9.4±6.2 ng/mL vs. 12.8±8.6 ng/mL; P=0.01). Resistin levels were also higher in the diabetic group compared to controls (2.1±1.4 ng/mL vs. 1.6±0.8 ng/mL; P=0.04). Adiponectin was correlated negatively with CIMT (r=-0.24, P=0.03), age (r=-0.30, P=0.02), BMI (r=-0.33, P=0.02), waist-to-hip ratio (WHR) (r=-0.38, P=0.01) and positively with creatinine (r=0.44, P=0.004). Leptin levels were correlated with total cholesterol (r=0.53, P=0.01) and high-density lipoprotein (HDL) (r=0.67, P=0.001). Resistin was correlated with CIMT (r=0.24, P=0.03) and systolic blood pressure (r=0.48, P=0.009). Multivariate analysis revealed resistin and creatinine to be independent predictors of CIMT among adiponectin, leptin, resistin, WHR, glycosylated hemoglobin (HbA1c), and creatinine.. Increased adiponectin correlates negatively and resistin positively with CIMT in type 1 diabetic patients, but adjusting for other known predictors reveals only resistin to be associated with subclinical atherosclerosis in this group of patients.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Blood Pressure; Body Mass Index; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Chi-Square Distribution; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Leptin; Lipids; Male; Resistin; Risk Assessment; Risk Factors; Turkey; Ultrasonography, Doppler; Waist Circumference; Young Adult

To determine whether leptin receptor (LEPR) 223A>G polymorphism has an effect on the plasma leptin levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM). The genotypes and allelic frequencies of the LEPR 223A>G were examined with polymerase chain reaction and restriction fragment length polymorphism in 301 patients with T2DM and 172 unrelated healthy subjects. The plasma concentrations of leptin were determined in all subjects. The mean plasma leptin levels in the T2DM group were significantly higher than that of controls and the plasma levels of leptin were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (GG, AG and AA) distribution of 223A>G polymorphism was 58.3, 32.5, and 9.2% in diabetic patients with macroangiopathy, 75.3, 22.1, and 2.6% in patients without macroangiopathy, and 70.3, 27.5, 2.2% in controls respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele A was higher in patients with macroangiopathy than in patients without macroangiopathy (25.6 vs. 16.3%; P < 0.05). Moreover, the plasma leptin levels were markedly higher in patients with AA genotype than those with AG or GG genotype in patients with macroangiopathy (P < 0.05). The LEPR 223A>G gene polymorphism associated with a predisposition to increased plasma leptin levels could constitute a useful predictive marker for diabetic macroangiopathy.

Topics: Alleles; Anthropometry; Demography; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leptin; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors

We aimed to evaluate whether leptin and ghrelin responses to cardiopulmonary bypass (CPB) are dependent on type 2 diabetes and whether these responses are associated with interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), cortisol and insulin.. We examined stress-response patterns in plasma leptin, ghrelin, hsCRP, IL-6, cortisol and insulin levels before and up to 5 days after cardiopulmonary bypass in 20 patients with type 2 diabetes and 20 patients without diabetes.. Plasma leptin levels increased significantly in both groups (p<0.05) and rose significantly higher in diabetics when compared with nondiabetic patients (p=0.004). Plasma ghrelin levels increased significantly only in diabetics (p=0.033). Patients with and without diabetes showed significantly elevated serum concentrations of IL-6, hsCRP, cortisol and insulin (p<0.005 for IL-6, hsCRP; p<0.05 for cortisol, insulin) but the difference between the two groups was nonsignificant. Leptin was independently predicted by hsCRP (p<0.05, F=2.9), gender (women p<0.001, F=4.7), body mass index (BMI p<0.0001, F=6.1) whereas ghrelin levels were not associated with any variables in the total patient population. (critical F=2.26, p≤0.05).. Acute phase response in diabetics differs by higher leptin levels independent of BMI, gender and IL-6, hsCRP, insulin and cortisol levels.

