Regina S. Moisés

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

Abstract 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 Students 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.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

Y‐chromosome identification by PCR and gonadal histopathology in Turner's syndrome without overt Y‐mosaicism

The frequency of gonadoblastoma is high in patients with Turners syndrome bearing cells with Y or partial Y‐chromosome. About 60% of patients with Turners syndrome have a 45,X karyotype. In 30% of them a Y‐sequence is disclosed by DNA analysis. To identify patients at risk of developing gonadoblastoma, a PCR based assay with SRY, ZFY and DYZ3 specific primers was carried out to detect different Y‐sequences in the DNA of peripheral lymphocytes from patients with Turners syndrome.

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations

OBJECTIVE Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy. DESIGN AND METHODS We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (n=12), atypical partial lipodystrophy (n=7), or generalized lipodystrophy (n=2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed. RESULTS ALL PATIENTS WITH TYPICAL FPLD WERE FOUND TO CARRY LMNA MUTATIONS: seven patients harbored the heterozygous p.R482W (c.1444C>T), two patients harbored the p.R482Q (c.1445G>A), and two individuals harbored the novel heterozygous variant p.N466D (c.1396A>G), all in exon 8. Also, a homozygous p.R584H (c.1751 G>A) mutation in exon 11 was found. Among patients with atypical partial lipodystrophy, two of them were found to have LMNA mutations: a novel heterozygous p.R582C variation (c.1744 C>T) in exon 11 and a heterozygous substitution p.R349W (c.1045C>T) in exon 6. Among patients with generalized lipodystrophy, only one harbored LMNA mutation, a heterozygous p.T10I (c.29C>T) in exon 1. CONCLUSIONS We have identified LMNA mutations in phenotypically diverse lipodystrophies. Also, our study broadens the spectrum of LMNA mutations in lipodystrophy.

Sulfonylrea Treatment in Permanent Neonatal Diabetes Due to G53D Mutation in the KCNJ11 Gene Improvement in glycemic control and neurological function

Previous studies have reported the successful switch from insulin to sulfonylrea therapy in some patients who have neonatal diabetes due to KCNJ11 mutations (1); however, data on adults are limited (2,3). Also, it has not yet been determined whether neurological symptoms can be improved by the action of sulfonylrea therapy. Here, we report the glycemic and neurological responses in an adult patient with the G53D mutation in the KCNJ11 gene who was transferred from insulin to sulfonylurea. A 26-year-old male patient was diagnosed with diabetes in the third month of …

A New Method for Body Fat Evaluation, Body Adiposity Index, Is Useful in Women With Familial Partial Lipodystrophy

BMI is a widely used method to evaluate adiposity. However, it has several limitations, particularly an inability to differentiate lean from fat mass. A new method, body adiposity index (BAI), has been recently proposed as a new measurement capable to determine fat excess better than BMI. The aim of this study was to investigate BAI as a mean to evaluate adiposity in a group of women with familial partial lipodystrophy (FPLD) and compare it with BMI. Thirteen women with FLPD Dunnigan type (FPLD2) and 13 healthy volunteers matched by age and BMI were studied. Body fat content and distribution were analyzed by dual X‐ray absorptiometry (DXA). Plasma leptin was also measured. BAI was significantly lower in FPLD2 in comparison to control group (24.6 ± 1.5 vs. 30.4 ± 4.3; P < 0.001) and presented a more significant correlation with total fat (%) (r = 0.71; P < 0.001) and fat Mass (g) (r = 0.80; P < 0.001) than BMI (r = 0.27; P = 0.17 for total fat and r = 0.52; P = 0.006 for fat mass). There was a correlation between leptin and BAI (r = −0.54; P = 0.004), but not between leptin and BMI. In conclusion, BAI was able to catch differences in adiposity in a sample of FPLD2 patients. It also correlated better with leptin levels than BMI. Therefore, we provide further evidence that BAI may become a more reliable indicator of fat mass content than the currently available measurements.

Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome

OBJECTIVE Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype-phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with WS and to examine the phenotype-genotype relationships in these patients. DESIGN AND METHODS Clinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with WS from 19 families. RESULTS We identified 15 different mutations in the WFS1 gene in 26 patients, among which nine are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although we did not find any clear phenotype-genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea. CONCLUSIONS Our data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype-genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5.

