Performance of glycated haemoglobin (HbA1c) as a screening test for diabetes and impaired glucose tolerance (IGT) in a high risk population--the Brazilian Xavante Indians.

AIMS: To examine the properties of HbA1c to detect diabetes and IGT in adult Brazilian Xavante Indians, a high risk population for diabetes. METHODS: The survey was carried out between October 2010 and January 2012 and based on a 75 g oral glucose tolerance test (OGTT). Basal and 2h capillary glycaemia were measured by HemoCue Glucose 201+; HbA1c using an automated high-performance liquid chromatography analyzer (Tosoh G7). RESULTS: 630 individuals aged ≥ 20 years were examined and 80 had a previous diagnosis of diabetes. Sensitivity, specificity and accuracy for HbA1c ≥ 6.5% (≥ 48 mmol/mol) were 71.3%, 90.5% and 87.2%. The areas under the ROC curve (AUC) was 0.88 (95%CI: 0.83-0.93). To identify IGT, HbA1c values between 5.7% and 6.4% (39-47 mmol/mol) presented sensitivity, specificity and accuracy of 87.2%, 24.7% and 51.4%, with an AUC of 0.62 (95%CI: 0.57-0.67). CONCLUSIONS: The ADA/WHO proposed cut-off of 6.5% (48 mmol/mol) for HbA1c was adequate to detect diabetes among the Xavante. However, the performance of the ADA proposed cut-off points for pre-diabetes, when used to detect IGT was inadequate and should not be recommended.

Variants of transcription factor 7-like 2 (TCF7L2) gene and incident glucose intolerance in Japanese-Brazilians.

Common variants of the transcription factor 7-like 2 (TCF7L2) gene have been found to be associated with type 2 diabetes in different ethnic groups. The Japanese-Brazilian population has one of the highest prevalence rates of diabetes. Therefore, the aim of the present study was to assess whether two single-nucleotide polymorphisms (SNPs) of TCF7L2, rs7903146 and rs12255372, could predict the development of glucose intolerance in Japanese-Brazilians. In a population-based 7-year prospective study, we genotyped 222 individuals (72 males and 150 females, aged 56.2 ± 10.5 years) with normal glucose tolerance at baseline. In the study population, we found that the minor allele frequency was 0.05 for SNP rs7903146 and 0.03 for SNP rs12255372. No significant allele or genotype association with glucose intolerance incidence was found for either SNP. Haplotypes were constructed with these two SNPs and three haplotypes were defined: CG (frequency: 0.94), TT (frequency = 0.027) and TG (frequency = 0.026). None of the haplotypes provided evidence for association with the incidence of glucose intolerance. Despite no associations between incidence of glucose intolerance and SNPs of the TCF7L2 gene in Japanese-Brazilians, we found that carriers of the CT genotype for rs7903146 had significantly lower insulin levels 2 h after a 75-g glucose load than carriers of the CC genotype. In conclusion, in Japanese-Brazilians, a population with a high prevalence of type 2 diabetes, common TCF7L2 variants did not make major contributions to the incidence of glucose tolerance abnormalities.

Variants of transcription factor 7-like 2 (TCF7L2) gene and incident glucose intolerance in Japanese-Brazilians

Common variants of the transcription factor 7-like 2 (TCF7L2) gene have been found to be associated with type 2 diabetes in different ethnic groups. The Japanese-Brazilian population has one of the highest prevalence rates of diabetes. Therefore, the aim of the present study was to assess whether two single-nucleotide polymorphisms (SNPs) of TCF7L2, rs7903146 and rs12255372, could predict the development of glucose intolerance in Japanese-Brazilians. In a population-based 7-year prospective study, we genotyped 222 individuals (72 males and 150 females, aged 56.2 ± 10.5 years) with normal glucose tolerance at baseline. In the study population, we found that the minor allele frequency was 0.05 for SNP rs7903146 and 0.03 for SNP rs12255372. No significant allele or genotype association with glucose intolerance incidence was found for either SNP. Haplotypes were constructed with these two SNPs and three haplotypes were defined: CG (frequency: 0.94), TT (frequency = 0.027) and TG (frequency = 0.026). None of the haplotypes provided evidence for association with the incidence of glucose intolerance. Despite no associations between incidence of glucose intolerance and SNPs of the TCF7L2 gene in Japanese-Brazilians, we found that carriers of the CT genotype for rs7903146 had significantly lower insulin levels 2 h after a 75-g glucose load than carriers of the CC genotype. In conclusion, in Japanese-Brazilians, a population with a high prevalence of type 2 diabetes, common TCF7L2 variants did not make major contributions to the incidence of glucose tolerance abnormalities.

Prevalence and 7-year incidence of Type II diabetes mellitus in a Japanese-Brazilian population: an alarming public health problem.

