Dal-Sik Kim

Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells

The excessive supply of fatty acids to the liver contributes to hepatic insulin resistance and endoplasmic reticulum (ER) stress associated with obesity or type 2 diabetes mellitus. Furthermore, excess and/or prolonged ER stress contributes to hepatic cell death deteriorating nonalcoholic fatty liver disease to steatohepatitis. The aim of this study was to investigate the effects of metformin on palmitate-induced ER stress and hepatic insulin resistance in HepG2 cells. Metformin significantly inhibited palmitate-induced cell death and apoptosis via caspase-3 activation. Metformin also blocked the induction of ER stress proteins (GRP78, Chop, Cleaved ATF-6, p-eIF2 alpha and XBP-1) and regulated serine phosphorylation of IRS-1. Metformin may therefore protect hepatocytes from death induced by saturated fatty acids. These data may also provide a further rationale for exploring the use of metformin in the treatment of non-alcoholic fatty liver disease, revealing its blocking effect for hepatic insulin resistance evoked by saturated fatty acids.

Impact of Visceral Fat on the Metabolic Syndrome and Nonalcoholic Fatty Liver Disease

Visceral fat has been reported to be associated with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS). We assessed the prevalence of both NAFLD and the MetS, measured visceral fat thickness (VFT), and estimated the physical activity indexes of 224 relatively healthy hospital workers. We also investigated the associations between both VFT and physical activity index and each of NAFLD and the MetS. The MetS was diagnosed according to the guidelines outlined by the Adult Treatment Panel III, and NAFLD was diagnosed by ultrasonography. Subjects with hepatitis B and C infections and those reporting moderate alcohol consumption were excluded from the study. The prevalence of the MetS was 11.6% and that of NAFLD was 41.5%. Many subjects with the MetS had NAFLD (73.1%), and some subjects with NAFLD (20.4%) also had several components of the MetS (p=0.001). VFT was significantly increased by both the addition of components of the MetS and the severity of NAFLD (p<0.001). In addition, VFT was independently associated with NAFLD (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.19) in subjects with more than 2 components of the MetS. In contrast, habitual physical activity was reversely associated with NAFLD (OR, 0.29; 95% CI, 0.10-0.87). In conclusion, an increased visceral fat content and reduced physical activity could be not only biological markers but also therapeutic targets in the treatment of NAFLD and the MetS.

A Double Mutation of the Ryanodine Receptor Type 1 Gene in a Malignant Hyperthermia Family with Multiminicore Myopathy

Background and purpose At least 100 Ryanodine receptor type 1 (RYR1) mutations associated with malignant hyperthermia (MH) and central core disease (CCD) have been identified, but 2 RYR1 mutations accompanying multiminicore myopathy in an MH and/or CCD family have been reported only rarely. Methods Fifty-three members of a large MH family were investigated with clinical, histopathologic, RYR1 mutation, and haplotyping studies. Blood creatine kinase (CK) and myoglobin levels were also measured where possible. Results Sequencing of the entire RYR1 coding region identified a double RYR1 mutation (R2435H and A4295V) in MH/CCD regions 2 and 3. Haplotyping analysis revealed that the two missense heterozygous mutations (c.7304G>A and c.12891C>T) were always present on a common haplotype allele, and were closely cosegregated with histological multiminicores and elevated serum CK. All the subjects with the double mutation showed elevated serum CK and myoglobin, and the obtained muscle biopsy samples showed multiminicore lesions, but only two family members presented a late-onset, slowly progressive myopathy. Conclusions We found multiminicore myopathy with clinical and histological variability in a large MH family with an unusual double RYR1 mutation, including a typical CCD-causing known mutant. These results suggest that multiminicore lesions are associated with the presence of more than two mutations in the RYR1 gene.

