Relationship between fasting plasma glucose and incidence of diabetes in children and adolescents.

AIM: To investigate the appropriate fasting plasma glucose threshold by which to define prediabetes in children and adolescents, based on its ability to predict incident paediatric diabetes. METHODS: In a nationwide survey of diabetes and renal disease conducted between 1992 and 2000 in all school-aged children in Taiwan, those with abnormal results in repeated urine tests received further physical examination and blood tests. Students who had blood tests for at least two time points were selected for the present study (N = 12 119). The incidence of paediatric diabetes, adjusted hazard ratio and predictive power of fasting plasma glucose were analysed. RESULTS: The incidence of paediatric diabetes increased with increasing fasting plasma glucose levels. Groups with fasting plasma glucose >5.6 mmol/l had a higher adjusted hazard ratio. The adjusted hazard ratio of incident diabetes for participants with higher fasting plasma glucose rose continuously when using a higher threshold for fasting plasma glucose. The area under the receiver-operating characteristic curve for fasting plasma glucose was 0.628 for predicting paediatric diabetes. The association between fasting plasma glucose and incident paediatric diabetes and the area under the receiver-operating characteristic curve were similar in boys and girls and were higher in the age group 12-18 years. According to receiver-operating characteristic curve analysis, the optimal thresholds, sensitivity and specificity were 4.75 mmol/l, 65% and 51%, respectively, for those aged 6-11 years and 5.19 mmol/l, 60% and 73%, respectively, for those aged 12-18 years. CONCLUSION: Fasting plasma glucose is associated with the incidence of paediatric diabetes. The results of the present study can be used as reference data to suggest a cut-off value to define paediatric prediabetes.

Association between thyroid dysfunction and dysglycaemia: a prospective cohort study.

AIMS: To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia. METHODS: In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted. RESULTS: During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.15, 95% CI 1.04-1.26), but were not at greater risk of diabetes (adjusted hazard ratio 0.96, 95% CI 0.64-1.44). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia. CONCLUSIONS: People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify.

Prescription trends and the selection of initial oral antidiabetic agents for patients with newly diagnosed type 2 diabetes: a nationwide study.

OBJECTIVES: The aim of this study was to examine the characteristics of patients, physicians, and medical facilities, and their association with prescriptions that do not include metformin as the initial oral antidiabetic agent. STUDY DESIGN: Observational, cross-sectional study. METHODS: Patients with incident type 2 diabetes between January 1, 2006, and December 31, 2010, were identified from the Taiwan National Insurance Research Database. We describe trends in the initial prescription of antidiabetic medications that do not contain metformin during the study period. A multivariable logistic model and a multilevel linear model were used in the analysis of factors at a range of levels (patient, physician, and medical facility), which may be associated with the selection of oral antidiabetic drugs. RESULTS: During the study period, the proportion of prescriptions that did not include metformin declined from 43.8% to 26.2%. Male patients were more likely to obtain non-metformin prescriptions (adjusted odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.08-1.23), and the likelihood that a patient would be prescribed a non-metformin prescription increased with age. Physicians aged ≥35 years and those with specialties other than endocrinology tended to prescribe non-metformin prescriptions. Metformin was less commonly prescribed in for-profit hospitals (adjusted OR: 1.34, 95% CI: 1.11-1.61) and hospitals in smaller cities (adjusted OR: 1.28, 95% CI: 1.05-1.57) and rural areas (adjusted OR: 1.83, 95% CI: 1.32-2.54). CONCLUSIONS: Disparities continue to exist in clinical practice with regard to the treatment of diabetes. These inequalities appear to be linked to a variety of factors related to patients, physicians, and medical facilities. Further study will be required to understand the effects of continuing medical education in enhancing adherence to clinical guidelines.

Cardiovascular risks associated with second-line oral antidiabetic agents added to metformin in patients with Type 2 diabetes: a nationwide cohort study.

