Association of MTHFR C677T (rs1801133) and A1298C (rs1801131) Polymorphisms with Serum Homocysteine, Folate and Vitamin B12 in Patients with Young Coronary Artery Disease.

C677T (rs1801133) and A1298C (rs1801131) MTHFR gene polymorphisms and/or nutritional deficiency of folate/vitamin B12 leading to hyperhomocysteinemia is an established risk factor for CAD. The objective of this study was to evaluate the clinical usefulness of association between MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms with serum homocysteine, folate and vitamin B12 in addition to conventional cardiovascular risk factors in patients with young CAD. Genomic DNA was isolated from the whole blood. Genotyping of MTHFR C677T (rs1801133) and MTHFR A1298C (rs1801131) polymorphisms in young CAD patients and healthy controls was performed by ARMS-PCR method. Serum homocysteine, vitamin B12 and folate were estimated by CMIA and lipid profile parameters were measured by automated chemistry analyzers. Serum homocysteine levels were significantly higher but serum folate and vitamin B12 levels were not significantly different among young CAD group as compared to control group. Statistically significant hyperhomocysteinemia was observed in carriers of T allele for MTHFR 677C/T (rs1801133) genotype in young CAD group but this association was not significant for MTHFR 1298A/C (rs1801131) polymorphism. The association between hyperhomocysteinemia and CAD in young group was not independent of conventional cardiovascular risk factors. Risk of hyperhomocysteinemia and young CAD could be monitored by MTHFR polymorphism detection followed by serum homocysteine, folate and vitamin B12 measurements. The findings could help to prevent or delay the occurrence of young CAD through appropriate measures.

Plasma glycation adducts and various RAGE isoforms are intricately associated with oxidative stress and inflammatory markers in type 2 diabetes patients with vascular complications.

BACKGROUND: The secondary vascular complications in diabetes mellitus (DM) are contributed by acute as well as inflammatory responses which get activated due to interaction between glycation adducts and respective receptors. AIM: The present work was performed to understand the relationship between Advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE) interaction with oxidative stress and inflammation in vascular complications. METHODS: For the present work we recruited 103 controls, 200 patients with type 2 DM, and 200 patients with Diabetic complications. Different Plasma glycation adducts (fructosamine, carbonyls, AGEs, ß-amyloid content, free amino groups, and free thiol groups); RAGE isoforms, level of antioxidant such as glutathione, catalase activity, nitric oxide level, total antioxidant capacity, and superoxide dismutase activity, as well as oxidative markers, and expression of Nε-carboxymethyl-lysine (CML), different isoforms of RAGE, NF-κB, and inflammatory markers were analyzed. RESULTS: Glycation adducts were higher in DM patients and more elevated in nephropathy patients where free amino groups and thiol groups lowered as compared to controls. sRAGE levels and expression were increased mainly in nephropathy. CML expression was higher in nephropathy patients. The antioxidant profile indicates a reduced level of different antioxidants while increased lipid peroxidation and intracellular ROS generation in DM and much higher in nephropathy patients. Expression of membrane RAGE, NF-κB, and inflammatory markers showed a remarkably increased level in DM patients with nephropathy. CONCLUSION: This work provides the first evidence of four different RAGE isoforms in diabetes and in complications. The glycation via the activation of RAGE, oxidative stress, and resultant inflammation plays a crucial role in the development of diabetic complications.

Gender dependent differences in lipid metabolism in individuals with type 2 diabetes mellitus.

AIM: The present study investigates gender dependent effects of insulin resistance on lipid profile and adipocytokines in individuals with diabetes receiving oral antidiabetic drugs (OADs). The aim was also to reveal the changes in the expression of genes involved in lipid metabolism and inflammation. METHODS: Lipid profile, adipocytokine levels and homeostatic model assessment of insulin resistance (HOMA-IR) was assessed in 100 patients with diabetes (M = 43, F = 57) matched for age and gender with healthy individuals (M = 45, F = 55). The expression pattern of genes was analyzed by quantitative real time PCR. RESULTS: Males consuming metformin with other drugs exhibited a positive association between HOMA-IR and cholesterol, triglyceride and very low density lipoprotein (VLDL). Females consuming only metformin and metformin with other drugs, showed a positive association of HOMA-IR with cholesterol and a negative association with adiponectin. In males and females with diabetes, a comparable expression of peroxisome proliferator activated receptor γ (PPARγ) while higher expression of sterol regulatory element binding protein 1 (SREBP1) was observed. Expression of fatty acid synthase (FAS), long chain acyl CoA Synthetases (ACSL), malonyl-CoA-acyl carrier protein transacylase (MCAT) and nuclear factor kappa ß (NFkß) was higher in men with diabetes than healthy males. Expression of tumor necrosis factor α (TNF-α) was higher in males and females with diabetes than respective healthy genders. CONCLUSION: Insulin resistance adversely affects lipid profile, adipocytokines in males with type 2 diabetes. Expression of genes involved in lipid metabolism and inflammation is found to be undesirably and differentially altered in both the genders.

