Convergence of innate immunity and insulin resistance as evidenced by increased nucleotide oligomerization domain (NOD) expression and signaling in monocytes from patients with type 2 diabetes

Despite the well known role of nucleotide oligomerization domain (NOD) receptor proteins in innate immunity, their association with diabetes is less explored. Here we report the transcriptional level of NODs and their downstream molecular signatures in CD14(+) monocytes from subjects with different grades of glucose tolerance. NOD1 and NOD2 mRNA expression were significantly up-regulated in monocytes from patients with type 2 diabetes (T2DM) and positively correlated with HOMA-IR and poor glycemic control. Patients with T2DM also exhibited increased monocyte activation markers (CD11b and CD36) and proinflammatory signals downstream of NOD (RIPK2 and NFκB) along with the increased circulatory levels of TNF-α and IL-6. In vitro stimulation of monocytes with NOD specific ligands-i-EDAP and MDP significantly up regulated the mRNA expression of NOD1 and NOD2 respectively in T2DM. Our study exposes up regulation of NODs in monocytes as an important component of inflammation and insulin resistance in patients with T2DM

Differential White Blood Cell Count and Type 2 Diabetes: Systematic Review and Meta-Analysis of Cross-Sectional and Prospective Studies

Objective: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.Research Design and Methods: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.Results: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I-2 = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.Conclusions: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate

Circulating levels of insulin-like-growth factor binding protein (IGFBP-1) in relation to insulin resistance, type 2 diabetes and metabolic syndrome (CURES - 118)

The objective was to assess the association of insulin-like growth factor binding protein-1 (IGFBP-1) with insulin resistance (IR), type 2 diabetes mellitus (T2DM), and metabolic syndrome (MS) in Asian Indians. Fifty subjects with normal glucose tolerance (NGT) and 50 with T2DM were randomly selected from the Chennai Urban Rural Epidemiology Study. Insulin-like growth factor binding protein-1 was measured by sandwich enzyme-linked immunosorbent assay. Serum insulin was estimated using Dako (Glostrup, Denmark) kits. Insulin resistance was calculated using the homeostasis model assessment. Subjects with T2DM had significantly decreased levels of IGFBP-1 (21.7 ± 3.5 ng/mL) compared with NGT subjects (34.4 ± 7.6 ng/mL, P < .001). The IGFBP-1 was significantly lower in NGT subjects with IR as measured by the homeostasis model assessment (25.5 ± 6.5 ng/mL) compared with NGT subjects without IR (40.7 ± 9.5 ng/mL, P < .001). On regression analysis, IR showed a significant association with IGFBP-1 even after adjusting for age, sex, body mass index, and glycated hemoglobin (β = -3.714, P < .001). Type 2 diabetes mellitus was significantly associated with IGFBP-1 even after adjusting for age, sex, and body mass index (β = -12.798, P < .001). The IGFBP-1 levels decreased with increasing number of metabolic abnormalities (P for trend < .001). Logistic regression analysis showed that IGFBP-1 had a strong negative association with MS even after adjusting for age and sex (odds ratio, 0.942; 95% confidence interval, 0.914-0.971; P < .001). Among Asian Indians, lower levels of circulating IGFBP-1 are seen in subjects with IR, T2DM, and MS

Association of hypoadiponectinemia with hypoglutathionemia in NAFLD subjects with and without type 2 diabetes

Objective: The aim of this study is to measure the extent of oxidative stress and to see whether it has any correlation to changes in adiponectin levels in NAFLD subjects with and without Type 2 diabetes. Methods: Subjects recruited from the Chennai Urban Rural Epidemiology Study comprise of 1: Normal Glucose Tolerance (NGT) subjects without NAFLD; 2: NGT with NAFLD; 3: Type 2 Diabetic patients [T2DM] without NAFLD and 4: T2DM with NAFLD. Thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCO), glutathione and adiponectin levels were measured by standard methods. Ultrasound of the liver was used to diagnose NAFLD. Results: T2DM subjects with NAFLD had significantly (p< 0.001) higher levels of thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCO) but lower (p< 0.001) GSH/GSSG ratio and adiponectin levels compared to other three groups. The association of hypoadiponectinemia with NAFLD/Type 2 diabetes was significant even after adjusting for age, gender and BMI, but lost when adjusted for parameters of oxidative stress. While palmitate significantly reduced GSH/GSSG ratio in hepatocytes, addition of exogenous recombinant adiponectin restored the GSH/GSSG ratio comparable to those of untreated cells. Conclusion: There exists an association of hypoglutathionemia and hypoadiponectinemia in subjects with NAFLD and/or T2DM. In addition to the known beneficial effects, out study also exposes the antioxidant nature of adiponectin

