Min Kyong Moon

A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women

Knowledge regarding the genetic risk loci for gestational diabetes mellitus (GDM) is still limited. In this study, we performed a two-stage genome-wide association analysis in Korean women. In the stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic control women were compared using 2.19 million genotyped or imputed markers. We selected 11 loci for further genotyping in stage 2 samples of 931 case and 783 control subjects. The joint effect of stage 1 plus stage 2 studies was analyzed by meta-analysis. We also investigated the effect of known type 2 diabetes variants in GDM. Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P = 6.65 × 10−16). A variant near MTNR1B, rs10830962, was also significantly associated with the risk of GDM (1.454; P = 2.49 × 10−13). We found that there is an excess of association between known type 2 diabetes variants and GDM above what is expected under the null hypothesis. In conclusion, we have confirmed that genetic variants in CDKAL1 and near MTNR1B are strongly associated with GDM in Korean women. There seems to be a shared genetic basis between GDM and type 2 diabetes.

Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women

CONTEXT Exercise training enhances insulin sensitivity. Changes in retinol-binding protein-4 (RBP4) and adiponectin levels are linked to insulin resistance. OBJECTIVE We tested whether the insulin-sensitizing effect of exercise is associated with age-related changes in circulating RBP4 and adiponectin levels in women. DESIGN, SUBJECTS, AND INTERVENTION We studied 36 healthy young (22.4 +/- 2.8 yr) and 38 middle-aged (59.8 +/- 5.9 yr) women. All subjects performed 60 min of aerobic exercise three times per week for 10 wk at about 70% maximal exercise capacity. RESULTS After a 10-wk training program, maximal exercise capacity was significantly increased in both young and middle-aged women, suggesting increased oxidative capacity. Insulin sensitivity was also improved, as indicated by decreases in plasma insulin levels and homeostasis model assessment for insulin resistance index. Serum adiponectin and RBP4 concentrations were increased and decreased more in older than younger women, respectively (P < 0.01). Concurrently, circulating transthyretin levels were also decreased in older subjects in response to exercise training. The older women showed higher correlations between changes in adiponectin or RBP4 levels and obesity indices or metabolic parameters than the younger group. When subjects showing increasing adiponectin or decreasing RBP4 levels were classified as responders, there were higher correlations between these changes in responders than in nonresponders. CONCLUSIONS We conclude that the mechanism for the insulin-sensitizing effects of exercise could involve increased adiponectin and reduced RBP4 levels in exercise-trained women. These data suggest that alterations in circulating RBP4 and adiponectin levels could play an important role in regulating insulin sensitivity.

Bisphenol A Impairs Mitochondrial Function in the Liver at Doses below the No Observed Adverse Effect Level

Bisphenol A (BPA) has been reported to possess hepatic toxicity. We investigated the hypothesis that BPA, below the no observed adverse effect level (NOAEL), can induce hepatic damage and mitochondrial dysfunction by increasing oxidative stress in the liver. Two doses of BPA, 0.05 and 1.2 mg/kg body weight/day, were administered intraperitoneally for 5 days to mice. Both treatments impaired the structure of the hepatic mitochondria, although oxygen consumption rate and expression of the respiratory complex decreased only at the higher dose. The hepatic levels of malondialdehyde (MDA), a naturally occurring product of lipid peroxidation, increased, while the expression of glutathione peroxidase 3 (GPx3) decreased, after BPA treatment. The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased. In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential. In conclusion, doses of BPA below the NOAEL induce mitochondrial dysfunction in the liver, and this is associated with an increase in oxidative stress and inflammation.

Genetic association study of adiponectin polymorphisms with risk of Type 2 diabetes mellitus in Korean population

Aims  To investigate any association between Type 2 diabetes mellitus and two single nucleotide polymorphisms (SNPs) in the adiponectin gene, T45G and G276T, in the Korean population.

Genetic polymorphisms in peroxisome proliferator-activated receptor gamma are associated with Type 2 diabetes mellitus and obesity in the Korean population.

Aims  We examined whether the common polymorphisms of the peroxisome proliferator‐activated receptor‐γ (PPARγ) gene are associated with Type 2 diabetes or obesity in the Korean population.

Long-term oral exposure to bisphenol A induces glucose intolerance and insulin resistance

Bisphenol A (BPA) is a widely used endocrine disruptor. Recent epidemiologic results have suggested an association between exposure to BPA and cardiovascular disease, type 2 diabetes, and obesity. We investigated the in vivo effects of long-term oral exposure to BPA on insulin resistance and glucose intolerance. In the present study, 4- to 6-week-old male mice on a high-fat diet (HFD) were treated with 50 μg/kg body weight per day of BPA orally for 12 weeks. Long-term oral exposure to BPA along with an HFD for 12 weeks induced glucose intolerance in growing male mice. Intraperitoneal glucose tolerance tests showed that the mice that received an HFD and BPA exhibited a significantly larger area under the curve than did those that received an HFD only (119.9±16.8 vs. 97.9±18.2 mM/min, P=0.027). Body weight, percentage of white adipose tissue, and percentage of body fat did not differ between the two groups of mice. However, treatment with BPA reduced Akt phosphorylation at position Thr308 and GSK3β phosphorylation at position Ser9 in skeletal muscle. BPA tended to decrease serum adiponectin levels and to increase serum interleukin 6 and tumor necrosis factor α, although these findings were not statistically significant. Treatment with BPA did not induce any detrimental changes in the islet area or morphology or the insulin content of β cells. In conclusion, long-term oral exposure to BPA induced glucose intolerance and insulin resistance in growing mice. Decreased Akt phosphorylation in skeletal muscle by way of altered serum adipocytokine levels might be one mechanism by which BPA induces glucose intolerance.