Reduction of blood lipid parameters by a 12-wk supplementation of aged black garlic: A randomized controlled trial

OBJECTIVE The cholesterol-lowering effects of garlic as part of a healthy diet remain controversial. The aim of this study was to investigate whether supplementation with aged black garlic (ABG) could improve blood lipid profiles in patients with mild hypercholesterolemia. METHODS We conducted a double-blind, randomized placebo-controlled trial. Sixty participants were randomly assigned to receive either ABG or placebo twice daily (total 6 g/d) before consumption of a meal every morning and evening for 12 wk. During the study, two participants dropped out of the ABG group, and three participants dropped out of the placebo group. Thus, the effects of AGB on fasting blood levels of lipids were evaluated in 28 participants and compared with the placebo group (n = 27). RESULTS Among lipid components, no significant differences in triglycerides, low-density lipoprotein cholesterol, total cholesterol, or free fatty acid levels were observed between the two groups. However, ABG increased high-density lipoprotein cholesterol levels compared with the placebo group at the end of the study. Moreover, a significant decrease in the levels of alipoprotein B and a significant increase in the ratio of low-density lipoprotein cholesterol/alipoprotein B were observed in the ABG group. No adverse effects were reported in any of the patients. CONCLUSION ABG supplementation reduced atherogenic markers and thus may have a cardioprotective effect beyond the gold standard medication in patients with mild hypercholesterolemia.

A case of 49,XXXXX in which the extra X chromosomes were maternal in origin.

This report describes an 11 month old female baby with features of pentasomy X. A molecular and cytogenetic evaluation revealed that her karyotype was 49,XXXXX and her extra X chromosomes were of maternal origin. She has muscular hypotonia, mental retardation, a cleft palate, mild hydrocephalus as a result of dilatation of both lateral ventricles, hyperextensible elbow joints, proximal radioulnar synostosis, clinodactyly of the fifth finger, valgus of the feet, and small hands and feet. In addition, she has a persistent pupillary membrane and congenital chorioretinal atrophy. The pathogenesis of pentasomy X is not clear at present, but it is thought to be caused by successive maternal non-dysjunctions.

Reference intervals for whole blood viscosity using the analytical performance-evaluated scanning capillary tube viscometer

OBJECTIVES This study was performed to establish the reference intervals for whole blood viscosity (WBV) using the analytical performance-evaluated scanning capillary tube viscometer (SCTV). DESIGN AND METHODS The analytical performance of the SCTV was evaluated using three different levels of QC materials and sixty human EDTA-blood samples. To establish the reference intervals for WBV, 297 healthy individuals (123 men and 174 women) were selected from 1083 subjects. RESULTS Within-day precisions with QC materials and human whole blood and between-day precisions with QC materials were below 5.0%, 6.6% and 8.0% in CVs at all shear rates, respectively. Comparison tests between the SCTV and the Brookfield viscometer showed a significant correlation (R(2)=0.972, p<0.001). The reference intervals for WBV in healthy men were 3.66-5.41cP at 300s(-1) and 23.15-36.45cP at 1s(-1) while those in women were 3.27-4.32cP at 300s(-1) and 18.20-27.36cP at 1s(-1), respectively. CONCLUSIONS Using the analytical performance-evaluated SCTV, the reference intervals for WBV were established in healthy adults, which could be beneficial to the clinical utility of WBV in the aspect of appropriate modalities for the improvement of blood viscosity.

An 8-wk, randomized, double-blind, placebo-controlled clinical trial for the antidiabetic effects of hydrolyzed ginseng extract

Background To investigate the antidiabetic effects of hydrolyzed ginseng extract (HGE) for Korean participants in an 8-wk, randomized, double-blinded, placebo-controlled clinical trial. Methods Impaired fasting glucose participants [fasting plasma glucose (FPG) ≥ 5.6mM or < 6.9mM] who had not been diagnosed with any disease and met the inclusion criteria were recruited for this study. The 23 participants were randomly divided into either the HGE (n = 12, 960 mg/d) or placebo (n = 11) group. Outcomes included measurements of efficacy (FPG, postprandial glucose, fasting plasma insulin, postprandial insulin, homeostatic model assessment-insulin resistance, and homeostatic model assessment-β) and safety (adverse events, laboratory tests, electrocardiogram, and vital signs). Results After 8 wk of HGE supplementation, FPG and postprandial glucose were significantly decreased in the HGE group compared to the placebo group. No clinically significant changes in any safety parameter were observed. Our study revealed that HGE is a potent antidiabetic agent that does not produce noticeable adverse effects. Conclusion HGE supplementation may be effective for treating impaired fasting glucose individuals.