AIM: To compare the cardiovascular risks associated with second-line oral antidiabetic agents added to initial metformin therapy in a large nationwide observational study. METHODS: We conducted a nationwide retrospective cohort study using the Taiwan National Health Insurance database. A total of 36 118 users of different add-on oral antidiabetic agents (sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors) after initial metformin therapy were included in the analysis. The reference group was sulphonylureas added to metformin, the most commonly used combination regimen. The main outcomes of interest were hospitalizations for any cardiovascular event including acute myocardial infarction, congestive heart failure and ischaemic stroke. In the main analysis, all patients were followed within their initiation groups until the study end, disregarding any changes in treatment status over time. RESULTS: In intention-to-treat analyses, there was no difference in the risk of any cardiovascular event among the add-on combination treatment groups, but significantly lower risks of acute myocardial infarction were found for the glinides plus metformin treatment group (crude hazard ratio 0.52, adjusted hazard ratio 0.39; 95% CI 0.20-0.75) and for the α-glucosidase inhibitors plus metformin treatment group (crude hazard ratio 0.63, adjusted hazard ratio 0.54; 95% CI 0.31-0.95). No difference in risk of congestive heart failure or ischaemic stroke risk was found among the combination treatment groups. In secondary as-treated analyses, similar but less significant associations were found as compared with the primary intention-to-treat analyses for all treatment groups. CONCLUSION: There were no differences in overall cardiovascular risks among several add-on second-line oral antidiabetic agents; however, glinide plus metformin and α-glucosidase inhibitors plus metformin combination therapies might be associated with lower risks of acute myocardial infarction.

Performance of homeostasis model assessment and serum high-sensitivity C-reactive protein for prediction of isolated post-load hyperglycaemia.

AIMS: To evaluate whether homeostasis model assessment and high-sensitivity C-reactive protein improve the prediction of isolated post-load hyperglycaemia. METHODS: The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose < 7 mmol/l and 2-h post-load plasma glucose ≥ 11.1 mmol/l. Risk scores of isolated post-load hyperglycaemia were constructed by multivariate logistic regression. An independent group (n = 154) was enrolled from 2010 to 2011 to validate the models' performance. RESULTS: One hundred and twenty-three subjects (8.28%) were newly diagnosed as having diabetes mellitus. Among those with undiagnosed diabetes, 64 subjects (52%) had isolated post-load hyperglycaemia. Subjects with isolated post-load hyperglycaemia were older, more centrally obese and had higher blood pressure, HbA(1c), fasting plasma glucose, triglycerides, LDL cholesterol, high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance and lower homeostasis model assessment of ß-cell function than those without diabetes. The risk scores included age, gender, BMI, homeostasis model assessment, high-sensitivity C-reactive protein and HbA(1c). The full model had high sensitivity (84%) and specificity (87%) and area under the receiver operating characteristic curve (0.91), with a cut-off point of 23.81; validation in an independent data set showed 88% sensitivity, 77% specificity and an area under curve of 0.89. CONCLUSIONS: Over half of those with undiagnosed diabetes had isolated post-load hyperglycaemia. Homeostasis model assessment and high-sensitivity C-reactive protein are useful to identify subjects with isolated post-load hyperglycaemia, with improved performance over fasting plasma glucose or HbA(1c) alone.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data.

AIMS/HYPOTHESIS: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. METHODS: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders.Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. RESULTS: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. CONCLUSIONS/INTERPRETATION: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.

Sex-specific genetic architecture of human fatness in Chinese: the SAPPHIRe Study.

To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex-genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype-sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.

Type 2 diabetes prevalence and incidence among adults in Taiwan during 1999-2004: a national health insurance data set study.

AIM: To evaluate annual prevalence and incidence of Type 2 diabetes and to examine possible trends among adults in Taiwan. METHODS: A retrospective nationwide longitudinal study using the Taiwan National Health Insurance Research Database collected during 1999-2004. Adult patients aged > or = 20 years old with prevalent and incident Type 2 diabetes were identified using ICD-9-CM diagnostic codes. Age-specific and age-direct-standardized annual incidence and prevalence were calculated to describe their trends in different gender and age group and compared using Poisson regression. RESULTS: During the study years, the age-standardized prevalence of Type 2 diabetes increased from 4.7 to 6.5% for men and from 5.3 to 6.6% for women. The increasing trends in prevalence were significant and higher among people aged < 40 and > or = 80 years. The age-standardized incidence rates of Type 2 diabetes per 1000 person-years were approximately 7.6 and remain stable for men, but decreasing from 7.7 to 6.9 for women. However, the incidence increased significantly in younger adults aged < 40 years whose relative incidence (RI with 95% confidence interval) was 1.31 (1.20-1.42) for men and 1.04 (1.01-1.08) for women. The incidence trends for people aged > or = 40 years were decreased for men and women. The differences in incidence trends between age groups and between genders were all statistically significant (all P < 0.001). CONCLUSIONS: This study demonstrated a substantial increasing trend in Type 2 diabetes prevalence during 1999-2004 among adults in Taiwan. Despite the incidence decreased in older people, young men aged 20-40 years were most susceptible to higher incidence of Type 2 diabetes.

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the K(ATP) channel and insulin secretion in rats.