Association of leukocyte count with varying degrees of glucose intolerance in Asian Indians: the Chennai Urban Rural epidemiology study (CURES-26)

Objective: This study assessed the association of leukocyte count with different grades of glucose intolerance in Asian Indian subjects. Methods: Three groups of subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study, representative of Chennai (formerly Madras), a city in southern India. Group 1 represented normal glucose tolerance (NGT) (n = 840), group 2 included impaired glucose tolerance (IGT) (n = 180), and group 3 included type 2 diabetes (n = 1170). Anthropometric measurements including weight, height, and waist measurements were obtained using standardized techniques. Leukocyte count was measured by an automated flow cytometry instrument (Sysmex SF-3000, Japan). Fasting insulin was measured by enzyme-linked immunosorbent assay and insulin resistance was calculated using the homeostasis model assessment (HOMA-IR). Results: Subjects with diabetes (8.0 ± 1.5 × 10<SUP>3</SUP>/μL) and IGT (7.9 ± 1.3 × 10<SUP>3</SUP>/μL) had a significantly higher mean leukocyte count compared to the NGT group (7.4 ± 1.5 × 10<SUP>3</SUP>/μL) (P &lt; 0.001). Leukocyte count was significantly increased in NGT subjects with insulin resistance (IR) as measured by HOMA-IR (7.5 ± 1.5 × 10<SUP>3</SUP>/μL; P &lt; 0.001) compared to NGT subjects without IR (7.0 ± 1.4 × 10<SUP>3</SUP>/μL). Regression analysis showed that there was a linear increase in mean leukocyte count with increasing severity of glucose intolerance, even after adjusting for age, waist circumference, and HOMA-IR. Conclusions: Among Asian Indians who are known to have high risk of premature coronary artery disease and diabetes, a significant association exists between leukocyte count and glucose intolerance

Transcriptional regulation of cytokines and oxidative stress by gallic acid in human THP-1 monocytes

Increased inflammation/prooxidation has been linked not only to Type 2 diabetes but also in prediabetes state. In this study we investigated hyperglycemia-mediated proinflammatory/prooxidant effects in THP-1 monocytes and tested whether gallic acid could attenuate changes in gene expression induced by high-glucose. Cells were treated either with 5.5 mM glucose or 25 mM glucose in the absence and presence of gallic acid. While oxidative DNA damage was assessed by COMET assay, GSH and GSSG levels were estimated fluorimetrically. Gene expression patterns were determined by RT-PCR. Cells treated with high-glucose showed increased DNA damage and glutathione depletion and this was attenuated in the presence of gallic acid. High-glucose treated cells exhibited increased mRNA expression of TNF-α, IL-6, NADPH oxidase and TXNIP and gallic acid attenuated these proinflammatory and prooxidant effects. Cells treated with high-glucose revealed a deficiency in mounting SOCS-3 expression and gallic acid upregulates this feedback regulatory signal. Gallic acid attenuates DNA damage, maintains glutathione turnover, and suppresses hyperglycemia-induced activation of proinflammatory and prooxidant gene expression. Gallic acid beneficially modulate transcription of functionally diverse groups of genes and its regulation of SOCS-3 and TXNIP signals is a newly identified mechanism that has therapeutic implications

Oxidized low-density lipoprotein and intimal medial thickness in subjects with glucose intolerance - the Chennai Urban Rural Epidemiology Study-25

