Kuppan Gokulakrishnan

A1C Cut Points to Define Various Glucose Intolerance Groups in Asian Indians

OBJECTIVE To determine A1C cut points for glucose intolerance in Asian Indians. RESEARCH DESIGN AND METHODS A total of 2,188 participants without known diabetes were randomly selected from the Chennai Urban Rural Epidemiology Study. All had fasting plasma glucose (FPG) and 2-h postload plasma glucose measurements after a 75-g load and were classified as having impaired fasting glucose (IFG) (American Diabetes Association [ADA] criteria, FPG ≥5.5 and <7 mmol/l, and World Health Organization [WHO] criteria, FPG ≥6.1 and <7 mmol/l), impaired glucose tolerance (IGT) (2-h postload plasma glucose ≥7.8 and <11.1 mmol/l), or diabetes (FPG ≥7 mmol/l and/or 2-h postload plasma glucose ≥11.1 mmol/l). A1C was measured using the Bio-Rad Variant machine. Based on receiver operating characteristic curves, optimum sensitivity and specificity were derived for defining A1C cut points for diabetes, IGT, and IFG. RESULTS Mean ± SD values of A1C among subjects with normal glucose tolerance, IGT, and diabetes were 5.5 ± 0.4, 5.9 ± 0.6, and 8.3 ± 2.0%, respectively (Ptrend < 0.001) with considerable overlap. To identify diabetes based on 2-h postload plasma glucose, the A1C cut point of 6.1% had an area under the curve (AUC) of 0.941 with 88.0% sensitivity and 87.9% specificity. When diabetes was defined as FPG ≥7.0 mmol/l, the A1C cut point was 6.4% (AUC = 0.966, sensitivity 93.3%, and specificity 92.3%). For IGT, AUC = 0.708; for IFG, AUC = 0.632 (WHO criteria) and 0.708 (ADA criteria), and the A1C cut point was 5.6%. CONCLUSIONS In Asian Indians, A1C cut points of 6.1 and 6.4% defined diabetes by 2-h postload plasma glucose or FPG criteria, respectively. A value of 5.6% optimally identified IGT or IFG but was <70% accurate.

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 (I2 = 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.

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 <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.

Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes

BackgroundMetformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India.MethodsType 2 diabetes patients from two secondary care diabetic centres (Europeans - UK and Indians - India) were studied. Serum vitamin B12, folate and biochemical parameters were measured.ResultsThe prevalence rates of vitamin B12 deficiency (<191 ng/L) were 27% and 12% in Europeans and Indians, respectively and higher in metformin treated type 2 diabetes patients. In linear regression analysis, after adjusting for all likely confounding factors, vitamin B12 independently associated with triglycerides in both the populations and cholesterol/HDL ratio in Indians. Logistic regression showed type 2 diabetes patients with vitamin B12 deficiency were at significantly higher odds of having coexisting coronary artery disease (CAD) in Europeans with similar but non-significant trend in Indians, after adjusting for all likely confounding factors.ConclusionsThe prevalence of vitamin B12 deficiency is common in type 2 diabetes patients and is associated with adverse lipid parameters. Type 2 diabetes management guidelines should include the recommendation for regular testing for B12 levels, especially for those on metformin.

1-Hour Venous Plasma Glucose and Incident Prediabetes and Diabetes in Asian Indians

BACKGROUND This study evaluated 1-h plasma glucose (1HrPG) levels during an oral glucose tolerance test (OGTT) in predicting progression to diabetes and prediabetes among individuals with normal glucose tolerance (NGT). SUBJECTS AND METHODS After analyzing the electronic records of 32,809 subjects who had undergone an OGTT, we identified 1,179 subjects who had NGT at baseline, defined as fasting plasma glucose (FPG) of < 100 mg/dL and 2-h plasma glucose (2HrPG) of < 140 mg/dL, who had at least one follow-up OGTT. Receiver operating characteristic curves were constructed to derive the optimal 1HrPG values, which were associated with the development of diabetes (FPG of ≥ 126 mg/dL or 2HrPG of ≥ 200 mg/dL) or prediabetes (FPG ≥ 100 to <1 26 mg/dL or 2HrPG of ≥ 140 to < 200 mg/dL) at follow-up in these NGT subjects. RESULTS On follow-up, 148 (12.6%) subjects developed diabetes, and 392 (33.2%) developed prediabetes. In those with 1HrPG values ≥ 155 mg/dL, 19.5% converted to diabetes compared with 10% among those with 1HrPG of ≥143 to < 155 mg/dL and 6.6% in those with 1HrPG < 143 mg/dL. Comparative figures for conversion to prediabetes were 52.2% (1HrPG values ≥ 155 mg/dL), 39.3% (1HrPG ≥ 143 to <155 mg/dL), and 26.0% (1HrPG < 143 mg/dL). The time to development of diabetes (mean ± SE) was also significantly shorter among those with 1HrPG values of ≥ 155 mg/dL (9.0±0.3 years) compared with those with 1HrPG ≥ 143 to < 155 mg/dL (10.6 ± 0.5 years) and 1HrPG < 143 mg/dL (11.6 ± 0.2 years). CONCLUSIONS Among NGT subjects with elevated 1HrPG values during an OGTT, progression to diabetes and prediabetes is greater, and the rate of progression is also faster.