AIMS/HYPOTHESIS: Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco- and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K(ATP)) channel might serve as a key step in the regulation of insulin secretion. METHODS: Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K(ATP) channel conductance with patch clamp techniques and insulin secretion measured by ELISA. RESULTS: Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K(ATP) channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K(ATP) channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. CONCLUSIONS/INTERPRETATION: Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazone-stimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser(385) residue of the Kir6.2 subunit of the K(ATP) channel by AMPK may play a role in insulin secretion.

Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase.

Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. This effect occurs in a concentration-dependent fashion and results in a parallel loss of hormone-stimulated oocyte maturation. These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules.

Surrogate estimates of insulin sensitivity in subjects with hypertension.

The purpose of the study is to compare surrogate estimates of insulin sensitivity with a directly measured insulin sensitivity index, steady-state plasma glucose (SSPG) from insulin suppression test (IST), in subjects with hypertension. Two hundred and twenty-eight hypertensive patients who received IST for SSPG were included for analysis. Estimates from fasting measurements alone, homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)), and indices from fasting and/or 2 h samples (ISI(0,120) and ISI(TX)) were calculated. In addition to Pearson and partial correlations, variance-component models were used to test the relationship between surrogate estimates of insulin sensitivity and SSPG. A large proportion of variance owing to covariates in the variance-component models indicated the goodness of model fit, irrespective of the independence among variables. SSPG was positively correlated with logarithmic transformation (Log) (HOMA-IR) and negatively correlated with QUICKI, Log (ISI(0,120)) and ISI(TX) (all P<0.0001). Log (ISI(0,120)) seemed to have a better correlation with SSPG (r=-0.72) than other measures in partial correlation. The proportion of variance owing to all covariates of Log (ISI(0,120)) and ISI(TX) were larger than those of Log (HOMA-IR) and QUICKI in the variance-component models. After adjustments for demographic and obesity covariates, the proportion of variance explained by Log (ISI(0,120)) were largest among the surrogate measures in the variance-component models. Our results showed that ISI(0,120) and ISI(TX) correlated better with SSPG than those used fasting measures alone (HOMA-IR and QUICKI). Log (ISI(0,120)) currently showing the strongest association with SSPG than other estimates is adaptable for use in large studies of hypertension.

Rosiglitazone (BRL 49653) enhances insulin secretory response via phosphatidylinositol 3-kinase pathway.

To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedione antihyperglycemic agent, on pancreatic insulin secretion, an in situ investigation by rat pancreatic perfusion was performed. At a basal glucose concentration of 6 mmol/l, RSG (0.045-4.5 micromol/l) stimulated insulin release in a dose-dependent manner. In addition, 4.5 micromol/l RSG potentiated the glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secretion were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. In contrast, the glucose-stimulated insulin secretion was not affected by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effect on insulin secretion in the presence of 10 mmol/l glucose, mediated through PI3K activity. The inability of LY294002 to inhibit glucose-induced insulin secretion suggests that different pathways are responsible for glucose and RSG signaling.

Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization.

Insulin receptor substrate-1 is a major substrate of insulin receptor Tyr kinase. We have now cloned the IRS-1 cDNA from human skeletal muscle, one of the most important target tissues of insulin action, localized and cloned the human IRS-1 gene, and studied the expression of the protein in Chinese hamster ovary cells. Human IRS-1 cDNA encodes a 1242 amino acid sequence that is 88% identical with rat liver IRS-1. The 14 potential Tyr phosphorylation sites include 6 Tyr-Met-X-Met motifs and 3 Tyr-X-X-Met motifs that are completely conserved in human IRS-1. Human IRS-1 has > 50 possible Ser/Thr phosphorylation sites and one potential ATP-binding site close to the NH2-terminal. The human IRS-1 gene contains the entire 5'-untranslated region and protein coding region in a single exon and was localized on chromosome 2 q36-37 by in situ hybridization. By Northern blot analysis, IRS-1 mRNA is rare and consists of two species of 6.9 and 6 kilobase. By using quantitative polymerase chain reaction after reverse transcription of total RNA from human fetal tissues, IRS-1 mRNA could be identified in all tissues. When human IRS-1 cDNA was expressed in Chinese hamster ovary cells, the protein migrated between 170,000-180,000 M(r) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was rapidly Tyr phosphorylated upon insulin stimulation. Thus, IRS-1 is widely expressed and highly conserved across species and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Sibling-based association study of the PPARgamma2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study. Stanford Asian-Pacific Program in Hypertension and Insulin Resistance.

