Chul Woo Ahn

Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population

AbstractAccording to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50–2.10, p = 5.0 × 10−11]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18–1.72, p = 1.8 × 10−4) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23–1.75, p = 2.1 × 10−5) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10–1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00–1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.

Effects of Pro12Ala polymorphism of peroxisome proliferator‐activated receptor γ2 gene on rosiglitazone response in type 2 diabetes

The aim of this study was to examine the effects of the Pro12Ala polymorphism of the peroxisome proliferator‐activated receptor (PPAR) γ2 gene on the response to rosiglitazone in patients with type 2 diabetes mellitus.

Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production

1-Methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinsons disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In the present study, we investigated the protective effects of rosiglitazone on MPP(+) induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as underlying mechanism. Our results suggested that the protective effects of rosiglitazone on MPP(+) induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase and regulating the expression of Bcl-2 and Bax. These data indicated that rosiglitazone might provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinsons disease.

Korean red ginseng (Panax ginseng) improves insulin sensitivity and attenuates the development of diabetes in Otsuka Long-Evans Tokushima fatty rats.

Ginseng has been reported to ameliorate hyperglycemia in experimental and clinical studies; however, its mechanism of action remains unclear. In this study, we investigated the metabolic effects and putative molecular mechanisms of Korean red ginseng (KRG, Panax ginseng) in animal models for type 2 diabetes mellitus (T2DM) and peripheral insulin-responsive cell lines. Korean red ginseng was administered orally at a dose of 200 mg/(kg d) to Otsuka Long-Evans Tokushima fatty rats for 40 weeks. Initially, chronic administration of KRG reduced weight gain and visceral fat mass in the early period without altering food intake. The KRG-treated Otsuka Long-Evans Tokushima fatty rats showed improved insulin sensitivity and significantly preserved glucose tolerance compared with untreated control animals up to 50 weeks of age, implying that KRG attenuated the development of overt diabetes. KRG promoted fatty acid oxidation by the activation of adenosine monophosphate-activated protein kinase (AMPK) and phosphorylation of acetyl-coenzyme A carboxylase in skeletal muscle and cultured C2C12 muscle cells. Increased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, nuclear respiratory factor-1, cytochrome c, cytochrome c oxidase-4, and glucose transporter 4 by KRG treatment indicates that activated AMPK also enhanced mitochondrial biogenesis and glucose utilization in skeletal muscle. Although these findings suggest that KRG is likely to have beneficial effects on the amelioration of insulin resistance and the prevention of T2DM through the activation of AMPK, further clinical studies are required to evaluate the use of KRG as a supplementary agent for T2DM.

A Polymorphism in the Zinc Transporter Gene, SLC30A8, Confers Resistance Against Posttransplantation Diabetes Mellitus in Renal Allograft Recipients

OBJECTIVE—Posttransplantation diabetes mellitus (PTDM) is a major metabolic complication in renal transplant recipients, and insulin secretory defects play an important role in the pathogenesis of PTDM. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8, has been reported to be associated with type 2 diabetes and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in the SLC30A8 gene and PTDM in renal allograft recipients. RESEARCH DESIGN AND METHODS—A total of 624 unrelated renal allograft recipients without previously diagnosed diabetes were enrolled. Rs13266634 was genotyped in the cohort, which consisted of 174 posttransplantation diabetic patients and 450 non-posttransplantation diabetic subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR. RESULTS—The prevalence of PTDM was 33.8% in patients carrying the R/R genotype, 26.8% in patients with the R/W genotype, and 19.8% in patients with the W/W genotype. There was a strong association between the number of W-alleles and PTDM risk reduction (P for trend = 0.007). Patients with at least one T-allele showed a decreased risk of PTDM compared with those with the R/R genotype (R/W, risk ratio [RR] 0.78, P = 0.126; W/W, RR 0.52, P = 0.007). The effect of the SLC30A8 genotype remained significant after adjustments for age, sex, body weight gain, and type of immunosuppressant (R/W, hazard ratio [HR] 0.77, P = 0.114; W/W, HR 0.58, P = 0.026). CONCLUSIONS—These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of PTDM in renal allograft recipients.

Effects of rosiglitazone and metformin on inflammatory markers and adipokines: decrease in interleukin‐18 is an independent factor for the improvement of homeostasis model assessment‐beta in type 2 diabetes mellitus

Objective  We examined the individual pharmacological effects of the addition of rosiglitazone and metformin to glimepiride on inflammatory markers and adipokines in patients with type 2 diabetes mellitus. We analysed the relationships between these variables, the measurements of insulin sensitivity and β‐cell function in patients treated with rosiglitazone plus glimepiride.