The aim of the present study was to assess the association of oxidized low-density lipoprotein (OX-LDL) with carotid intimal medial thickness (IMT) in different grades of glucose intolerance in Asian Indians. Three groups were recruited from the Chennai Urban Rural Epidemiology Study, a population-based study: group 1, normal glucose tolerance (NGT) (n = 175); group 2, impaired glucose tolerance (IGT) (n = 175); and group 3, type 2 diabetes mellitus (n = 175). Oxidized LDL (enzyme-linked immunosorbent assay) and carotid IMT (high-resolution B-mode ultrasonography) were assessed. Subjects with diabetes had higher IMT values (0.85 &#177; 0.30 mm) compared with those who have IGT (0.79 &#177; 0.16 mm, P &lt; .05) and NGT (0.71 &#177; 0.12 mm, P &lt; .001). Subjects with diabetes (40.1 &#177; 13.1 U/L) and IGT (34.3 &#177; 12.8 U/L) had significantly higher mean OX-LDL values compared with the NGT group (26.2 &#177; 16.6 U/L, P &lt; .001). Oxidized LDL showed a correlation with IMT (total population: r = 0.294, P &lt; .001; subjects with NGT: r = 0.444, P &lt; .001; and subjects with IGT: r = 0.481, P &lt; .001). In multiple linear regression analysis, OX-LDL showed a strong association with IMT (&#946; = .005, P &lt; .001), even after adjusting for age, sex (&#946; = .003, P &lt; .001), and glucose intolerance (&#946; = .002, P &lt; .001). In conclusion, OX-LDL levels increase with increasing glucose intolerance. Oxidized LDL is associated with carotid IMT and this is independent of age, sex, and glucose intolerance status

Serum Total Adiponectin Is Associated with Impaired Glucose Tolerance in Asian Indian Females but Not in Males

Objective: Adiponectin may play a role in the development of type 2 diabetes and cardiovascular disease (CVD). However, little is known about the relationship between adiponectin and impaired glucose tolerance (IGT). We investigated the association between adiponectin and IGT and between adiponectin and cardiovascular risk factors among subjects with IGT. Research Design and Methods: Subjects with normal glucose tolerance (NGT)(n = 571) and impaired glucose tolerance (n = 167) were recruited from the Chennai Urban Rural Epidemiology Study in south India. Serum total adiponectin levels were measured using a radioimmunoassay (Linco Research, St. Charles, MO). High sensitivity C-reactive protein (hsCRP) was estimated by nephelometry. Results: In sex-stratified analyses, adiponectin was significantly associated with IGT in females [odds ratio (OR): 0.93, 95% confidence interval (CI): 0.872-0.991, p = 0.026] after controlling for age, waist circumference, blood pressure, alcohol consumption, smoking, lipid profile, and glycemic indices; in males there was no significant association (OR = 0.90, 95% CI: 0.798-1.012, p = 0.078). In prediabetic females, adiponectin was not associated with any CVD risk factors (age, waist circumference, blood pressure, cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, fasting glucose, fasting insulin, and insulin resistance level), but was associated negatively with 2-hour postplasma glucose levels (r = -0.243, p &lt; 0.05) and hsCRP (r = -0.219, p &lt; 0.05) after adjusting for demographic and biomedical indices. No associations with CVD risk factors were observed in males with IGT. Conclusion: Serum total adiponectin levels are associated with IGT, 2-hour postplasma glucose, and hsCRP in Asian Indian females but not in males

Oxidative stress is independently associated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes

Objective: Our work is aimed at exploring the interrelationship of oxidative stress and insulin resistance in NAFLD subjects with and without type 2 diabetes in a population-based study. Methods: Subjects [n = 200] were recruited from the Chennai Urban Rural Epidemiology Study. 1: Normal glucose tolerance (NGT) subjects without NAFLD; 2: NGT with NAFLD; 3: type 2 diabetic subjects [T2DM] without NAFLD and 4: T2DM with NAFLD. Thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCC) and glutathione levels were measured by standard methods. Ultrasound of the liver was used to diagnose NAFLD. Results TBARS and PCC levels were significantly elevated and GSH/GSSG ratio was significantly decreased in diabetic subjects with NAFLD compared to all other groups (p trend &lt; 0.001). Oxidative stress markers significantly associated with NAFLD even after adjusting for age, gender, BMI and glycemic status. Conclusions Increased oxidative stress is independently associated with NAFLD in Asian Indians without and with T2DM