Topics: Blood Glucose; Body Mass Index; C-Reactive Protein; Cardiopulmonary Bypass; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Ghrelin; Humans; Hydrocortisone; Insulin; Interleukin-6; Leptin; Male; Middle Aged

Obesity and type 2 diabetes increase the risk of atherosclerosis. It is unknown to what extent this reflects direct effects on the arterial wall or secondary effects of hyperlipidaemia.. The effect of obesity and type 2 diabetes on the development of atherosclerosis and inflammation, in the absence or presence of hyperlipidaemia, was assed in wild-type (n = 36) and human apolipoprotein B (apoB) transgenic mice (n = 27) that were fed normal chow or 60% fat for 12 months.. Fat-feeding caused obesity, glucose intolerance and elevated plasma leptin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in both wild-type and apoB transgenic mice. In wild-type mice, plasma very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) were unaffected by fat-feeding. ApoB transgenic mice had mildly elevated plasma LDL-C (approximately 1 mmol L(-1)), which was slightly increased by fat-feeding. Sixty-four per cent of fat-fed wild-type mice vs. 7% of chow-fed wild-type mice had lipid-staining intimal lesions in the aortic root (P = 0.002). Eighty-six per cent of fat-fed apoB transgenic mice had lipid-staining lesions and the median lesion area was 8.0 times higher than in fat-fed wild-type mice (P = 0.001). Intracellular adhesion molecule-1 staining of the aortic endothelium was most pronounced in the fat-fed apoB transgenic mice.. Our findings suggest that diet-induced type 2 diabetes causes early atherosclerosis in the absence of dyslipidaemia, and that even a moderate level of LDL-C markedly augments this effect.

Topics: Animals; Arteritis; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dietary Fats; Disease Models, Animal; Female; Humans; Hyperlipidemias; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Random Allocation; Risk Factors; Statistics as Topic; Time Factors; Vascular Cell Adhesion Molecule-1

We investigated the role of leptin and its interaction with endothelin 1 (ET-1) in fibronectin (FN) synthesis and cardiomyocyte hypertrophy, two characteristic features of diabetic cardiomyopathy.. Endothelial cells [human umbilical vein endothelial cells (HUVECs)] were examined for FN production and neonatal rat cardiomyocytes for hypertrophy, following incubation with glucose, ET-1, leptin and specific blockers. FN, ET-1, leptin and leptin receptors mRNA expression and FN protein were measured. Myocytes were also morphometrically examined. Furthermore, hearts from streptozotocin-diabetic rats were analysed.. Glucose caused increased FN mRNA and protein expression in HUVECs and cardiomyocytes hypertrophy along with upregulation of ET-1 mRNA, leptin mRNA and protein. Glucosemimetic effects were seen with leptin and ET-1. Leptin receptor antagonist (leptin quadruple mutant) and dual endothelin A endothelin B (ETA/ETB) receptor blocker bosentan normalized such abnormalities. Hearts from the diabetic animals showed hypertrophy and similar mRNA changes.. These data indicate that in diabetes increased FN production and cardiomyocyte hypertrophy may be mediated through leptin with its interaction with ET-1.

Topics: Analysis of Variance; Animals; Cells, Cultured; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Extracellular Matrix Proteins; Fibronectins; Humans; Hypertrophy; Leptin; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Statistics, Nonparametric; Umbilical Veins

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes.. MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files.. At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality.. In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.

