Chang-Hsun Hsieh

Association and interaction analyses of genetic variants in ADIPOQ, ENPP1, GHSR, PPARγ and TCF7L2 genes for diabetic nephropathy in a Taiwanese population with type 2 diabetes

BACKGROUNDnDiabetic nephropathy (DN) is a common microvascular complication of diabetes. In this study, we aimed to explore both primary effects of single-locus and multilocus interactions to test the hypothesis that the type 2 diabetes (T2D) genes may contribute to the aetiology of DN in T2D independently and/or through complex interactions in a Taiwanese population with T2D.nnnMETHODSnWe genotyped six single nucleotide polymorphisms (SNPs) for five common T2D genes including adiponectin, C1Q and collagen domain containing (ADIPOQ), ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1), growth hormone secretagogue receptor (GHSR), peroxisome proliferator-activated receptor gamma (PPARgamma) and transcription factor 7-like 2 (TCF7L2). There were 216 T2D patients diagnosed with DN and 178 age-similar T2D without DN (control) subjects. To investigate gene-gene interactions, we employed both generalized multifactor dimensionality reduction (GMDR) method and logistic regression models.nnnRESULTSnSingle-locus analyses showed significant main effects of ENPP1 (P = 0.0032; adjusted OR = 1.85; 95% CI = 1.17-2.92) on the risk of DN in T2D. Furthermore, a potential gene-gene interaction involving ENPP1 and GHSR was suggested in the best two-locus GMDR model (P = 0.021). The significant three-locus GMDR model (P < 0.001) was also identified among ADIPOQ, GHSR and TCF7L2. Analyses using logistic regression models confirmed the gene-gene interactions.nnnCONCLUSIONSnThe results suggest that the SNPs from the T2D-related genes may contribute to the risk of DN in T2D independently and/or in an interactive manner in Taiwanese T2D patients.

The effect of testosterone supplement on insulin sensitivity, glucose effectiveness, and acute insulin response after glucose load in male type 2 diabetics

Our understanding of the effect of androgens on insulin action and glucose metabolism is incomplete. Several different models and methods have been used to study androgen effects, with some studies indicating that higher testosterone levels are associated with increased insulin resistance. In polycystic ovary syndrome, where high testosterone levels are frequently found, affected patients have a higher risk of diabetes. In contrast, increased insulin resistance was found in both hypergonadotropic and hypogonadotropic men with hypoandrogenism, patients with Klinefelters syndrome and men with idiopathic gonadotropin deficiency. Insulin resistance is considered to be one of the cornerstones in the state that ultimately leads to clinically established type 2 diabetes mellitus. In addition, men with type 2 diabetes have relative hypogonadism. Therefore, supplementation with testosterone might play a role in improving both insulin resistance and hypogonadism. The study population consisted of 11 male patients with type 2 diabetes. Their mean age was 57.7 ± 3.41 years, the body mass index (BMI) was 24.4 ± 1.02 kg/m2, and the waist-to-hip ratio (W/H) was 0.91 ± 0.05. The patients were all treated with oral hypoglycemic agents. The men received androgen injections every 3 weeks intramuscularly for 12 weeks. The injections were testosterone depot 100 mg/3 weeks. Insulin sensitivity, glucose effectiveness and area under acute insulin response were calculated from minimal model algorithms. There were no significant differences in the value of BMI, W/H ratios, plasma lipid concentrations, testosterone, homeostasis model assessment (HOMA) of insulin sensitivity, and beta-cell function, before and after supplementation of testosterone. Furthermore, the insulin sensitivity (SI) (1.04 ± 0.25, 1.11 ± 0.36 x 10−5 min−1/pM; p = 0.43), glucose effectiveness (EG) (0.018 ± 0.003, 0.017 ± 0.002 min−1; p = 0.29), and acute insulin response (AIR) after a glucose load (45.7 ± 24.3, 50.1 ± 32.5 pM; p = 0.45) did not change significantly after supplementation with testosterone. In our study, there was no improvement of SI, EG, and AIR after 3 months of Testosterone Depot treatment in type 2 diabetes, but we believe that duration and dosage of the androgen therapy might play an important role in improving insulin sensitivity. The mechanisms by which testosterone causes insulin resistance is unknown, and larger studies on androgen treatment in type 2 diabetic patients are necessary.

