Gwanpyo Koh

Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents.

Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.

CD26/DPP4 Levels in Peripheral Blood and T Cells in Patients With Type 2 Diabetes Mellitus

CONTEXT Dipeptidyl peptidase 4 (CD26/DPP4) is expressed on blood T cells and also circulates in a soluble form (sCD26/DPP4). OBJECTIVE We aimed to evaluate blood T cell and circulating CD26/DPP4 and its association with metabolic parameters in patients with type 2 diabetes mellitus (T2DM). DESIGNS We measured CD26/DPP4 expression (percentage of CD26(+) cells using flow cytometry) on CD4(+) and CD8(+) T cells, serum CD26/DPP4 level and activity, and various metabolic parameters in T2DM patients not on DPP4 inhibitor therapy (n = 148). Nondiabetic subjects (n = 50) were included as a control group. RESULTS Compared with the healthy controls, CD26/DPP4 expression on CD4(+) T cells and CD8(+) T cells was higher in T2DM patients. Serum CD26/DPP4 levels and enzymatic activities were also higher in patients with T2DM than in the control group only when metformin and/or thiazolidinedione-treated T2DM patients were excluded; metformin and/or thiazolidinedione-treated T2DM patients had lower values compared with other T2DM patients. Various parameters in T2DM patients were related to CD26/DPP4 expression on the T cells (hemoglobin A1c), serum sCD26/DPP4 (hemoglobin A1c and insulin resistance assessed by updated homeostasis model assessment), and serum CD26/DPP4 activity (insulin resistance assessed by updated homeostasis model assessment, γ-glutamyl transferase, and alanine aminotransferase) by multivariate analyses. After active glucose control for 12 weeks in drug-naive T2DM patients (n = 50), CD26/DPP4 expression on blood T cells was significantly decreased. CONCLUSIONS Our results suggest that the CD26/DPP4 level on blood T cells was associated with glucose control status in patients with T2DM.

Polymorphisms in Interleukin-1β and Interleukin-1 Receptor Antagonist Genes Are Associated with Kidney Failure in Korean Patients with Type 2 Diabetes mellitus

Background/Aim: Cytokines play an important role in the pathogenesis of kidney diseases. The aim of the study was to investigate the impact of interleukin (IL)-1 cluster genes on diabetic nephropathy in Korean patients with type 2 diabetes mellitus (DM). Methods: We investigated –511 C/T polymorphism of IL-1β and tandem repeat polymorphism in intron 2 of IL-1 receptor antagonist in type 2 DM patients with end-stage kidney failure as compared with patients without nephropathy. Results: The IL1B2 allele was found more frequently in patients with kidney failure than in controls (57.4 vs. 46.1%, p < 0.05). An excessive homozygous carriage of IL1B2 was found in patients with kidney failure when compared with controls (30.5 vs. 18.3%, p < 0.05). The allelic frequency of IL1RN*2 was also higher in cases than in controls without nephropathy (8.4 vs. 2.8 %, p < 0.05). The carriage rate of IL1RN*2 was significantly associated with an increased risk of kidney failure (15.8 vs. 5.6%; OR 3.19, 95% CI 1.24–8.17). The risk of kidney failure was highest in those carrying both IL1RN*2 and IL1B2 (OR 3.90, 95% CI 1.34–11.40). Conclusion: IL1B2 and IL1RN*2 genotypes of the IL-1 cluster genes are associated with diabetic nephropathy in Korean patients with type 2 DM.

2-Deoxy-d-ribose induces cellular damage by increasing oxidative stress and protein glycation in a pancreatic β-cell line

2-Deoxy-D-ribose (dRib) is a sugar with a high reducing capacity. We previously reported that dRib induced damage in pancreatic beta-cells. The aim of this study was to investigate the mechanism of dRib-induced beta-cell damage. 2-Deoxy-D-ribose provoked cytotoxicity and apoptosis within 24 hours in HIT-T15 cells. Three antiglycating agents-diethylenetriaminepentaacetic acid, aminoguanidine, and pyridoxamine-dose dependently inhibited dRib-triggered cytotoxicity and significantly suppressed apoptosis induced by dRib. 2-Deoxy-d-ribose increased intracellular reactive oxygen species and protein carbonyl levels in a dose-dependent manner. Diethylenetriaminepentaacetic acid and aminoguanidine significantly reduced dRib-induced rises in intracellular reactive oxygen species. All 3 inhibitors decreased the production of intracellular protein carbonyls by dRib. On incubation with albumin, dRib increased dicarbonyl and advanced glycation end product formation. Aminoguanidine and pyridoxamine significantly decreased the dicarbonyl and advanced glycation end product augmentations. These results suggest that both oxidative stress and protein glycation are important mechanisms of dRib-induced damage in a pancreatic beta-cell line.

Clinical experience of an iontophoresis based glucose measuring system.