Topics: Atherosclerosis; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Chemokine CCL2; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glucose Tolerance Test; Humans; Insulin; Italy; Leptin; Life Style; Middle Aged; Prognosis; Risk Factors; Stroke

Leptin, an adipocyte-secreted hormone, plays an important role in regulating neuroendocrine and immune function as well as insulin resistance and metabolism. Our objective was to examine the relationship between leptin levels and cardiovascular morbidity and overall mortality in women with type 2 diabetes.. This prospective cohort study included 1,194 women with a confirmed diagnosis of type 2 diabetes, who provided a blood sample at baseline in 1989-1990. Participants were followed for 12 years for the development of health outcomes including cardiovascular disease (CVD) events as well as total mortality.. There were 218 new CVD events and 228 deaths from all causes. Cox proportional hazards analysis was used to estimate the relative risks (RRs) for each quintile level of leptin compared with the lowest quintile. Leptin levels were positively associated with several CVD risk factors including BMI and inflammatory markers, but were not independently associated with the incidence of CVD or total mortality in women with diabetes. The multivariate RRs (95% CIs) for CVD across the quintiles of leptin were 0.96 (0.61-1.53), 0.99 (0.61-1.61), 1.04 (0.63-1.71), 1.02 (0.59-1.75) (p for trend = 0.83).. Although circulating leptin levels are associated with obesity and inflammatory markers, they are not significantly related to the risk of CVD or mortality in women with diabetes.

Topics: Adult; Aged; Blood Specimen Collection; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Leptin; Life Style; Middle Aged; Prospective Studies; Risk Factors; Surveys and Questionnaires; Survival Analysis

Type 2 diabetes is a heterogeneous syndrome characterized by defective insulin secretion and/or insulin resistance. In distinct from Caucasian populations, Japanese type 2 diabetic patients are divided into two categories: one with insulin resistance and the other with normal insulin sensitivity. This unique feature allows us to explore the factors responsible for the evolution of insulin resistance in Japanese type 2 diabetic patients. In this article, we describe the factors responsible for insulin resistance in Japanese type 2 diabetic patients and discuss the relationships between these factors and atherosclerosis. Japanese type 2 diabetic patients with insulin resistance had significantly higher concentrations of triglyceride, remnant-like particle cholesterol, subcutaneous and visceral abdominal fat areas, leptin, high sensitive C-reactive protein (hs-CRP), and soluble E-selectin and lower concentration of adiponectin when compared to those with normal insulin sensitivity. There were, however, no significant difference in tumor necrosis factor (TNF)-alpha and soluble TNF receptors between the two groups. Serum triglyceride was positively correlated to visceral abdominal fat area, while serum leptin was positively correlated with subcutaneous abdominal fat area. In contrast, serum adiponectin was negatively correlated to visceral abdominal fat area. High sensitive CRP was positively correlated to BMI, triglyceride, and leptin, but was negatively correlated to adiponectin. Tumor necrosis factor-alpha and soluble TNF receptors, however, were not associated with any of these factors. Thus, it may be hypothesized that Japanese type 2 diabetic patients are divided into two categories: one with normal insulin sensitivity and the other with insulin resistance. The former group has a low cardiovascular risk factor, whereas the latter one has a markedly increased cardiovascular disease risk factor. Furthermore, abdominal fat related insulin resistance seems to be associated with insulin resistance in Japanese type 2 diabetic patients. In this section, we would like to focus on the factors contributing to insulin resistance and discuss the association of these factors with atherosclerosis in Japanese type 2 diabetic patients.

Topics: Adiponectin; Atherosclerosis; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Insulin Resistance; Japan; Leptin; Triglycerides

The aim of the present study was to explore the relationship between tissue levels of leptin, soluble interleukin-6 receptor (sIL-6R), high-sensitive-C-reactive protein (hs-CRP) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in atherosclerotic plaques, and traditional risk factors. Coronary artery specimens were obtained from 35 consecutive patients (26 men and nine women) who underwent coronary artery bypass grafting procedure. The mean tissue levels of leptin, hs-CRP and sIL-6R were significantly higher in patients with diabetes mellitus than without diabetes mellitus. When patients were classified according to the smoking status, the mean tissue levels of leptin, hs-CRP and sIL-6R were significantly higher in current smokers than both former smokers and non-smokers. In addition, the mean tissue levels of leptin and sIL-6R were significantly higher in former smokers than non-smokers. There was a positive association between leptin and hs-CRP, sIL-6R and plasma glucose in all patients. Plasma HDL levels were associated negatively with atherosclerotic tissue levels of leptin. Tissue levels of sIL-6R were associated significantly in a positive manner with leptin, hs-CRP and plasma glucose, while tissue levels of hs-CRP were associated with both leptin and sIL-6R. In conclusion, it is attractive to speculate that hs-CRP, sIL-6R and leptin could act synergistically in course of local inflammatory activity and those molecules may not be just markers of inflammation and cardiovascular risk but are also likely to play a pathogenic role in atheromatous plaque. In addition, atherosclerotic tissue levels of CRP, sIL-6R and leptin were significantly higher in current smokers and patients with diabetes.