Gene-Gene Interactions Among Genetic Variants from Obesity Candidate Genes for Nonobese and Obese Populations in Type 2 Diabetes

Recent studies indicate that obesity may play a key role in modulating genetic predispositions to type 2 diabetes (T2D). This study examines the main effects of both single-locus and multilocus interactions among genetic variants in Taiwanese obese and nonobese individuals to test the hypothesis that obesity-related genes may contribute to the etiology of T2D independently and/or through such complex interactions. We genotyped 11 single nucleotide polymorphisms for 10 obesity candidate genes including adrenergic beta-2-receptor surface, adrenergic beta-3-receptor surface, angiotensinogen, fat mass and obesity associated gene, guanine nucleotide binding protein beta polypeptide 3 (GNB3), interleukin 6 receptor, proprotein convertase subtilisin/kexin type 1 (PCSK1), uncoupling protein 1, uncoupling protein 2, and uncoupling protein 3. There were 389 patients diagnosed with T2D and 186 age- and sex-matched controls. Single-locus analyses showed significant main effects of the GNB3 and PCSK1 genes on the risk of T2D among the nonobese group (p = 0.002 and 0.047, respectively). Further, interactions involving GNB3 and PCSK1 were suggested among the nonobese population using the generalized multifactor dimensionality reduction method (p = 0.001). In addition, interactions among angiotensinogen, fat mass and obesity associated gene, GNB3, and uncoupling protein 3 genes were found in a significant four-locus generalized multifactor dimensionality reduction model among the obese population (p = 0.001). The results suggest that the single nucleotide polymorphisms from the obesity candidate genes may contribute to the risk of T2D independently and/or in an interactive manner according to the presence or absence of obesity.

Correlation of plasma leptin and adiponectin with insulin sensitivity and β-cell function in children – the Taipei Children Heart Study

To investigate the association between plasma leptin and adiponectin and insulin sensitivity in children, 580 school children (294 boys and 286 girls) with mean age of 13.3 years (12–16 years) were randomly selected from the Taipei Children Heart Study. Baseline measurements included body weight, body mass index (BMI), plasma glucose, insulin, proinsulin, leptin and adiponectin levels. Insulin resistance and β‐cell function were assessed using the method of homeostatic model, HOMA‐IR and HOMA‐β, respectively. We found that girls had higher levels of plasma leptin, adiponectin and HOMA‐β than boys. There was no significant difference in HOMA‐IR between boys and girls. Plasma leptin concentrations were positively correlated with body weight, BMI, insulin and proinsulin concentrations, HOMA‐IR and HOMA‐β, whereas plasma adiponectin levels were inversely associated with body weight, BMI and proinsulin levels in both sexes. In girls, adiponectin concentrations were negatively correlated with insulin concentration and HOMA‐IR. In multiple regression analyses, plasma leptin was more positively associated with insulin and proinsulin levels, HOMA‐IR and HOMA‐β than was adiponectin in boys. This association persisted even after adjusting for body weight, BMI and pubertal status. In conclusion, plasma leptin was more strongly associated with insulin sensitivity and β‐cell function than was adiponectin among children, particularly in boys.

The insulin sensitivity, glucose sensitivity, and acute insulin response to glucose load in adolescent type 2 diabetes in Taiwanese

Insulin sensitivity (SI), glucose sensitivity (SG), acute insulin response to glucose load (AIR), and obesity in adolescent type 2 diabetes patients (young diabetes, YDM) in Taiwan were studied.

Metabolic characteristics in individuals with impaired glucose homeostasis

We sought to clarify whether impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or both (IFG/IGT) represent the most severe impairment in insulin resistance (IR) and insulin secretion. Among the 159 Chinese subjects, 21 were diagnosed as having IFG, 103 as having IGT and 35 as having both. IR and beta‐cell function were assessed using homeostatic model assessment (HOMA) and an insulin‐suppression test (IST). No differences were evident between the groups in blood pressure, body mass index, plasma insulin fasting levels and lipid profiles. However, plasma 2‐h insulin levels were higher in the IGT and IFG/IGT groups. Beta‐cell functions were not different between these groups. But, the result of glucose tolerance was different, in which the IFG/IGT and IFG groups displayed higher insulin sensitivity than IGT via HOMA instead of no difference via IST in the three patient groups.

