Ken C. Chiu

Association Study of the Genetic Polymorphisms of the Transcription Factor 7-Like 2 (TCF7L2) Gene and Type 2 Diabetes in the Chinese Population

OBJECTIVE—Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene is one of the few validated genetic variants with large effects on the risk of type 2 diabetes in the populations of European ancestry. In this study, we aimed to explore the effect of the TCF7L2 polymorphisms in a Han Chinese population. RESEARCH DESIGN AND METHODS—We genotyped 20 single nucleotide polymorphisms (SNPs) across the TCF7L2 gene in 1,520 unrelated subjects from a Han Chinese population in Taiwan. The associations of SNPs and haplotypes with type 2 diabetes and linkage disequilibrium (LD) structure of the TCF7L2 gene were analyzed. RESULTS—The previously reported SNPs rs7903146 T- and rs12255372 T-alleles of the TCF7L2 gene were rare and were not associated with type 2 diabetes in a Chinese population, which may attribute to the low frequencies of these two SNPs. SNP rs290487 located in an LD block close to the 3′ end of the gene was associated with type 2 diabetes (allele-specific P = 0.0021; permuted P = 0.03). The odds ratio was 1.36 for the CT genotype (95% CI 1.08−1.71; P = 0.0063) and 1.51 for the CC genotype (1.10 −2.07; P = 0.0085) compared with the TT genotype, corresponding to a population attributable risk fraction of 18.7%. The haplotypes composed of rs290487 were also significantly associated with type 2 diabetes (global P = 0.012). CONCLUSIONS—We identified a novel risk-conferring genetic variant of TCF7L2 for type 2 diabetes in a Chinese population. Our data suggested that the TCF7L2 genetic polymorphisms are major determinants for risk of type 2 diabetes in the Chinese population.

Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population

Vitamin D and its receptor have been suggested to play a role in the pathogenesis of type 1 diabetes mellitus. We have therefore studied the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes, and rates of glutamic acid decarboxylase (GAD65) autoantibody and islet cell autoantibody (ICA512) positivity.

The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians

BackgroundAlthough vitamin D receptor (VDR) polymorphisms have been shown to be associated with abnormal glucose metabolism, the reported polymorphisms are unlikely to have any biological consequences. The VDR gene has two potential translation initiation sites. A T-to-C polymorphism has been noted in the first ATG (f allele), abolishing the first translation initiation site and resulting in a peptide lacking the first three amino acids (F allele). We examined the role of this polymorphism in insulin sensitivity and beta cell function. This study included 49 healthy Caucasian subjects (28 females, age 28 ± 1 years old, body mass index 24.57 ± 0.57 kg/m2, waist-hip ratio 0.81 ± 0.01 cm/cm). They were all normotensive (less than 140/90 mmHg) and glucose tolerant, which was determined by a standard 75-gm oral glucose tolerance test. Their beta cell function (%B) and insulin sensitivity (%S) were calculated based on the Homeostasis Model Assessment (HOMA). Their genotypes were determined by a polymerase chain reaction-restriction fragment length polymorphism analysis. Phenotypes were compared between genotypic groups.ResultsThere were 18 FF, 21 Ff, and 10 ff subjects. Since only 10 ff subjects were identified, they were pooled with the Ff subjects during analyses. The FF and Ff/ff groups had similar glucose levels at each time point before and after a glucose challenge. The Ff/ff group had higher insulin levels than the FF group at fasting (P=0.006), 30 minutes (P=0.009), 60 minutes (P=0.049), and 90 minutes (P=0.042). Furthermore, the Ff/ff group also had a larger insulin area under the curve than the FF group (P=0.009). While no difference was noted in %B, the Ff/ff group had a lower %S than the FF group (0.53 vs. 0.78, P=0.006). A stepwise regression analysis confirmed that the Fok I polymorphism was an independent determinant for %S, accounting for 29.3% of variation in %S when combined with waist-hip ratio.ConclusionsWe report that the Fok I polymorphism at the VDR gene locus is associated with insulin sensitivity, but has no influence on beta cell function in healthy Caucasians. Although this polymorphism has been shown to affect the activation of vitamin D-dependent transcription, the molecular basis of the association between this polymorphism and insulin resistance remains to be determined.

Beta cell function declines with age in glucose tolerant Caucasians.