Currently finger pricking is the common method of blood glucose measurement in patients with diabetes mellitus. However, diabetes patients have proven to be reluctant to check their glucose profiles regularly because of the discomfort associated with this technique. Recently, a non-invasive and continuous Reverse Iontophoresis based Glucose Monitoring Device (RIGMD) was developed in Korea. The study was conducted during the period November 2003-January 2004 on 19 in-patients. Glucose measurements were performed using RIGMD between 10 a.m. and 4 p.m. Concurrent plasma glucose levels were checked hourly and subsequently compared with RIGMD data. The mean error of RIGMD measurements was -3.45±52.99 mg/dL with a mean absolute relative error of 20±15.16%. Measurements obtained by RIGMD were correlated with plasma glucose levels (correlation coefficient; 0.784 (p<0.05)) and this correlation was independent of time of data collection. However, after excluding confounding variables this correlation coefficient exhibited a tendency to increase. 98.9% of the results were clinically acceptable by Clarke error grid analysis. We concluded that RIGMD does not have the reliability and accuracy required to wholly replace conventional methods. However, further technical advancements that reduce its shortcomings would make this device useful for the management of diabetes.

Correlations between Glucagon Stimulated C-peptide Levels and Microvascular Complications in Type 2 Diabetes Patients

Background This study aimed to investigate whether stimulated C-peptide is associated with microvascular complications in type 2 diabetes mellitus (DM). Methods A cross-sectional study was conducted in 192 type 2 diabetic patients. Plasma basal C-peptide and stimulated C-peptide were measured before and 6 minutes after intravenous injection of 1 mg glucagon. The relationship between C-peptide and microvascular complications was statistically analyzed. Results In patients with retinopathy, basal C-peptide was 1.9±1.2 ng/mL, and stimulated C-peptide was 2.7±1.6 ng/mL; values were significantly lower compared with patients without retinopathy (P=0.031 and P=0.002, respectively). In patients with nephropathy, basal C-peptide was 1.6±0.9 ng/mL, and stimulated C-peptide was 2.8±1.6 ng/mL; values were significantly lower than those recorded in patients without nephropathy (P=0.020 and P=0.026, respectively). Stimulated C-peptide level was associated with increased prevalence of microvascular complications. Age-, DM duration-, and hemoglobin A1c-adjusted odds ratios for retinopathy in stimulated C-peptide value were 4.18 (95% confidence interval [CI], 1.40 to 12.51) and 3.35 (95% CI, 1.09 to 10.25), respectively. The multiple regression analysis between nephropathy and C-peptide showed that stimulated C-peptide was statistically correlated with nephropathy (P=0.03). Conclusion In patients with type 2 diabetes, the glucagon stimulation test was a relatively simple method of short duration for stimulating C-peptide response. Stimulated C-peptide values were associated with microvascular complications to a greater extent than basal C-peptides.

Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients

Background Recent studies have revealed that C-peptide induces smooth muscle cell proliferation and causes human atherosclerotic lesions in diabetic patients. The present study was designed to examine whether the basal C-peptide levels correlate with cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. Methods Data was obtained from 467 patients with T2DM from two institutions who were followed for four years. The medical findings of all patients were reviewed, and patients with creatinine >1.4 mg/dL, any inflammation or infection, hepatitis, or type 1 DM were excluded. The relationships between basal C-peptide and other clinical values were statistically analyzed. Results A simple correlation was found between basal C-peptide and components of metabolic syndrome (MS). Statistically basal C-peptide levels were significantly higher than the three different MS criteria used in the present study, the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Programs (NCEPs), World Health Organization (WHO), and the International Diabetes Federation (IDF) criteria (NCEP-ATP III, P=0.001; IDF, P<0.001; WHO, P=0.029). The multiple regression analysis between intima-media thickness (IMT) and clinical values showed that basal C-peptide significantly correlated with IMT (P=0.043), while the analysis between the 10-year coronary heart disease risk by the United Kingdom Prospective Diabetes Study risk engine and clinical values showed that basal C-peptide did not correlate with IMT (P=0.226). Conclusion Basal C-peptide is related to cardiovascular predictors (IMT) of T2DM, suggesting that basal C-peptide does provide a further indication of cardiovascular disease.

Hypoglycemia at Admission in Patients With Acute Myocardial Infarction Predicts a Higher 30-Day Mortality in Patients With Poorly Controlled Type 2 Diabetes Than in Well-Controlled Patients