Topics: Aged; Blood Glucose; C-Reactive Protein; Cholesterol; Coronary Artery Bypass; Coronary Artery Disease; Diabetic Angiopathies; Female; Humans; Inflammation Mediators; Leptin; Male; Middle Aged; Receptors, Interleukin-6; Receptors, Leptin; Risk Factors; Smoking; Vascular Cell Adhesion Molecule-1

Diabetes is a risk factor for the development of cardiovascular diseases associated with impaired angiogenesis or increased endothelial cell apoptosis.. Here it is shown that angiogenic repair of ischemic hindlimbs was impaired in Lepr(db/db) mice, a leptin receptor-deficient model of diabetes, compared with wild-type (WT) C57BL/6 mice, as evaluated by laser Doppler flow and capillary density analyses. To identify molecular targets associated with this disease process, hindlimb cDNA expression profiles were created from adductor muscle of Lepr(db/db) and WT mice before and after hindlimb ischemia using Affymetrix GeneChip Mouse Expression Set microarrays. The expression patterns of numerous angiogenesis-related proteins were altered in Lepr(db/db) versus WT mice after ischemic injury. These transcripts included neuropilin-1, vascular endothelial growth factor-A, placental growth factor, elastin, and matrix metalloproteinases implicated in blood vessel growth and maintenance of vessel wall integrity.. These data illustrate that impaired ischemia-induced neovascularization in type 2 diabetes is associated with the dysregulation of a complex angiogenesis-regulatory network.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Elastin; Gene Expression Profiling; Hindlimb; Ischemia; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microcirculation; Muscle, Skeletal; Neovascularization, Physiologic; Neuropilin-1; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic

Topics: Adiponectin; Aged; Aging; Atherosclerosis; Biomarkers; Blood Pressure; Body Mass Index; Carotid Arteries; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Female; Humans; Leptin; Male; Pulse; Regression Analysis; Severity of Illness Index; Sulfonylurea Compounds; Tunica Intima

Leptin signaling may promote atherothrombosis and lead to cardiovascular disease. However, whether leptin is associated with human atherosclerosis, distinct from thrombosis, is unknown. We determined the association of plasma leptin levels with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in a cross-sectional study of type 2 diabetes. Leptin levels were associated with CAC after adjusting for established risk factors [odds ratio (95% confidence interval) for 5 ng/ml leptin increase: 1.31 (1.10-1.55); P = 0.002]. Leptin remained associated with CAC after further controlling for body mass index (BMI) [1.29 (1.07-1.55); P = 0.008], waist circumference [1.30 (1.09-1.57); P = 0.003], C-reactive protein (CRP) levels [1.28 (1.07-1.55); P = 0.008], and subclinical vascular disease [1.30 (1.08-1.57); P = 0.006]. Addition of BMI (P = 0.97), waist (P = 0.55), or CRP (P = 0.39) to a model with leptin failed to improve the model's explanatory power, whereas addition of leptin to a model with BMI (P = 0.029), waist (P = 0.006), or CRP (P = 0.005) improved the model significantly. Plasma leptin levels were associated with CAC in type 2 diabetes after controlling adiposity and CRP. Whether leptin signaling promotes atherosclerosis directly or represents a therapeutic target for the prevention of atherosclerotic cardiovascular disease remains to be explored.