Association of high sensitivity C-Reactive Protein [hsCRP] and Tumour Necrosis Factor-α [TNF-α] with carotid Intimal Medial Thickness in subjects with different grades of glucose intolerance—The Chennai Urban Rural Epidemiology Study (CURES-31)

OBJECTIVE To assess the association of high sensitivity C-Reactive Protein [hsCRP] and Tumour Necrosis Factor-alpha [TNF-alpha] with IMT in Asian Indians with different grades of glucose intolerance. DESIGN AND METHODS Subjects with normal glucose tolerance [NGT](n=150), impaired glucose tolerance [IGT] (n=150) and type 2 diabetes (DM) (n=150) were recruited from the Chennai Urban Rural Epidemiology Study [CURES], in south India. hsCRP was estimated by nephelometry and TNF-alpha by enzyme linked immunosorbent assay. Carotid IMT was assessed by high resolution B-mode ultrasonography. RESULTS hsCRP and TNF-alpha levels were higher in those with DM [p<0.001] and IGT [p<0.001] compared to NGT. In linear regression analysis, both hsCRP [p=0.003] and TNF-alpha [p=0.001] showed an association with IMT among NGT subjects even after adjusting for age and gender. Among IGT subjects, TNF-alpha was associated with IMT [p<0.001], while no association was observed either with hsCRP or TNF-alpha in diabetic subjects. In NGT subjects, mean IMT was highest in those with high values [III tertile] of both TNF-alpha and hsCRP [0.83+/-0.1 mm; p<0.001] followed by those with high TNF-alpha+low hsCRP [0.74+/-0.09 mm; p<0.001], high hsCRPlow TNF-alpha [0.67+/-0.09 mm; p<0.001], and lowest in those with both low TNF-alpha and hsCRP [I tertile] [0.63+/-0.05 mm. CONCLUSION We conclude that in Asian Indians 1. Levels of hsCRP and TNF-alpha increase with increasing severity of glucose intolerance 2. Both hsCRP and TNF-alpha are associated with IMT in NGT subjects while TNF-alpha alone is associated with IMT in IGT subjects 3. hsCRP and TNF-alpha have a cumulative effect on mean IMT values in NGT subjects.

Circulating levels of insulin-like growth factor binding protein–1 in relation to insulin resistance, type 2 diabetes mellitus, and metabolic syndrome (Chennai Urban Rural Epidemiology Study 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.

Angiopoietin-2 levels in glucose intolerance, hypertension, and metabolic syndrome in Asian Indians (Chennai Urban Rural Epidemiology Study-74)

The aim of the study was to look at the association of angiopoietin-2 (Ang-2) in Asian Indian subjects with different grades of glucose intolerance and in those with hypertension and metabolic syndrome (MS). Three groups were recruited from the Chennai Urban Rural Epidemiology Study, a population-based study in southern India, as follows: group 1, normal glucose tolerance(n = 45); group 2, impaired glucose tolerance (IGT) (n = 45); and group 3, type 2 diabetes mellitus (T2DM) (n = 40). Angiopoietin-2 was estimated by enzyme-linked immunosorbent assay. Hypertension was diagnosed based on medical history, drug treatment of hypertension, and/or if the subjects had systolic blood pressure at least 130 mm Hg and/or diastolic blood pressure at least 85 mm Hg. Metabolic syndrome was defined using modified National Cholesterol Education Program-Adult Treatment Panel III guidelines. Subjects with T2DM had higher age-adjusted Ang-2 values (3741 +/- 1429 pg/mL) compared with subjects with IGT (1907 +/- 855 pg/mL) and normal glucose tolerance (1462 +/- 856 pg/mL) (P for trend < .001). Regression analysis showed that there was a linear increase in mean Ang-2 values with increasing severity of glucose intolerance, even after adjusting for age, sex, and body mass index. Angiopoietin-2 levels were also elevated in subjects with hypertension (P = .004) and in subjects with MS even in the absence of fasting hyperglycemia (P = .011). There was also a linear increase in the mean values of Ang-2 with increase in number of components of MS (P for trend < .001). This study demonstrates that increased levels of Ang-2 are seen in Asian Indian subjects with IGT, T2DM, and hypertension and in subjects with MS even in the absence of fasting hyperglycemia.

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.

Relationship of betatrophin with youth onset type 2 diabetes among Asian Indians

BACKGROUND AND AIMS Betatrophin is emerging as a marker for compensatory beta cell proliferation. While betatrophin has been mainly investigated in adults, there is a lack of data on betatrophin levels in youth-onset type 2 diabetes mellitus (T2DM-Y). The aim of this study was to determine levels of betatrophin and its association with T2DM-Y in Asian Indian participants. METHODS We recruited 100 individuals with normal glucose tolerance (NGT; n=50) and newly-diagnosed cases (within 18 months of first diagnosis) of T2DM-Y (n=50) with onset between 12 and 24 years of age from a large tertiary diabetes center in Chennai in southern India. Insulin resistance was measured by homeostatic model (HOMA-IR) and insulin secretion by oral disposition index (DIO). Betatrophin levels were measured by enzyme-linked immunosorbent assay. RESULTS Betatrophin levels were significantly lower in the T2DM-Y group compared with the NGT group (803 vs 1104 pg/ml, p<0.001). Betatrophin showed a significant inverse correlation with waist circumference (p=0.035), HOMA-IR (p<0.001), fasting and 2 h postprandial glucose (p<0.01), glycated hemoglobin (p=0.019) and a positive correlation with fasting C-peptide (p<0.001) and DIO (p=0.012). In regression analysis, betatrophin was independently associated with T2DM-Y even after adjustment for age, gender, and waist circumference (OR per standard deviation: 0.562, 95% CI: 0.342-0.899, p=0.019). However, the association was lost when HOMA-IR was included in the model (OR: 1.141, 95% CI: 0.574-2.249; p=0.646). CONCLUSION Betatrophin levels are lower in T2DM-Y and this association is likely mediated through insulin resistance.