Efficacy and safety of exenatide once‐weekly vs exenatide twice‐daily in Asian patients with type 2 diabetes mellitus

To compare safety and efficacy of the extended‐release formulation exenatide once weekly (EQW) vs exenatide twice daily (EBID) for 26 weeks in type 2 diabetes patients from China, India, Japan, South Korea and Taiwan.

The Prevalence of the Metabolic Syndrome in Korean Adults: Comparison of WHO and NCEP Criteria

The aims of this study were to compare the prevalence of the metabolic syndrome according to the WHO and NCEP ATP III criteria in Korean adults, and to compare the prevalence of the metabolic syndrome with the results in previous Korean studies. The study comprised 1,230 subjects (627 men, 603 women) aged 30-79 years (mean 52.4±10.3 years) who underwent medical check-up from April to June, 2001 in the Korea Association of Health (KAH). The prevalence of the metabolic syndrome according to the modified WHO criteria was 21.8% of men and 19.4% of women. However, the prevalence was increased 1.6 times (34.2%) in men and 2.0 times (38.7%) in women using the modified NCEP criteria. The prevalence of the metabolic syndrome has varied widely according to differences in the criteria. Thus, further studies are necessary to define the appropriate criteria of the metabolic syndrome for Korean adults.

Predictive Clinical Parameters for the Therapeutic Efficacy of Sitagliptin in Korean Type 2 Diabetes Mellitus

Background Sitagliptin is a highly selective dipeptidyl peptide-4 (DPP-4) inhibitor that increases blood levels of active glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrophic polypeptide (GIP), resulting in increased insulin secretion. While studies conducted in other countries have indicated the efficacy and safety of using sitagliptin to treat type 2 diabetes mellitus (T2DM), its predictors of effects to sitagliptin are not well understood. Therefore, we evaluated the predictive clinical parameters for the therapeutic benefits of sitagliptin when added to an ongoing metformin or sulfonylurea therapy in Korean T2DM subjects. Methods We obtained data from 251 Korean T2DM subjects who had recently started taking sitagliptin as add-on therapy. Exclusion criteria included any insulin use. Changes in HbA1c (ΔHbA1c) and fasting plasma glucose (ΔFPG) were assessed by comparing baseline levels prior to sitagliptin administration to levels 12 and 24 weeks after treatment. Responders were defined as subjects who experienced decrease from baseline of >10% in ΔHbA1c or >20% in ΔFPG levels at 24 weeks. Results We classified 81% of the subjects (204 out of 251) as responders. The responder group had a lower mean body mass index (23.70±2.40 vs. 26.00±2.26, P≤0.01) and were younger (58.83±11.57 years vs. 62.87±12.09 years, P=0.03) than the non-responder group. Conclusion In Korean T2DM subjects, sitagliptin responders had lower body mass index and were younger compared to non-responders.

Serum and tear levels of nerve growth factor in diabetic retinopathy patients

PURPOSE To measure serum and tear nerve growth factor (NGF) concentrations in diabetic retinopathy (DR) patients to determine whether the NGF correlated with parameters associated with DR. DESIGN Cross-sectional comparative study. METHODS The study enrolled 254 DR patients and 71 nondiabetic controls. Patient demographic characteristics and diabetic parameters, including blood sugar levels, HbA1c, liver and renal function, were evaluated in two separate university hospitals. Serum and tear NGF concentrations and the ratio of NGF to total protein (TP) in serum and tear fluid were determined. RESULTS Serum and tear NGF levels were found to be higher in proliferative diabetic retinopathy (PDR) patients (98.7+/-12.1 ng/ml in serum, 45.6+/-6.3 ng/ml in tear) than in nondiabetic controls (18.5+/-6.1 ng/ml in serum and 8.3+/-4.7 ng/ml in tear) and nonproliferative diabetic retinopathy (NPDR) patients (26.6+/-5.1 ng/ml in serum and 8.6+/-4.2 ng/ml in tear; p<.001 for both serum and tear differences). Similarly, NGF levels were higher in PDR patients than in controls and NPDR patients after adjusting for possible confounding factors such as age, gender, serum blood urea nitrogen, creatinine, and diabetic parameters. In addition, the NGF-to-TP ratio for both serum and tear fluid was higher in the PDR group compared with the control and NPDR groups. NGF levels correlated well with diabetes duration, HbA1c, and blood sugar levels and diabetic nephropathy. CONCLUSIONS NGF concentration may be a good parameter for evaluating DR status. In addition, serum and tear NGF concentrations correlated strongly, indicating that tear fluid assays may offer an effective, accurate, and noninvasive option for NGF measurement.