Impact of Clinical Characteristics of Individual Metabolic Syndrome on the Severity of Insulin Resistance in Chinese Adults

The impact the metabolic syndrome (MetS) components on the severity of insulin resistance (IR) has not been reported. We enrolled 564 subjects with MetS and they were divided into quartiles according to the level of each component; and an insulin suppression test was performed to measure IR. In males, steady state plasma glucose (SSPG) levels in the highest quartiles, corresponding to body mass index (BMI) and fasting plasma glucose (FPG), were higher than the other three quartiles and the highest quartiles, corresponding to the diastolic blood pressure and triglycerides, were higher than in the lowest two quartiles. In females, SSPG levels in the highest quartiles, corresponding to the BMI and triglycerides, were higher than in all other quartiles. No significant differences existed between genders, other than the mean SSPG levels in males were greater in the highest quartile corresponding to BMI than that in the highest quartile corresponding to HDL-cholesterol levels. The factor analysis identified two underlying factors (IR and blood pressure factors) among the MetS variables. The clustering of the SSPG, BMI, triglyceride and HDL-cholesterol was noted. Our data suggest that adiposity, higher FPG and triglyceride levels have stronger correlation with IR and subjects with the highest BMI have the highest IR.

The Genetic Background Difference Between Diabetic Patients with and without Nephropathy in a Taiwanese Population by Linkage Disequilibrium Mapping Using 382 Autosomal STR Markers

The genome-wide linkage disequilibrium screening for loci associated with genetic difference between diabetic patients with and without nephropathy was conducted employing 382 autosomal STR markers involving 185 diabetic subjects. Among them, 25 STR markers showed evidence for nominal association with a difference between the two diabetic groups. To investigate the reliability of the association result, the E2a/Pbx1-activated gene in pre-B cells 1 (EB-1) gene was selected from 267 diabetic subjects for single-nucleotide polymorphism genotyping because its genomic region encircles the significant STR marker D12S346. It is clear that some single-nucleotide polymorphisms and haplotypes of the EB-1 gene are associated with genetic difference between diabetic patients with and without nephropathy. This study further indicates that diabetic nephropathy is indeed a genetically heterogeneous group of diseases with similar clinical phenotypes.

Association study between apolipoprotein E gene polymorphism and diabetic nephropathy in a Taiwanese population.

BACKGROUNDnDiabetic nephropathy (DN) is the most common cause of end-stage renal disease in Taiwan. Recent studies have demonstrated that the gene for apolipoprotein E (APOE) is associated with end-stage renal disease in African Americans. In this study, we aimed to test the hypothesis that common single-nucleotide polymorphisms in the APOE gene might contribute to the development of DN in a Taiwanese population with type 2 diabetes (T2D).nnnMETHODSnWe enrolled 180 patients with T2D found to have DN and 178 age- and sex-matched patients with T2D but without DN. The single-nucleotide polymorphisms rs7412 and rs429358 and common allele variants in the APOE gene were evaluated to test any association with DN. Multivariate logistic regression testing was used to determine factors associated with the risk of DN.nnnRESULTSnThe DN group had lower high-density lipoprotein cholesterol levels and longer duration of diabetes, higher systolic and diastolic blood pressure, and higher blood urea nitrogen, creatinine, and triglyceride concentrations than the group with T2D but without DN. Analyses showed no significant effects of APOE rs7412 and APOE rs429358 on the frequencies of the allele and genotype between subjects with T2D with and without DN. There were also no significant effects of APOE2 or E4 carriers on the development of DN, but multivariate logistic regression testing revealed that the duration of diabetes and triglyceride and hemoglobin A1c concentrations had independent effects on the development of DN.nnnCONCLUSIONnThe APOE gene might not contribute to the risk of DN in Taiwanese patients with T2D.

Genetic variants of retinol-binding protein 4 in adolescents are associated with liver function and inflammatory markers but not with obesity and insulin resistance

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, 114 Taipei, Taiwan, Republic of China 2School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China 3Department of Health, Taitung Hospital, 950 Taitung, Taiwan, Republic of China 4Division of Endocrinology and Metabolism, Cardinal Tien Hospital, 235 New Taipei City, Taiwan, Republic of China