Kuang-Chung Shih

Common PCSK1 haplotypes are associated with obesity in the Chinese population.

Prohormone convertase subtilisin/kexin type 1 (PCSK1) genetic polymorphisms have recently been associated with obesity in European populations. This study aimed to examine whether common PCSK1 genetic variation is associated with obesity and related metabolic phenotypes in the Chinese population. We genotyped nine common tag single‐nucleotide polymorphisms (tagSNP) of the PCSK1 gene in 1,094 subjects of Chinese origin from the Stanford Asia‐Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. One SNP in the PCSK1 gene (rs155971) were nominally associated with risk of obesity in the SAPPHIRe cohort (P = 0.01). A common protective haplotype was associated with reduced risk of obesity (23.79% vs. 32.89%, P = 0.01) and smaller waist circumference (81.71 ± 10.22 vs. 84.75 ± 10.48 cm, P = 0.02). Another common haplotype was significantly associated with increased risk of obesity (37.07% vs. 23.84%, P = 0.005). The global P value for haplotype association with obesity was 0.02. We also identified a suggestive association of another PCSK1 SNP (rs3811951) with fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMAIR), triglycerides, and high‐density lipoprotein cholesterol (P = 0.05, 0.003, 0.001, 0.04, and 0.04, respectively). These data indicate common PCSK1 genetic variants are associated with obesity in the Chinese population.

Replication of genome‐wide association signals of type 2 diabetes in Han Chinese in a prospective cohort

Background  A recent genome‐wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort.

Lack of effect of simvastatin on insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia: results from a double-blind, randomized, placebo-controlled crossover study.

Aims To evaluate the effects of simvastatin on serum lipids and insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia.

Safety and efficacy of twice-daily exenatide in Taiwanese patients with inadequately controlled type 2 diabetes mellitus

BACKGROUND/PURPOSE Exenatide has been predominantly studied in non-Asian populations. The purpose of this study was to investigate the safety and efficacy of twice-daily (BID) exenatide versus placebo in a subpopulation of Taiwanese patients from a larger study on Asian patients. METHODS Patients unable to achieve glycemic control with metformin alone or metformin in combination with sulfonylurea were randomly assigned to self-administer either 5 μg exenatide or placebo BID for 4 weeks, then 10 μg exenatide or placebo BID for an additional 12 weeks, in addition to their regular oral therapy. RESULTS Fifty patients from Taiwan were enrolled in this study (54.0% male; age: 50.9 ± 9.4 years; weight: 71.0 ± 11.6 kg; 8.1 ± 1.0% hemoglobin A1c (HbA1c)). The exenatide-treated patients demonstrated a statistically significant greater reduction in HbA1c from baseline to the endpoint (least-squares [LS] mean [95% confidence interval (CI)]: -0.8% [-1.4 - -0.2]; p = 0.009) compared with patients who received placebo (LS mean [95% CI]: -0.1% [-0.7-0.4]) with an LS mean [95% CI] between-group difference of -0.7% (-1.3 - -0.1) (p = 0.025). A statistically significant higher number of exenatide-treated patients achieved HbA1c targets of ≤ 7% (p = 0.020) and ≤ 6.5% (p = 0.021) by the endpoint compared with patients who received placebo. Exenatide-treated patients experienced a statistically significant reduction in weight from baseline to endpoint (exenatide-placebo adjusted mean difference [95% CI]: -1.6 kg [-2.7 - -0.6]; p = 0.004) compared with the placebo group. The symptomatic hypoglycemia rate (mean patient/year ± standard deviation) was higher in exenatide-treated patients (4.86 mean patient/year ± 7.36) than placebo-treated patients (0.27 mean patient/year ± 1.32). Thirteen (50.0%) exenatide-treated patients and nine (37.5%) placebo-treated patients reported one or more treatment-emergent adverse events; nausea was the most frequently reported side effect (exenatide, 4 [15.4%]; placebo, 0 [0.0%]). CONCLUSION This subgroup analysis of Taiwanese patients was consistent with the overall study results, which showed that exenatide BID is superior to placebo for improving glycemic control in Asian patients with type 2 diabetes who experienced inadequate glycemic control when using oral antidiabetic therapy.

Effect of growth hormone on dawn phenomenon in patients with type 2 diabetes

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.

Insulin-like growth factor-1 increases endothelin receptor A levels and action in cultured rat aortic smooth muscle cells