Topics: Adult; Aged; Calcinosis; Coronary Artery Disease; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Leptin; Male; Middle Aged

Recent data suggest that plasma leptin may represent a cardiovascular risk factor in diabetic patients. To gain further insight into the role of leptin in atherogenesis associated with diabetes, we investigated in the present study the role of this hormone in the regulation of macrophage lipoprotein lipase (LPL), a proatherogenic cytokine overexpressed in patients with type 2 diabetes. Treatment of human macrophages with leptin (1-10 nmol/l) increased LPL expression, at both the mRNA and protein levels. Pretreatment of these cells with anti-leptin receptor (Ob-R) antibody, protein kinase C (PKC) inhibitors, calphostin C, and GF109203X, or the antioxidant N-acetylcysteine (NAC) blocked the effects of leptin. Similar results were observed in leptin-treated J774 macrophages. In these cells, leptin increased the membrane expression of conventional PKC isoforms and downregulation of endogenous PKC expression abolished the effects of leptin on macrophage LPL expression. In leptin-treated J774 cells, enhanced LPL synthetic rate and increased binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL gene promoter were also observed. This latter effect was abrogated by GF109203X. Overall, these data demonstrate that binding of leptin at the macrophage cell surface increases, through oxidative stress- and PKC-dependent pathways, LPL expression. This effect appears to be exerted at the transcriptional level and to involve AP-1 activation.

Topics: Animals; Arteriosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Expression Regulation, Enzymologic; Humans; Leptin; Lipoprotein Lipase; Macrophages; Mice; Monocytes; Nuclear Proteins; Oxidative Stress; Promoter Regions, Genetic; Protein Kinase C; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Transcription Factor AP-1; Tumor Cells, Cultured

Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fasting; Female; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Proteins; Triglycerides

Leptin and TNF alpha are thought to influence blood pressure. Therefore, the aim of our study was to investigate leptin and TNF alpha levels and their association with blood pressure, sex steroids, insulin, creatinine and lipids in type 2 diabetic patients. In 424 type 2 diabetic patients (79 hypertensive females [+Hf], 79 normotensive females [-Hf]; 133 hypertensive males [+Hm], 133 normotensive males [-Hm]) matched for sex, age and BMI serum leptin levels were measured by RIA and TNF alpha, insulin, estradiol, progesterone by ELISA as well as free testosterone by RIA. Leptin levels were comparable in +Hf and -Hf (16.5 +/- 1.0 microg/l vs 16.3 +/- 1.0 microg/l) but higher in +Hm as compared to -Hm (8.3 +/- 0.47 microg/l vs 6.5 +/- 0.34 microg/l; p<0.05). In addition, in comparison to -Hm serum levels of insulin (190 +/- 10 pmol/l vs 161 +/- 11 pmol/l; p< 0.005) and also of creatinine (118.6 +/- 3.6 micromol/l vs 101.7 +/- 2.3; p< 0.0001) were higher in +Hm. Pearson's Correlation coefficient revealed a positive correlation between levels of leptin and diastolic blood pressure (p<0.05) and also between leptin and insulin (p<0.001) in males, however, only before correction for BMI. No correlation between leptin and creatinine was found in males and females. Levels of TNF alpha were comparable in all subgroups. No correlation between levels of TNF alpha and serum leptin levels, blood pressure and insulin was found. In females TNF alpha was positively correlated with creatinine (p<0.001) and in males positively with progesterone (p<0.001). Taken together, higher serum leptin levels were found in hypertensive type 2 diabetic males as compared to normotensives, which may be related to the BMI and higher levels of insulin. These findings are accompanied by a trend to lower levels of free testosterone in hypertensive type 2 diabetic males. TNF alpha levels were comparable in female and male hypertensive and normotensive type 2 diabetic subjects.

Topics: Aged; Body Mass Index; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hypertension; Insulin; Leptin; Male; Reference Values; Testosterone; Tumor Necrosis Factor-alpha