Correlation of Serum Adiponectin and Leptin levels in Obesity and Type 2 Diabetes Mellitus.

INTRODUCTION: Indian phenotype includes higher waist circumference despite lower body mass index, thereby making Indians more prone to diabetes and its complications. AIM: The present study aimed to analyze the serum levels of adiponectin and leptin in the participants with type 2 diabetes mellitus (T2DM) and obesity and their correlation with hypertension and dyslipidemia. MATERIALS AND METHODS: In the study, 50 diabetics and 50 controls aged between 40 and 60 years were included in the study. RESULTS: Adiponectin levels were significantly higher in diabetics than in nondiabetic participants irrespective of gender (P ≤ 0.04 in males, P ≤ 0.02 in females). Leptin levels were significantly higher in diabetics compared to nondiabetics (P ≤ 0.001) in both males and females. CONCLUSION: Adiponectin and leptin levels may be used as important clinical markers for T2DM and obesity.

Gender dependent effects of fasting blood glucose levels and disease duration on biochemical markers in type 2 diabetics: A pilot study.

AIM: The impact of fasting blood glucose levels (FBG) and disease duration on type 2 diabetes in Indian population is still unclear. The present study examines gender-dependent effects of FBG and disease duration on lipid profile, adipocytokines and related biochemical parameters in diabetic individuals. METHODS: Type 2 diabetic individuals (n=100) were classified depending on FBG: patients with normal FBG (Glucose<126mg/dl) and patients with high FBG (Glucose≥126mg/dl); and disease duration: ≥0-≤3yr, >3-≤7yr, >7yr. RESULTS: Males with high FBG had significantly higher serum glucose, triglycerides, very low density lipoprotein (VLDL), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and waist hip ratio (WHR) than males with normal FBG. Females with high FBG had significant increase in serum glucose, adiponectin and creatinine while decrease in leptin levels than females with normal FBG. Males with high FBG had higher WHR, superoxide dismutase, SGOT, SGPT and lower adiponectin, leptin than females with high FBG. Significant positive association was observed between glucose and cholesterol, triglyceride, VLDL and urea in males with high FBG. With chronic diabetes for >7yr, males had increased systolic blood pressure, glucose, LDL, urea and low catalase activity as compared to other disease duration groups. However, females had higher adiponectin, creatinine and lower body mass index and cholesterol. CONCLUSIONS: High FBG in males adversely affects lipid profile, adipocytokines and liver function. Some of these effects exacerbate as disease progresses. Higher adiponectin may have desirable effects on metabolic markers in females.

Relationship between plasma glycation with membrane modification, oxidative stress and expression of glucose trasporter-1 in type 2 diabetes patients with vascular complications.

BACKGROUND OF STUDY: Enhanced protein glycation in diabetes causes irreversible cellular damage through membrane modifications. Erythrocytes are persistently exposed to plasma glycated proteins; however, little are known about its consequences on membrane. Aim of this study was to examine the relationship between plasma protein glycation with erythrocyte membrane modifications in type 2 diabetes patients with and without vascular complications. METHOD: We recruited 60 healthy controls, 85 type 2 diabetic mellitus (DM) and 75 type 2 diabetic patients with complications (DMC). Levels of plasma glycation adduct with antioxidants (fructosamine, protein carbonyl, ß-amyloids, thiol groups, total antioxidant status), erythrocyte membrane modifications (protein carbonyls, ß-amyloids, free amino groups, erythrocyte fragility), antioxidant profile (GSH, catalase, lipid peroxidation) and Glut-1 expression were quantified. RESULT: Compared with controls, DM and DMC patients had significantly higher level of glycation adducts, erythrocyte fragility, lipid peroxidation and Glut-1 expression whereas declined levels of plasma and cellular antioxidants. Correlation studies revealed positive association of membrane modifications with erythrocyte sedimentation rate, fragility, peroxidation whereas negative association with free amino groups, glutathione and catalase. CONCLUSION: Our data suggest that plasma glycation is associated with oxidative stress, Glut-1 expression and erythrocyte fragility in DM patients. This may further contribute to progression of vascular complications.

Adipocytokines and anthropometric measures in type 2 diabetics.