AIMS/HYPOTHESIS: In 1993, the prevalence of glucose intolerance was studied in a sample of 647 first-generation and second-generation Japanese-Brazilians. Their cohort was followed until 2000, when a second survey was conducted, this included the first and second generations, aged 30 or more years. The aims were to estimate the prevalence of glucose intolerance and 7-yr incidence of Type II (non-insulin-dependent) diabetes mellitus in this population. METHODS: Prevalence rates were obtained for 1330 subjects examined in 2000. The incidence of diabetes mellitus was calculated for those classified as normal glucose tolerant in 1993 (n=253). A Student's t test and the Cox proportional hazard model were used in data analysis. RESULTS: In the year 2000, higher proportions of subjects were observed in all categories of glucose intolerance than those found in 1993. The overall incidence of diabetes was 30.9 per 1000 per year. A worse profile was observed among incident cases of diabetes, characterized by higher baseline values of anthropometric and metabolic variables as compared to those who had not developed diabetes. Analysis considering the simultaneous effects of demographic, nutritional and metabolic variables and physical activity levels for the development of diabetes showed that age, sex, waist circumference, fasting and 2-h plasma glucose concentrations were independent predictors. CONCLUSION/INTERPRETATION: Our data point towards a worsening of glucose tolerance status among Japanese-Brazilians, who show one of the highest prevalence rates of diabetes mellitus worldwide. This could reflect their strong genetic susceptibility associated with unfavourable environmental conditions.

Specific insulin and proinsulin in normal glucose tolerant first-degree relatives of NIDDM patients.

In order to identify early abnormalities in non-insulin-dependent diabetes mellitus (NIDDM) we determined insulin (using an assay that does not cross-react with proinsulin) and proinsulin concentrations. The proinsulin/insulin ratio was used as an indicator of abnormal beta-cell function. The ratio of the first 30-min increase in insulin to glucose concentrations following the oral glucose tolerance test (OGTT; I30-0/G30-0) was taken as an indicator of insulin secretion. Insulin resistance (R) was evaluated by the homeostasis model assessment (HOMA) method. True insulin and proinsulin were measured during a 75-g OGTT in 35 individuals: 20 with normal glucose tolerance (NGT) and without diabetes among their first-degree relatives (FDR) served as controls, and 15 with NGT who were FDR of patients with NIDDM. The FDR group presented higher insulin (414 pmol/l vs 195 pmol/l; P = 0.04) and proinsulin levels (19.6 pmol/l vs 12.3 pmol/l; P = 0.03) post-glucose load than the control group. When these groups were stratified according to BMI, the obese FDR (N = 8) showed higher fasting and post-glucose insulin levels than the obese NGT (N = 9) (fasting: 64.8 pmol/l vs 7.8 pmol/l: P = 0.04, and 60 min post-glucose: 480.6 pmol/l vs 192 pmol/l: P = 0.01). Also, values for HOMA (R) were higher in the obese FDR compared to obese NGT (2.53 vs 0.30; P = 0.075). These results show that FDR of NIDDM patients have true hyperinsulinemia (which is not a consequence of cross-reactivity with proinsulin) and hyperproinsulinemia and no dysfunction of a qualitative nature in beta-cells.

Specific insulin and proinsulin in normal glucose tolerant first-degree relatives of NIDDM patients

In order to identify early abnormalities in non-insulin-dependent diabetes mellitus (NIDDM) we determined insulin (using an assay that does not cross-react with proinsulin) and proinsulin concentrations. The proinsulin/insulin ratio was used as an indicator of abnormal ß-cell function. The ratio of the first 30-min increase in insulin to glucose concentrations following the oral glucose tolerance test (OGTT; I30-0/G30-0) was taken as an indicator of insulin secretion. Insulin resistance (R) was evaluated by the homeostasis model assessment (HOMA) method. True insulin and proinsulin were measured during a 75-g OGTT in 35 individuals: 20 with normal glucose tolerance (NGT) and without diabetes among their first-degree relatives (FDR) served as controls, and 15 with NGT who were FDR of patients with NIDDM. The FDR group presented higher insulin (414 pmol/l vs 195 pmol/l; P = 0.04) and proinsulin levels (19.6 pmol/l vs 12.3 pmol/l; P = 0.03) post-glucose load than the control group. When these groups were stratified according to BMI, the obese FDR (N = 8) showed higher fasting and post-glucose insulin levels than the obese NGT (N = 9) (fasting: 64.8 pmol/l vs 7.8 pmol/l; P = 0.04, and 60 min post-glucose: 480.6 pmol/l vs 192 pmol/l; P = 0.01). Also, values for HOMA (R) were higher in the obese FDR compared to obese NGT (2.53 vs 0.30; P = 0.075). These results show that FDR of NIDDM patients have true hyperinsulinemia (which is not a consequence of cross-reactivity with proinsulin) and hyperproinsulinemia and no dysfunction of a qualitative nature in ß-cells

Glucose regulates the expression of Gi-proteins in cultured BC3H-1 myocytes.