As type 2 diabetes results from an imbalance between insulin sensitivity and beta cell function, either or both may worsen with age. However, existing data are controversial on the effect of ageing on both insulin sensitivity and beta cell function.

Fish oil modulates macrophage P44/P42 mitogen-activated protein kinase activity induced by lipopolysaccharide.

BACKGROUNDnMitogen-activated protein kinase (MAPK) cascades represent a major signal system to transduce extracellular signals into cellular responses. Overactivity of MAPK has been implicated in the development of many diseases, including cancer and sepsis. This study investigated the hypothesis that fish oil altered the membrane phospholipid composition and modulated MAPK activity.nnnMETHODSnRAW 264.7 cells, a mouse macrophage (Mphi) cell line, were grown in eicosapentaenoic acid (EPA)-rich media (114 micromol/L) for 48 hours. Mphi were washed and exposed to Escherichia coli lipopolysaccharide (LPS; 1 microg/mL) for 10 minutes. Both total and activated (phosphorylated) portions of MAPK (P44 and P42) were determined by Western blot assays. AP-1 transcription factor activity was determined by electrophoretic mobility gel shift assays (EMSA). Mphi tumor necrosis factor (TNF) mRNA expression was measured by Northern blot assays.nnnRESULTSnLPS stimulation induced RAW cell phosphorylation of P44/P42. In contrast, RAW cells grown in EPA-rich media had less P44/P42 activation in the presence of LPS. Total P44/P42 were not affected by EPA or LPS. Similarly, EPA also inhibited AP-1 activity. Inhibition of P44/P42 activity with PD98059 reduced both AP-1 activity and TNF mRNA expression of LPS-stimulated Mphi.nnnCONCLUSIONSnOur data suggest that fish oil regulates macrophage proinflammatory gene activation, at least in part, by modulating the MAPK activity.

The insertion allele at the angiotensin I—Converting enzyme gene locus is associated with insulin resistance

Plasma angiotensin I-converting enzyme (ACE) levels are genetically predetermined and are correlated with a deletion (D) insertion (I) polymorphism at the ACE gene locus. A subset of diabetic patients are noted to have elevated ACE levels. Treatment with ACE inhibitors has been shown to improve insulin sensitivity in both diabetic and nondiabetic subjects. We examined the relationship of D/I polymorphism and insulin sensitivity in 24 glucose-tolerant subjects by an oral glucose tolerance test (OGTT) and glucose clamps. Subjects with the I allele had higher insulin levels at 90 minutes (515 +/- 69 v 250 +/- 43 pmol/L, P = .008) and higher insulin area under the curve (56,200 +/- 8,148 v 33,300 +/- 8,114, P = .022) after glucose challenge compared with subjects without the I allele. During the euglycemic clamp, subjects with the I allele require less glucose infusion to maintain euglycemia than subjects without the I allele (5.343 +/- 0.743 v 8.944 +/- 1.272 mg/kg/min, P = .020). We conclude that the I allele is associated with insulin resistance in glucose-tolerant and normotensive African-Americans.

Insertion/deletion polymorphism of the angiotensin I—converting enzyme gene in patients with hypertension, non—insulin-dependent diabetes mellitus, and coronary heart disease in Taiwan

An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been identified that determines most of the plasma ACE activity genetically. Association of the D allele with insulin sensitivity and of the D/D genotype with coronary heart disease (CHD) has been reported in various ethnic populations. To study the role of this genetic polymorphism in patients with hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and NIDDM with CHD in a Taiwanese population, we used a polymerase chain reaction (PCR)-based genotyping technique with an insertion-specific primer for confirmation of the I allele. One hundred ninety-seven unrelated normal controls, 67 subjects with hypertension, 107 subjects with NIDDM, and 70 subjects with NIDDM and CHD were recruited for this study; all were Han Chinese. Subjects without a history of diabetes were studied by a standard 75-g oral glucose tolerance test. Hypertension was diagnosed according to the Fifth Joint National Committee criteria, and CHD was confirmed by a history of acute myocardial infarction and coronary angiographic intervention. The frequency of the I allele of the ACE gene in the normal population was 64.2%, which was higher than reported in white populations. The prevalence of the I allele of the ACE gene was not significantly increased in subjects with hypertension (73.1%), NIDDM (62.1%), and NIDDM with CHD (65%) compared with healthy controls. The I allele of the ACE gene did not correlate with demographic and metabolic variables. I/D polymorphism of the ACE gene is not a marker for hypertension, NIDDM, or CHD in this Taiwanese population.