The peroxisome proliferator activated receptor (PPAR) gamma2 is a transcription factor that has been shown to be involved in adipocyte differentiation, adipogenesis, and insulin sensitivity. To address the role of PPARgamma2 in glucose homeostasis and insulin sensitivity, among many other objectives, we conducted a sibling-controlled association study in a multicenter program - the Stanford Asian-Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe). Approximately 2525 subjects in 734 Chinese and Japanese families have been recruited from six field centers for SAPPHIRe. In total, 1702 subjects including parents and siblings from 449 families have been genotyped for PPARgamma2, of which 328 families were Chinese and 121 Japanese. Only 88 subjects of the 1525 siblings screened for the P12A polymorphism were found to be carriers of the A variant, the most common variant of the PPARgamma2 gene. A variant frequencies of the siblings were 4.27% in Chinese and 2.72% in Japanese. A sibling-controlled association study was performed through genetically discordant sibships (i.e., P/P genotype vs. P/A + A/A genotypes). Specifically, we examined whether there were differences in metabolic variables between the discordant siblings within families. In total, 88 subjects carrying either 1 or 2 A alleles had at least one sibling who was discordant for the P12A polymorphism, yielding a total of 180 individuals from 47 families for analyses, among which 92 siblings were homozygous for wild-type P allele. Siblings with the A variant tended to have lower levels of fasting plasma glucose (OG-10), and lower glucose levels at 60 min following oral glucose loading after adjusting for age, gender, and body mass index. Using a mixed model treating family as a random effect, we found that P12A polymorphism of the PPARgamma2 gene contributes significantly to the variance in fasting plasma glucose, glucose level at 60 min, and insulin-resistance homeostasis model assessment. Our results suggest that within families siblings with the A variant in the PPARgamma2 gene may be more likely to have better glucose tolerance and insulin sensitivity independent of obesity in Chinese and Japanese populations.

Insulin sensitivity differs among ethnic groups with a compensatory response in beta-cell function.

OBJECTIVE: A drastic difference is evident in the prevalence of type 2 diabetes among ethnic groups. We examined the role of beta-cell function and insulin sensitivity in this disparity among 4 ethnic groups. RESEARCH DESIGN AND METHODS: beta-Cell function and insulin sensitivity were assessed in 77 healthy glucose-tolerant subjects using a hyperglycemic clamp (18 Asian-Americans, 9 African-Americans, 34 Caucasians, and 16 Mexican-Americans). RESULTS: A wide range of variation was evident in clinical features of the studied subjects. Insulin sensitivity index and the second-phase insulin response differed among the 4 groups (P = 0.0023 and P = 0.0082, respectively), whereas the first-phase insulin response was marginally different (P = 0.1090). Stepwise regression analysis revealed that ethnicity was an independent determinant for the insulin sensitivity index (P = 0.0014) after adjusting for sex, age, diastolic blood pressure, waist-to-hip ratio, and BMI. Also, a compensatory response of beta-cell function was observed among the ethnic groups. CONCLUSIONS: In this study, we observed a drastic difference in insulin sensitivity among the different ethnic groups and observed that their beta-cell function compensates for the prevailing insulin sensitivity. The difference in the prevalence of abnormal glucose tolerance in different ethnic groups could be a result of differences in insulin sensitivity

Link between hypertension and diabetes mellitus epidemiological study of Chinese adults in Taiwan.

OBJECTIVE: To elucidate the relationship between hypertension and non-insulin-dependent diabetes. RESEARCH DESIGN AND METHODS: The study consisted of a random sample of adults aged greater than or equal to 40 yr from the Ta-An district of Taipei City and 5 of 12 villages of Taiwan province, which had established primary health-care centers since 1984. A total of 11,478 subjects were recruited into the survey with a response rate of 65.3 and 72%, respectively. Blood glucose and blood pressure levels were measured, and a structured questionnaire was given to each participant. Those identified as having diabetes received further blood tests for lipids and creatinine and were evaluated for vascular complications. RESULTS: The age- and sex-adjusted prevalence of hypertension among diabetic subjects was twice that of nondiabetic subjects (30.6 vs. 16.4%, P less than 0.0005). Hypertensive subjects had a higher prevalence of diabetes than normotensive subjects (10.2 vs. 4.9%, P less than 0.0005). Among hypertensive subjects, the prevalence of diabetes was 12.7% for those taking antihypertensive drugs and 9.1% for those not taking any drug (P less than 0.05). The prevalence of diabetes significantly increased as mean arterial pressure rose, whether the subjects were stratified by various factors. Multiple regression analysis, including sex, age, body mass index, and other risk factors as independent variables, also showed a significant association between diabetes and hypertension. CONCLUSIONS: The univariate and multivariate analyses revealed that there seemed to be a tight link between hypertension and non-insulin-dependent diabetes. Family history of diabetes, diabetes duration, diabetes regimen, control of blood glucose, and the presence of nephropathy, as attested by proteinuria, did not contribute to the risk of hypertension. Further studies are necessary to determine whether these two conditions are causally related.

Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 heterozygotes and IDDM in Taiwanese families.

OBJECTIVE: To study the human leukocyte antigen (HLA)-DQ heterodimers in the susceptible DR haplotypes for patients with insulin-dependent diabetes mellitus (IDDM) in Taiwan. RESEARCH DESIGN AND METHODS: Extended class II HLA haplotypes were studied in 57 unrelated IDDM patients, 31 simplex IDDM families, and 105 unrelated control subjects recruited from the same area in Taiwan. Class II HLA genotyping was based on PCR-SSO DNA typing techniques. Extended class II HLA haplotypes were deduced unequivocally by the Taiwanese pedigree studies. RESULTS: DR3/DR3, DR3/DR4, and DR3/DR9 genotypes were strongly associated with IDDM susceptibility in this population. In addition to the reported DR3/DR4 in Caucasians, the heterozygotic effect of DR3/DR9 for IDDM was remarkable in the Taiwanese population. Extended HLA haplotypes studies revealed that DRB1*0301/DQA1*0501/DQB1*0201, DRB1*0405/DQA1*0301/DQB1*0302, and DRB1*0405/DQA1*0301/DQB1*0401 were the susceptible haplotypes in this population. There were several hypothetical ways to produce susceptible HLA-DQ heterodimers to explain the susceptibility carried by DR3/DR4 and DR3/DR9 genotypes. Among all DR4 subtypes, only DRB1*0405 was associated with the increased risk of IDDM. CONCLUSIONS: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

No association between the Gly971Arg variant of the insulin receptor substrate 1 gene and NIDDM in the Taiwanese population.

OBJECTIVE: To study the role of the Gly971Arg variant of the insulin receptor substrate 1 (IRS-1) gene in the development of NIDDM in the Chinese population living in Taiwan. RESEARCH DESIGN AND METHODS: A total of 82 unrelated normal control subjects, 89 subjects with NIDDM, and 23 multiplex families were recruited in Taiwan. All of them were Han Chinese. Pedigree members without a history of diabetes were studies by the standard 75-g oral glucose tolerance test. Detection of the Gly971Arg variant of the IRS-1 gene was performed by polymerase chain reaction and restriction fragment-length polymorphism analysis. RESULTS: The frequency of Gly971Arg variant of the IRS-1 gene in the normal population was 1.2% which was lower than frequencies reported in white populations. The prevalence of the Gly971Arg variant was not significantly increased in both the nonselected NIDDM population (1.1%) and the probands of the multiplex families (4.3%). More importantly, the Gly971Arg variant of the IRS-1 gene did not cosegregate with BMI and NIDDM in these families, CONCLUSIONS: The Gly971Arg variant of the IRS-1 gene is an infrequent normal allele among Taiwanese. This variant is neither associated nor cosegregated with NIDDM in the Taiwanese population and families. Gly971Arg of IRS-1 gene does not play an important role in the development of NIDDM in this population.

HLA-DQB1 codon 57 and IDDM in Chinese living in Taiwan.

OBJECTIVE: To study the human leukocyte antigen (HLA)-DQB1 genetic background in the Chinese population in Taiwan and its association with the low incidence of insulin-dependent diabetes mellitus (IDDM) in this population. RESEARCH DESIGN AND METHODS: Forty-eight IDDM patients and 59 nondiabetic unrelated control subjects were recruited from the population in Taiwan. HLA-DQB1 exon 2 was enzymatically amplified by polymerase chain reaction. HLA-DQB1 alleles were diagnosed by dot blotting and hybridization with 16 sequence-specific oligonucleotide probes. RESULTS: DQB1*0201 and DQB1*0302 alleles were more frequent and DQB1*0301 and DQB1*0601 were less frequent in Chinese with IDDM than in control subjects. Genotypes for homozygous non-aspartic acid residue (NA/NA) at position 57 were positively associated with IDDM at a relative risk of 4.34 (P < 0.001), and those for homozygous aspartic acid (A/A) were negatively associated with IDDM at a relative risk of 0.14 (P < 0.001). Among the NA/A heterozygotes, only DQB1*0201/DQB1*0303 was significantly increased in IDDM subjects. CONCLUSIONS: The amino acid residue at position 57 of HLA-DQ beta-chain is significantly associated with the development or prevention of IDDM in Chinese subjects living in Taiwan. Other genetic and environmental factors may also play important roles in pathogenesis of IDDM.