Bong Soo Cha

beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus.

Background. Our study was undertaken to investigate the pathogenesisand possible risk factors for postrenal transplantation diabetes mellitus(PTDM). Methods. We recruited 114 patients with normal glucose tolerance(NGT) and performed both 75-g oral glucose tolerance tests (OGTT) and shortinsulin tolerance tests 1 week before and 9–12 months aftertransplantation. Results. The subjects were classified into three groups by WorldHealth Organization criteria on the basis of OGTT after transplantation: (a)36 (31.6%) subjects with normal glucose tolerance; (b) 51 (45.7%) subjectswith impaired glucose tolerance (IGT); and (c) 27 (23.7%) subjects withpostrenal transplantation diabetes mellitus. Dosages of steroid andcyclosporine were equivalent among the three groups. Before transplantation,the fasting and 2-hr plasma glucose and proinsulin/insulin (PI/I) ratios weresignificantly higher in the IGT and PTDM groups than in the NGT group, but theinsulin sensitivity index (ISI) was not significantly different among thethree groups. In addition, the area under the curve-insulin on OGTT wassignificantly lower in the PTDM group than in the NGT group. Aftertransplantation, however, the ISI was increased in all groups. Furthermore,the ISI and PI/I ratios revealed significantly higher values in the PTDM groupthan in the NGT group aftertransplantation. Conclusions. These results revealed that fasting and 2-hr plasma glucoselevels, as well as the proinsulin/insulin ratio before transplantation, areboth possible indicators of &bgr;-cell dysfunction and may be predictors forthe development of PTDM. Furthermore, &bgr;-cell dysfunction, rather thaninsulin resistance, was proven to be the main factor for the pathogenesis ofPTDM.

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.

Peroxisomal-proliferator-activated receptor alpha activates transcription of the rat hepatic malonyl-CoA decarboxylase gene: a key regulation of malonyl-CoA level.

MCD (malonyl-CoA decarboxylase), which catalyses decarboxylation of malonyl-CoA, is known to play an important role in the regulation of malonyl-CoA concentration. Recently, it has been observed that the expression of MCD is significantly decreased in the hearts of the PPARalpha (peroxisome-proliferator-activated receptor alpha) (-/-) mice, where the rate of fatty-acid oxidation is decreased by the increased malonyl-CoA level [Campbell, Kozak, Wagner, Altarejos, Dyck, Belke, Severson, Kelly and Lopaschuk (2002) J. Biol. Chem. 277, 4098-4103]. This suggests that MCD may be transcriptionally regulated by PPARalpha. To investigate whether PPARalpha is truly responsible for transcriptional regulation of the rat MCD gene, transient reporter assay was performed in CV-1 cells. The promoter activity was increased by 17-fold in CV-1 cells co-transfected with PPARalpha/retinoid X receptor alpha expression plasmid. In sequence analysis of the promoter region, three putative PPREs (PPAR response elements) were identified, and promoter deletion analysis showed that PPRE2 and PPRE3 were functional. Electrophoretic mobility-shift assays revealed that PPARalpha/retinoid X receptor alpha heterodimer indeed bound to the two PPREs, and the binding specificity of PPARalpha on PPRE was also confirmed by experiments with mutated oligonucleotides. These results indicate that the elements behaved as a responsive site to PPARalpha activation. MCD mRNA levels in WY14643-treated rat hepatoma cells as well as in the liver of fenofibrate-fed Otsuka Long-Evans Tokushima fatty rats were also found to be increased, suggesting that PPARalpha can activate the rat hepatic MCD transcription by binding to the PPREs in the promoter. We propose that MCD performs an important role in understanding the regulatory mechanism between activated PPARalpha and fatty-acid oxidation by altering the malonyl-CoA concentration.

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.

Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway

Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.