Genetic Variants of TCF7L2 Are Associated with Insulin Resistance and Related Metabolic Phenotypes in Taiwanese Adolescents and Caucasian Young Adults

OBJECTIVESnThe effect of TCF7L2 rs7903146 on glucose homeostasis is considered primarily due to impaired insulin secretion in European populations. Because we previously demonstrated that TCF7L2 rs290487 near the 3 end of TCF7L2 was significantly associated with type 2 diabetes (T2D) in Taiwanese subjects, we aimed to investigate potential mechanisms underlying the associations of rs290487 with T2D.nnnMETHODSnEighteen single nucleotide polymorphisms (SNPs) were tested for association with glucose/insulin homeostasis as well as other quantitative metabolic phenotypes using the quantitative transmission disequilibrium test in 525 Taiwanese adolescent twin-pairs and siblings. The results were further replicated in 116 nondiabetic normotensive Caucasian young adults.nnnRESULTSnAmong the 18 SNPs, rs290487 C allele was significantly associated with higher 60-, 90-, and 120-min glucose concentrations (P = 0.001, 0.01, and 0.02, respectively); higher 60- and 90-min insulin concentrations (P = 0.01 and 0.01, respectively); and a lower insulin sensitivity index (P = 0.04). No association was found for rs290487 with measures of insulin secretion. The rs290487 C allele was also associated with HOMA-IR (P = 0.005) and insulin sensitivity index (P = 0.01) in Caucasian young adults. Another SNP, rs10749127 C allele located in intron 4, was also associated with features of the metabolic syndrome, including elevated systolic (P = 0.02) and diastolic (P = 2.0 x 10(-4)) blood pressure, triglycerides (P = 7.0 x 10(-4)), and uric acid (P = 0.03). In a meta-analysis, the rs290487 C allele was confirmed to be associated with an increased risk of T2D (odds ratio, 1.11; 95% confidence interval, 1.03-1.19; P = 0.005) across East Asian populations.nnnCONCLUSIONSnThese findings support an important role for T2D risk-conferring gene TCF7L2 in insulin resistance in both Taiwanese and Caucasian youth and underscore the emerging role of Wnt signaling in insulin resistance.

The A54T polymorphism at the intestinal fatty acid binding protein 2 is associated with insulin resistance in glucose tolerant Caucasians

BackgroundAn A54T polymorphism at the fatty acid binding protein 2 (FABP2) locus was found to be associated with insulin resistance in non-diabetic Pima Indians. To see whether this association is present in other populations, we performed a cross sectional study to examine the role of this polymorphism on insulin resistance in 55 healthy and normotensive Caucasian subjects with normal glucose tolerance. Insulin sensitivity (%S) and beta cell function (%B) were assessed using the Homeostasis Model Assessment (HOMA). Their genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. The relationship between the genotypes and the phenotypes was examined.ResultsAfter genotyping, we identified 24 AA, 27 AT and 4 TT subjects. The TT subjects were combined with the AT subjects during the analysis due to its small sample size. No differences were noted in gender distribution, clinical features, and fasting lipid profile between the two genotypic groups (AA vs. AT/TT). The AT/TT group had a higher fasting plasma insulin concentration and a lower %S than the AA group (p = 0.0444 and p = 0.0461, respectively). However, no differences were noted in plasma glucose concentrations and %B. Univariate analysis revealed that this polymorphism explained 7.3% of the variation in %S. Multivariate analysis revealed that the polymorphism was an independent determinant for %S (p = 0.0434) and with body mass index accounted for 28.7% of the variation in %S. In contrast, this polymorphism had no impact on %B.ConclusionsThe A54T polymorphism at the FABP2 locus is a risk factor for insulin resistance in a Caucasian population.

The Arg16Gly polymorphism of human β2‐adrenoreceptor is associated with type 2 diabetes in Taiwanese people

objective u2002The significance of the association of amino terminal polymorphisms in β2‐adrenoreceptor (ADRB2) with obesity and type 2 diabetes is controversial and differs among ethnic groups. In this study, the association of ADRB2 with risk and age of onset of type 2 diabetes has been examined in a Taiwanese population.