To examine whether glucose has regulatory effects on the expression of Gi-proteins, BC3H-1 myocytes were incubated for 24 hr in the presence of various concentrations of glucose (0-25 mM) and the amount of Gi-proteins was detected by pertussis toxin ADP-ribosylation and immunoblot analysis. Both detection methods showed a progressive decrease in the amount of Gi proteins in cells treated with increasing concentrations of glucose. A maximal reduction of 40% was observed after a 24 hr exposure to 25 mM glucose. The reduction in Gi-proteins correlated with a decrease in insulin-stimulated glucose transport.

Pertussis toxin catalyzed ADP-ribosylation of a 41 kDa G-protein impairs insulin-stimulated glucose metabolism in BC3H-1 myocytes.

In this study, we examined the effects of pertussis toxin (PT) on the ADP-ribosylation of guanine nucleotide binding proteins (G-proteins) and various insulin-stimulated processes in cultured BC3H-1 myocytes. Treatment of intact myocytes with 0.1 microgram/ml PT for 24 hours resulted in the complete ribosylation of a 41 kDa protein. The 41 kDa PT substrate was immunoprecipitated with antibodies directed against a synthetic peptide corresponding to a unique sequence in the alpha subunit of Gi-proteins. PT treatment of intact cells had no effect on insulin receptor binding or internalization. However, PT inhibited insulin-stimulated glucose transport at all insulin-concentrations tested (1-100 ng/ml). Maximally stimulated glucose transport was reduced by 50% +/- 15%. Insulin-stimulated glucose oxidation was also decreased by 31% +/- 8%. The toxin had no significant effect on the basal rates of glucose transport and glucose oxidation. The time course of PT-induced inhibition on glucose transport correlated with the time course of the "in vivo" ADP-ribosylation of the 41 kDa protein. The results suggest that a 41 kDa PT-sensitive G-protein, identical or very similar to Gi, is involved in the regulation of glucose metabolism by insulin in BC3H-1 cells.

Relationship between insulin antibodies and metabolic control in type I diabetes mellitus.

1. The objective of the present study was to investigate whether a change in insulin therapy from bovine to purified porcine insulin would result in a decreased level of insulin antibodies (IA) in type I diabetic patients and whether there would be better metabolic control. 2. Insulin antibodies were measured by ELISA. Fifteen type I diabetic patients were prospectively followed for 8 months with monthly evaluations after changing insulin therapy from bovine to purified porcine insulin. 3. Group I patients (N = 4) had IA greater than or equal to 1.5 (value obtained by dividing the ELISA absorbance of the tested serum by the absorbance of a standard serum) at the beginning of the study. For group I patients, the modification of insulin therapy caused a 57% reduction in insulin antibody levels, and this reduction was correlated with a decrease in 24-hour glycosuria (rs = 0.66, P less than 0.001) and glycated protein (rs = 0.65, P less than 0.01). Group II patients (N = 8) had IA less than 1.5 and greater than or equal to 0.3 and group III (N = 3) had IA less than 0.3. Insulin antibody levels were unchanged during the follow-up period in both group II and group III. 4. We also studied endogenous insulin secretion, measured as fasting C-peptide, and its relationships with metabolic control and insulin antibody levels. Patients with residual insulin secretion (C-peptide greater than 60 pmol/l) showed lower levels of 24-h glycosuria, glycated protein and glycated hemoglobin. Furthermore, in this group of patients a negative correlation was found between C-peptide and insulin antibody levels (rs = -0.36, P less than 0.01). 5. We conclude that insulin antibodies could be one of the factors having a detrimental effect on metabolic control.

Relationship between insulin antibodies and metabolic control in type I diabetes mellitus

1. The objective of the presente study was to investigate whether a change in insulin therapy from bovine to purified porcine insulin would result in a decreased level of insulin antibodies (IA) in type I diabetic patients and whether there would be better metabolic control. 2. Insulin antibodies were measured by ELISA. Fifteen type I diabetic patients were prospectively followed for 8 months with monthly evaluations after changing insulin therapy from bovine to purified porcine insulin. 3. Group I patient (N = 4) had > ou = 1.5 (value obtained by dividing the ELISA absorbande of the tested serum by the absorbance of a standard serum) at the beginning of the study. For group I patients, the modification of insulin therapy caused a 57% reduction in insulin antibody levels, and this reduction was correlated with a decrease in 24-hour glycosuria (rs = 0.66, P < 0.001) and glicated protein (rs = 0.65, P < 0.01). Group II patients (N = 8) had IA < 1.5 and > ou = 0.3 and group III (N = 3 had IA < 0.3. Insulin antiblody levels were unchanged during the follow-up period in both group II and group III. 4. We also studied endogenous insulin secretion, measured as fasting C-peptide, and its relationships with metabolic control and insulin antibody levels. Patient with residual insulin secretion (C-peptide > 60 pmol/l) showed lower levels of 24-h glycosuria, glycated protein and glycated hemoglobin. Furthermore, in this group of patients a negative correlation was found between C-peptide and insulin antibody levels (rs=0.36, P < 0.01). 5. We conclude that insulin antibodies could be one of the factors having a detrimental effect on metabolic control