Effect of Red Ginseng on cytochrome P450 and P-glycoprotein activities in healthy volunteers

Background We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers. Methods This article describes an open-label, crossover study. CYP probe cocktail drugs, caffeine, losartan, dextromethorphan, omeprazole, midazolam, and fexofenadine were administered before and after RG supplementation for 2 wk. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data using analysis of variance after RG administration versus before RG administration. Results Fourteen healthy male participants were evaluated, none of whom were genetically defined as poor CYP2C9, 2C19, and CYP2D6 metabolizers based on genotyping. Before and after RG administration, the geometric least-square mean metabolic ratio (90% CI) was 0.870 (0.805–0.940) for caffeine to paraxanthine (CYP1A2), 0.871 (0.800–0.947) for losartan (CYP2C9) to EXP3174, 1.027 (0.938–1.123) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.373 (0.864–2.180) for dextromethorphan to dextrorphan (CYP2D6), and 0.824 (0.658–1.032) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast) for fexofenadine (P-gp) was 0.963 (0.845–1.098). Administration of concentrated RG for 2 wk weakly inhibited CYP2C9 and CYP3A4 and weakly induced CYP2D6. However, no clinically significant drug interactions were observed between RG and CYP and P-gp probe substrates. Conclusion RG has no relevant potential to cause CYP enzyme- or P-gp-related interactions. Clinical trial registration number (ClinicalTrials.gov): NCT02056743.

Effect of fermented red ginseng on cytochrome P450 and P‐glycoprotein activity in healthy subjects, as evaluated using the cocktail approach

Aims We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P‐glycoprotein (P‐gp), in healthy volunteers. Methods This study was an open‐label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). Results Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least‐square mean metabolic ratio (90% CI) was 0.901 (0.830–0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720–0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925–1.197) for omeprazole (CYP2C19) to 5‐hydroxyomeprazole, 1.150 (0.860–1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673–0.990) for midazolam (CYP3A4) to 1‐hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast) for fexofenadine (P‐gp) was 1.322 (1.112–1.571). Conclusion No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two‐week administration of concentrated fermented red ginseng. However, the inhibition of P‐gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P‐gp substrate drugs.

New novel mutation of the ATP7B gene in a family with Wilson disease.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The WD gene codes for a copper transporting P-type ATPase (ATP7B) are located on chromosome 13q14.3. Mutation of this gene disrupts copper homeostasis, resulting in the accumulation of copper in the liver, brain, kidneys and corneas and copper toxication at these sites. Since the detection of the WD gene in 1993, approximately 300 disease-specific muations have been identified. We recently evaluated a Korean family with WD. The proband, a 17-year-old boy, visited our hospital due to abnormal behaviors including generalized slow movement, dysphagia, drooling and ataxia. Laboratory results revealed decreases in serum copper and ceruloplasmin and an increase in urinary excretion of copper. He had liver cirrhosis, brain lesions and Kayser-Fleischer corenal rings. Molecular genetic analysis of the ATP7B gene demonstrated that he was heterozygous for deletion mutation c.2697_2723del27 in exon 11. Further study of family members revealed that his father and younger brother had the same mutation. The c.2697_2723del27 deletion mutation in exon 11 has not yet been reported as a causative muation of WD and is an in-frame deletion not expected to lead to a frame shift. Therefore, we report a novel mutation of the ATP7B gene in a family with WD.