Beta-cell function in individuals carrying the mitochondrial tRNA leu (UUR) mutation.

Objectives: To assess the &bgr;-cell function in individuals with mitochondrial DNA A3243G mutation with normal glucose tolerance (NGT) or diabetes mellitus (DM). Furthermore, in diabetic individuals, we evaluated the effect of coenzyme Q10 supplementation on insulin secretory response. Methods: Eight mutation-positive individuals with NGT (n = 4) or DM (n = 4) were studied. &bgr;-Cell function was evaluated by C-peptide levels before and after a mixed liquid meal (Sustacal) challenge and by first-phase insulin response. Results: Fasting and Sustacal-stimulated C-peptide levels were significantly lower in diabetic patients than that in controls (area under the curve: 104.1 ± 75.7 vs 520.8 ± 173.8, P = 0.001), whereas in individuals with NGT, this response was preserved (area under the curve: 537.8 ± 74.3 vs 520.8 ± 179.8, P = 0.87). The duration of diabetes was negatively correlated with fasting C-peptide levels (r = −0.961, P = 0.038). Among the 3 patients with residual insulin secretion, the short-term treatment with coenzyme Q10 (3 months) improved C-peptide levels in 2 of them. The first-phase insulin response was diminished in 2 individuals with NGT, the oldest ones. Conclusions: We showed an impaired insulin secretory capacity in individuals carrying the A3243G mutation, this possibly being the primary defect contributing to the development of DM. In addition, our data suggest that this could be a functional defect.

Association of genetic variants in the adiponectin encoding gene (ADIPOQ) with type 2 diabetes in Japanese Brazilians

AIM The objective of this study is to assess the contribution of ADIPOQ variants to type 2 diabetes in Japanese Brazilians. METHODS We genotyped 200 patients with diabetes mellitus (100 male and 100 female, aged 55.0 years [47.5-64.0 years]) and 200 control subjects with normal glucose tolerant (NGT) (72 male and 128 female, aged 52.0 years [43.5-64.5 years]). RESULTS Whereas each polymorphism studied (T45G, G276T, and A349G) was not significantly associated with type 2 diabetes mellitus, the haplotype GGA was overrepresented in our diabetic population (9.3% against 3.1% in NGT individuals, P=.0003). Also, this haplotype was associated with decreased levels of adiponectin. We also identified three mutations in exon 3: I164T, R221S, and H241P, but, owing to the low frequencies of them, associations with type 2 diabetes could not be evaluated. The subjects carrying the R221S mutation had plasma adiponectin levels lower than those without the mutation (2.10 microg/ml [1.35-2.55 microg/ml] vs. 6.68 microg/ml [3.90-11.23 microg/ml], P=.015). Similarly, the I164T mutation carriers had mean plasma adiponectin levels lower than those noncarriers (3.73 microg/ml [3.10-4.35 microg/ml] vs. 6.68 microg/ml [3.90-11.23 microg/ml]), but this difference was not significant (P=.17). CONCLUSIONS We identified in the ADIPOQ gene a risk haplotype for type 2 diabetes in the Japanese Brazilian population.

Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p.T10I mutation

Lipodystrophies are a group of heterogeneous disorders characterized by the loss of adipose tissue and metabolic complications. The main familial forms of lipodystrophy are Congenital Generalized Lipodystrophy and Familial Partial Lipodystrophy (FPLD). FPLD may result from mutations in the LMNA gene. Besides FPLD, mutations in LMNA have been shown to be responsible for other inherited diseases called laminopathies. Here we describe the case of a 15-year-old girl who was referred to our service due to diabetes mellitus and severe hypertriglyceridemia. Physical examination revealed generalized loss of subcutaneous fat, confirmed by DEXA (total body fat 8.6%). As the patient presented with pubertal-onset of generalized lipodystrophy and insulin resistance, molecular analysis of the LMNA gene was performed. We identified a heterozygous substitution in exon 1 (c.29C>T) predicting a p.T10I mutation. In summary, we describe an atypical phenotype of lipodistrophy associated with a de novo appearance of the p.T10I mutation in LMNA gene.