Insulin is known to cause an increase in endothelin‐1 (ET‐1) receptors in vascular smooth muscle cells (SMCs), but the effect of insulin‐like growth factor 1 (IGF‐1) on ET‐1 receptor expression is not known. We therefore carried out the present study to determine the effect of IGF‐1 on the binding of ET‐1 to, and ET type A receptor (ETAR) expression and ET‐1‐induced 3H‐thymidine incorporation in, vascular SMCs. In serum‐free medium, IGF‐1 treatment increased the binding of 125I‐ET‐1 to SMC cell surface ET receptors from a specific binding of 20.1% ± 3.1% per mg of protein in control cells to 45.1% ± 8.6% per mg of protein in cells treated with IGF‐1 (10 nM). The effect of IGF‐1 was dose‐related, with a significant effect (1.4‐fold) being seen at 1 nM. The minimal time for IGF‐1 treatment to be effective was 30 min and the maximal effect was reached at 6 h. Immunoblotting analysis showed that ETAR expression in IGF‐1‐treated cells was increased by 1.7‐fold compared to controls. Levels of ETAR mRNA measured by the RT‐PCR method and Northern blotting were also increased by 2‐fold in IGF‐1‐treated SMCs. These effects of IGF‐1 were abolished by cycloheximide or genistein. Finally, ET‐1‐stimulated thymidine uptake and cell proliferation were enhanced by IGF‐1 treatment, with a maximal increase of 3.2‐fold compared to controls. In conclusion, in vascular SMCs, IGF‐1 increases the expression of the ET‐1 receptor in a dose‐ and time‐related manner. This effect is associated with increased thymidine uptake and involves tyrosine kinase activation and new protein synthesis. These findings support the role of IGF‐1 in the development of atherosclerotic, hypertensive, and diabetic vascular complications.

Diagnosis of Insulin Resistance in Hypertensive Patients by the Metabolic Syndrome: AHA vs. IDF Definitions

Background:  Subjects with the metabolic syndrome are accompanied by insulin resistance (IR). However, it is not clear how well the newly defined metabolic syndrome identifies IR specifically in hypertensive subjects.

The Effect of Exercise on Lipid Profiles and Inflammatory Markers in Lean Male Adolescents: A Prospective Interventional Study

Background Physical activity improves body composition and inflammatory markers in obese individuals, but little is known about the nonobese population. Objective The aim of this study was to investigate associations between exercise and inflammatory cytokines in lean male adolescents in Taiwan. Methods This interventional study enrolled a total of 79 normal body weight male adolescents [mean age, 16.8 (1.0) years] from the Army Academy of Taiwan. Body composition and inflammatory markers were measured at baseline and upon completion of a 12-week exercise intervention program. Results Subjects’ postintervention anthropometric measures, including waist circumference [74.6 (5.2) → 72.6 (5.2) cm], hip circumference [92.3 (4.1) → 89.9 (5.0) cm], body fat mass [10.2 (3.2) → 8.2 (3.2) kg], and body fat percentage [15.8% (4.2) → 12.6 (4.5)%] declined significantly compared to preintervention (all P < 0.001), as did systolic blood pressure (P = 0.002) and mean blood pressure (P = 0.020). Postintervention body height and free fat mass increased significantly (both P < 0.001). Subjects’ postintervention lipids including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides increased significantly (all P < 0.001). Inflammatory markers including adiponectin [14.32 (6.68) → 31.31 (30.53) μg/mL, P < 0.001], interleukin 6 [2.15 (4.81) → 2.86 (6.37) pg/mL, P = 0.005], and C-reactive protein [1.00 (2.57) → 2.30 (4.17) μg/mL, P < 0.001] increased significantly postintervention, but not leptin. Conclusions Exercise training significantly improves body composition and anti-inflammatory adiponectin levels in lean male adolescents.

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.

Endothelin Type A Receptor Genotype is a Determinant of Quantitative Traits of Metabolic Syndrome in Asian Hypertensive Families: A SAPPHIRe Study

Co-heritability of hypertension and insulin resistance (IR) within families not only implies genetic susceptibility may be responsible for these complex traits but also suggests a rational that biological candidate genes for hypertension may serve as markers for features of the metabolic syndrome (MetS). Thus we determined whether the T323C polymorphism (rs5333) of endothelin type A (ETA) receptor, a predominant receptor evoking potent vasoconstrictive action of endothelin-1, contributes to susceptibility to IR-associated hypertension in 1694 subjects of Chinese and Japanese origins. Blood pressures (BPs) and biochemistries were measured. Fasting insulin level, insulin-resistance homeostasis model assessment (HOMAIR) score, and area under curve of insulin concentration (AUCINS) were selected for assessing insulin sensitivity. Genotypes were obtained by methods of polymerase chain reaction-restriction fragment length polymorphism. Foremost findings were that minor allele frequency of the T323C polymorphism was noticeable lower in our overall Asian subjects compared to multi-national population reported in gene database; moreover both the genotypic and allelic frequencies of the polymorphism were significantly different between the two ethnic groups we studied. The genotype distributions at TT/TC/CC were 65, 31, 4% in Chinese and 51, 41, 8% in Japanese, respectively (p < 0.0001). Additionally, carriers of the C homozygote revealed characteristics of IR, namely significantly higher levels of fasting insulin, HOMAIR score, and AUCINS at 29.3, 35.3, and 39.3%, respectively, when compared to their counterparts with TT/TC genotypes in Chinese. Meanwhile, the CC genotype was associated with a higher level of high density lipoprotein cholesterol in Japanese. No association of the polymorphism with BP was observed. This study demonstrated for the first time that T323C polymorphism of ETA receptor gene was associated with an adverse insulin response in Chinese and a favorite atherogenic index in Japanese.