AIM: Type 2 diabetes mellitus has assumed pandemic proportions worldwide. Aggressive management of hyperglycemia in diabetics is a primary goal of treatment. We have previously reported favorable effects of oral hypoglycemic agents on adipocytokines. Aim of the present study was to investigate the relationship of adipocytokines with anthropometric measures and biochemical parameters in type 2 diabetics. METHODS: Clinically diagnosed type 2 diabetics and age, gender matched healthy volunteers were recruited for study. Anthropometric measurements like height, weight, waist-circumference, hip-circumference were recorded and BMI, waist-hip ratio were calculated. Fasting blood samples were collected from participants and sera were analyzed for glucose, glycated haemoglobin, total cholesterol, SGOT, SGPT, insulin, adiponectin and leptin. Correlation of adipocytokines with anthropometric and biochemical parameters was assessed in healthy and diabetic individuals. RESULTS: BMI and WHR in diabetics were significantly higher than healthy population. BMI did not show significant association with adipocytokines. Diabetic males with WHR≥0.9 showed negative association with adiponectin and positive association with leptin. WC did not show significant association with adipocytokines in males. Irrespective of WC, healthy females exhibited positive association with leptin. Diabetic females with WC≥88cm showed leptin to be positively associated with WC. Such association of adipocytokines with WHR was not detected in females. CONCLUSIONS: Body fat distribution can be considered as a parameter in assessing adipokine imbalance. Central adiposity is a better measure of adipokine imbalance than BMI. Abdominal obesity in diabetics correlates with altered levels of adipocytokines indicating its importance in diabetic individuals.

Diabetes and Complications: Cellular Signaling Pathways, Current Understanding and Targeted Therapies.

Diabetes is a metabolic disorder and over the past decades, it has become a major cause of morbidity and mortality affecting the youth and middle-aged as it is the fourth leading cause of disease related to death. In both type 1 and type 2 diabetes the severe pathogenesis cause micro vascular complications: nephropathy, retinopathy, neuropathy and macro vascular complications: cardiovascular disease, heart attacks and stroke. Under hyperglycemia, activation of different signaling mechanisms such as an increased polyol pathway, advanced-glycation end product formation, activation of Protein Kinase C and hexosamine pathway leads to the over expression of reactive oxygen species and causes pathogenesis of diabetic complications. It is necessary to understand these pathways in diabetic complications causing damage to the secondary system of the body. In the past decade the understanding of these biochemical changes has increased tremendously and various molecules have been exploited as therapeutic targets for diabetic complications as better therapeutic approach. In this review, a brief overview about diabetes mellitus and chronic complications with their current understandings of cellular/molecular mechanisms and targeted therapies along with novel therapeutic strategies is discussed.

Circulatory adipocytokines and lipid profile variations in type-2 diabetic subjects: desirable side-effects of antidiabetic drugs.

AIM: Inspite of availability of a variety of drugs to treat type 2 diabetes, little is known about their effects on other systems. Normalization of glucose metabolism by these drugs may consequently affect the secretory function in adipocytes. Secretory adipocytokines like adiponectin and leptin are emerging as novel therapeutic targets for type 2 diabetes mellitus (T2DM). The present study was undertaken to analyze the effects of commonly used Oral Hypoglycemic Agents (OHAs) alone, or in combination with other drugs and/or insulin on circulatory adiponectin and leptin levels, lipid profile, and blood pressure in diabetic subjects. METHODS: The study was undertaken at IRSHA and Bharati Vidyapeeth Medical College and Hospital, MS, India. Clinically diagnosed T2DM subjects and age, gender matched healthy controls were recruited. Fasting blood was collected from each subject and the blood samples were analyzed for circulatory adipocytokines and lipid parameters using commercial kits. RESULTS: Serum adiponectin levels were significantly increased while leptin significantly decreased in diabetic men (p<0.05) and women (p<0.001) on OHA, as compared to healthy controls. Triglyceride levels significantly decreased (p<0.05) in diabetic men, however, they remained unchanged in women despite same drug treatment. Serum HDL and LDL levels (p<0.001) were significantly lower in diabetic women as compared to healthy women. Systolic (p<0.05) and diastolic (p<0.001) blood pressure was significantly high in diabetic men but remained unchanged in women. CONCLUSIONS: Frequently used OHAs significantly improve circulatory levels of adipocytokines. Selecting best treatment option for each patient is a key, and 2012 European Association for the Study of Diabetes (EASD) and ADA guidelines recommend diabetes treatment to be individualized depending on various socioeconomic and lifestyle factors. We recommend regular analysis of circulatory adipocytokines in T2DM patients to help clinicians select the best treatment option to normalize levels of these important therapeutic targets.