OBJECTIVE We aimed to evaluate the association between hypoglycemia at admission and 30-day mortality in patients with acute myocardial infarction (AMI) and to determine whether these associations differed according to diabetes-control status in AMI patients with diabetes. RESEARCH DESIGN AND METHODS We analyzed the prognostic significance of hypoglycemia and hyperglycemia in 34,943 AMI patients with or without type 2 diabetes from two AMI registries: the Korea Acute Myocardial Infarction Registry (KAMIR) and the Korea Working Group on Myocardial Infarction (KorMI). RESULTS The patients were divided into five groups according to serum-glucose levels at admission: <3.9 mmol/L (<70 mg/dL); 3.9–7.72 mmol/L (70–139 mg/dL); 7.78–11.06 mmol/L (140–199 mg/dL); 11.11–14.39 mmol/L (200–259 mg/dL); and ≥14.44 mmol/L (≥260 mg/dL). The 30-day mortality rates in the lowest and highest glucose groups were higher than those in other groups; the lowest glucose group had the highest mortality for patients with type 2 diabetes, after adjusting for multiple factors. We also extracted and compared four subgroups from the patients with type 2 diabetes, based on hemoglobin A1c and serum-glucose levels at admission: group A, <6.5% (48 mmol/mol) and <3.9 mmol/L; group B, <6.5% (48 mmol/mol) and ≥11.11 mmol/L; group C, ≥8% (64 mmol/mol) and <3.9 mmol/L; and group D, ≥8% (64 mmol/mol) and ≥11.11 mmol/L. Group C had the highest 30-day mortality rate among the groups. CONCLUSIONS These data suggest that hypoglycemia at admission affects clinical outcomes differently in AMI patients with type 2 diabetes depending on the diabetes-control status.

Prevalence of the Metabolic Syndrome in Type 2 Diabetic Patients

연구배경: 국내 제2형 당뇨병환자에서의 대사증후군 유병률에 대한 보고가 많지 않았다. 본 연구는 최근 대학병원에서 진료중인 제2형 당뇨병환자를 대상으로 대사증후군의 유병률과 관련된 인자를 알아보고자 하였다. 방법: 2006년 국내 대학병원 13개 기관의 내분비내과를 방문한 제2형 당뇨병환자 4,240명(남성 2,033명, 여성 2,207명, 평균연령 58.7±11.3세, 당뇨병의 이환기간 8.9±7.6년)을 대상으로 2005년 발표된 AHA/NHLBI의 대사증후군 진단기준과 대한비만학회에서 제시한 복부비만(허리둘레) 기준을 적용하여 대사증후군으로 정의하였다. 결과: 대상 환자의 77.9%가 대사증후군을 동반하였고, 남성(76.7%)에 비해 여성(78.9%)에서 대사증후군의 유병률이 약간 높았으나 연령을 보정한 후 차이는 없었다. 대사증후군의 구성요소 개수의 평균은 2.4 (±1.1)개 이었다. 대사증후군의 구성요소 각각의 유병률은 복부비만 56.8%, 고중성지방혈증 42.0%, 저고밀도지단백 콜레스테롤혈증 65.1%, 고혈압 74.9%로 나타나 고혈압이 가장 흔하였다. 복부비만과 고혈압은 여성에서 남성보다 높은 빈도를 보였고, 저고밀도지단백 콜레스테롤혈증은 남성에서 더 높게 나타났다. 대사증후군은 나이가 증가함에 따라 증가하며, 특히 여자에서 뚜렷한 증가를 보였다. 한편 당뇨병 이환기간에 따른 대사증후군 유병률은 차이가 없었다. 대사증후군의 동반을 결정하는 인자를 알기 위해 다중로지스틱회귀분석을 시행한 결과 전신비만이 동반된 경우 6.3배, 나이가 증가할수록, 구체적으로 40대 1.5배, 50대 1.5배, 60대 2.2배, 70대 이상 3.4배 높은 것으로 나타났다. 결론: 한국인 제2형 당뇨병환자에서 대사증후군은 77.9%이었고, 대사증후군은 비만이 있고, 나이가 40대 이상일수록 높은 것으로 나타났다.

Characteristics of subjects with very low serum low-density lipoprotein cholesterol and the risk for intracerebral hemorrhage.

Background/Aims The clinical implications of hypocholesterolemia have not been well studied, although some studies have revealed an association between hypocholesterolemia and intracerebral hemorrhage (ICH). We evaluated the clinical characteristics of subjects with very low-density lipoprotein cholesterol (LDL-C) and compared the risk for ICH using various clinical parameters. Methods Using hospital records, we evaluated the clinical characteristics of subjects with LDL-C levels ≤ 40 mg/dL (very low LDL-C group). We also evaluated the risk for ICH in this very low LDL-C group and in subjects with low LDL-C ≤ 70 mg/dL (low LDL-C group). Results Among 34,415 subjects who presented at the laboratory for serum LDL-C measurements, 250 subjects had a very low serum LDL-C level (≤ 40 mg/dL). About half of the subjects were statin users; the very low LDL levels in the other subjects were likely attributable to alcohol consumption or a various chronic illness such as liver disease or end-stage renal disease (ESRD). ICH occurred in three subjects with very low LDL-C, all of whom had no history of statin use. ESRD tended to be associated with ICH in subjects with serum LDL-C ≤ 70 mg/dL. Conclusions About 1% of the subjects whose LDL-C was measured in the hospital had a LDL-C level ≤ 40 mg/dL, and about half of these subjects had no history of hypolipidemic therapy. ICH incidence was not related to LDL-C level or statin use.