Background and Data Configuration Process of a Nationwide Population-Based Study Using the Korean National Health Insurance System

Background The National Health Insurance Service (NHIS) recently signed an agreement to provide limited open access to the databases within the Korean Diabetes Association for the benefit of Korean subjects with diabetes. Here, we present the history, structure, contents, and way to use data procurement in the Korean National Health Insurance (NHI) system for the benefit of Korean researchers. Methods The NHIS in Korea is a single-payer program and is mandatory for all residents in Korea. The three main healthcare programs of the NHI, Medical Aid, and long-term care insurance (LTCI) provide 100% coverage for the Korean population. The NHIS in Korea has adopted a fee-for-service system to pay health providers. Researchers can obtain health information from the four databases of the insured that contain data on health insurance claims, health check-ups and LTCI. Results Metabolic disease as chronic disease is increasing with aging society. NHIS data is based on mandatory, serial population data, so, this might show the time course of disease and predict some disease progress, and also be used in primary and secondary prevention of disease after data mining. Conclusion The NHIS database represents the entire Korean population and can be used as a population-based database. The integrated information technology of the NHIS database makes it a world-leading population-based epidemiology and disease research platform.

Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients

OBJECTIVE: To evaluate the effects of low-dose growth hormone (GH) therapy combined with diet restriction on changes in body composition and the consequent change in insulin resistance in newly-diagnosed obese type 2 diabetic patients.DESIGN: Double-blind and placebo-controlled trial of 25-kcal/kg IBW diet daily with GH (n = 9; rhGH, 0.15 IU/kg body weight/week) or placebo (n = 9) for 12 weeks.SUBJECTS: Eighteen newly-diagnosed obese type 2 diabetic patients (age 42–56 y, body mass index 28.1±2.7 kg/m2).MEASUREMENTS: Body composition and fat distribution parameters (by bioelectrical impedance analyzer and CT scans), serum IGF-1; serum glucose, insulin and free fatty acid (FFA) during oral glucose tolerance test (OGTT); HbA1c; serum lipid profiles; and glucose disposal rate (GDR) by euglycemic hyperinsulinemic clamp at baseline and after treatment.RESULTS: The fraction of body weight lost as fat lost was significantly greater (0.98±0.39 vs 0.52±0.32 kg/kg, P<0.05) and visceral fat area was decreased more in the GH-treated group compared to the placebo-treated group (27.9 vs 21.6%, P<0.05). Lean body mass and muscle area were reduced in the placebo-treated group, whereas an increase in both was observed in the GH-treated group. GDR the was significantly increased in only the GH-treated group (4.67±1.05 vs 6.95±0.91 mg/kg/min, P<0.05). The GH-induced increase in GDR was positively correlated with the decrease in the ratio of visceral fat area/muscle area (r = 0.588, P = 0.001). Serum glucose levels and insulin- and FFA-area under the curve during OGTT and HbA1c were significantly decreased after GH treatment. LDL-cholesterol level was decreased in only the GH-treated group.CONCLUSION: Low-dose GH treatment combined with dietary restriction resulted not only in a decrease of visceral fat but also in an increase of muscle mass with a consequent improvement of the insulin resistance observed in obese type 2 diabetic patients.

The association between sleep duration and general and abdominal obesity in Koreans: data from the Korean National Health and Nutrition Examination Survey, 2001 and 2005.

This study aimed to investigate the association between self‐reported sleep duration and general and abdominal obesity in Korean adults. A total of 8,717 adults aged 20–65 years from the Korean National Health and Nutrition Examination Survey (KNHANES) 2001 and 2005 were included. General obesity was defined as BMI ≥25 kg/m2 and abdominal obesity as waist circumference ≥90 cm in men and ≥85 cm in women. To control for sociodemographic and lifestyle factors and comorbidities, multivariable logistic regression was used to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of general and abdominal obesity across the following sleep duration categories: ≤5, 6, 7, 8, and ≥9 h/day. Mean sleep duration (±s.d.) was 6.9 ± 1.3 h. Those sleeping ≤5 h/day had the highest BMI and waist circumference compared with those sleeping 7, 8, or ≥9 h/day (P < 0.05 for all comparisons). After controlling for sociodemographic and lifestyle factors, the adjusted ORs (95% CIs) associated with sleeping ≤5 h/day (vs. 7 h/day) were 1.25 (1.06–1.48) for general obesity and 1.24 (1.03–1.48) for abdominal obesity. Further adjustment for hypertension and diabetes mellitus did not significantly affect the associations. These data suggest that short sleep duration is significantly associated with a modest increase in general and abdominal obesity in Korean adults.