Preoperative Predictive Factors for Parathyroid Carcinoma in Patients with Primary Hyperparathyroidism

This study was conducted to review the clinical characteristics of parathyroid carcinoma (PC) and to evaluate potential preoperative predictive factors for PC in patients with primary hyperparathyroidism (PHPT). We performed a retrospective review of electronic medical records of 194 patients with pathologically confirmed PHPT in affiliated teaching hospitals of Seoul National University from January 2000 to March 2011. Adenoma was diagnosed in 171 patients, hyperplasia in 12, and carcinoma in 11. Several biochemical measurements were higher in patients with PC than in patients with benign disease, including serum total calcium (P < 0.001), intact parathyroid hormone (P = 0.003), and alkaline phosphatase (ALP) (P < 0.001). Tumors were larger in PC than in benign disease (P < 0.001). Multivariate analysis revealed that serum ALP level (P < 0.001) and tumor size were associated with PC (P = 0.03). Tumor size and serum ALP level were evaluated as preoperative predictive factors for PC using ROC analyses: a tumor size of 3.0 cm (sensitivity 90.9%, specificity 92.1%) and serum ALP level of 285 IU/L (83.3%, 97.0%) had predictive value for the diagnosis of PC in patients with PHPT. In conclusion, elevated serum ALP and a large parathyroid mass at the time of diagnosis can be helpful to predict PC in patients with PHPT.

Effect of Low Serum Total Bilirubin Levels (£0.32 mg/dl) on Risk of Coronary Artery Disease in Patients With Metabolic Syndrome

The objective of this study was to investigate the effects of low serum bilirubin levels on the risk for future coronary artery disease (CAD) in a prospective cohort. CAD events were examined according to baseline serum bilirubin levels in a prospective large-scale, community-based Korean cohort in 2 subsequent prospective biennial surveys. A total of 8,593 subjects were included, 0.9% of whom reported newly developed CAD events during the 4 years of follow-up. Cox regression analyses showed that the lowest serum total bilirubin level category (bilirubin ≤0.32 mg/dl) was an independent risk factor for future CAD events (adjusted hazard ratio [HR] 1.890, 95% confidence interval [CI] 1.088 to 3.284; p = 0.024). Subjects with metabolic syndrome had a higher risk for future CAD events than those without metabolic syndrome (HR 3.366, 95% CI 2.079 to 5.448, p <0.001). Low bilirubin levels increased the CAD risk in subjects with metabolic syndrome further (HR 2.016, 95% CI 1.069 to 3.800; p = 0.030), with these subjects showing a >6 times higher risk for CAD than subjects with bilirubin levels >0.32 mg/dl and no metabolic syndrome (HR 6.228, 95% CI 3.118 to 12.437; p <0.001). In conclusion, the addition of low serum bilirubin levels to the traditional risk factors for CAD, such as metabolic syndrome, may yield an improvement of risk prediction.

The effects of chronic exercise on the inflammatory cytokines interleukin-6 and tumor necrosis factor-α are different with age

Aging is associated with chronic low-grade inflammation, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are key mediators of the inflammatory process. IL-6, especially muscle-derived IL-6, is expected to mediate the beneficial metabolic effects of exercise. There was no report that directly compares the effects of chronic endurance exercise on cytokine responses between old and young subjects in the same situation. Therefore, we compared the effects of endurance exercise on the expression of IL-6 and TNF-α in old and young rats. Young (3-month-old) and old (20-month-old) male Fisher rats were trained for 12 weeks on the treadmill. We measured serum TNF-α and IL-6 concentrations by enzyme-linked immunosorbent assay and examined mRNA expression of TNF-α and IL-6 in muscle, liver, and white adipose tissue using reverse transcription - polymerase chain reaction. We found that old rats had higher basal IL-6 levels in the liver, as well as in the serum and the muscle. After chronic endurance exercise, young rats exhibited significant decreases in serum TNF-α levels and hepatic IL-6 expression. However, old rats exhibited no significant changes in either serum or tissue cytokine levels after endurance exercise. These findings suggest that chronic endurance exercise could influence the inflammatory response of hepatic tissues, as well as muscle, and that the effects of chronic endurance exercise on inflammatory cytokine levels are different between old and young rats and an exercise program tailored for old subjects will be needed to obtain beneficial anti-inflammatory effects from exercise.

S-Adenosyl-L-methionine ameliorates TNFα-induced insulin resistance in 3T3-L1 adipocytes

An association between inflammatory processes and the pathogenesis of insulin resistance has been increasingly suggested. The IκB kinase-β (IKK-β)/ nuclear factor-κB (NF-κB) pathway is a molecular mediator of insulin resistance. S-Adenosyl-L-methionine (SAM) has both antioxidative and anti-inflammatory properties. We investigated the effects of SAM on the glucose transport and insulin signaling impaired by the tumor necrosis factor α (TNFα) in 3T3-L1 adipocytes. SAM partially reversed the basal and insulin stimulated glucose transport, which was impaired by TNFα. The TNFα-induced suppression of the tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1) and Akt in 3T3-L1 adipocytes was also reversed by SAM. In addition, SAM significantly attenuated the TNFα-induced degradation of IκB-α and NF-κB activation. Interestingly, SAM directly inhibited the kinase activity of IKK-β in vitro. These results suggest that SAM can alleviate TNFα mediated-insulin resistance by inhibiting the IKK-β/NF-κB pathway and thus can have a beneficial role in the treatment of type 2 diabetes mellitus.