Jong Suk Park

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.

Insulin resistance independently influences arterial stiffness in normoglycemic normotensive postmenopausal women.

Objective:Cardiovascular disease risk increases after menopause, which may be related to insulin resistance, and arterial stiffness is a significant predictor of atherosclerosis. We investigated the relationships among insulin resistance, adiponectin, and arterial stiffness in normoglycemic normotensive postmenopausal women. Methods:From 9,555 participants who had routine health checkups, 455 normoglycemic normotensive postmenopausal women were enrolled. Serum concentrations of glucose, total cholesterol, triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) and adiponectin were measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Pulse wave velocity (PWV) was evaluated to assess arterial stiffness. Results:The women were stratified into three groups according to their HOMA-IR values, and comparisons were made among the three groups. There were significant differences in metabolic parameters between the groups. The mean age, body mass index, waist circumference, fasting plasma glucose, TG, systolic blood pressure (SBP), diastolic blood pressure (DBP), aortic PWV, and peripheral PWV increased sequentially with the degree of insulin resistance. Meanwhile, HDL-C and adiponectin levels decreased with the worsening of insulin resistance. Age, body mass index, fasting plasma glucose, TG, insulin, SBP, HOMA-IR, aortic PWV, and peripheral PWV were significantly higher in women with central obesity, and HDL-C and adiponectin were significantly lower in women with central obesity. Aortic PWV and peripheral PWV were significantly correlated with age, waist circumference, total cholesterol, SBP, DBP, insulin, and HOMA-IR, but adiponectin was not associated with PWV. The results of multiple regression analysis indicated that SBP, DBP, and insulin resistance were independently correlated with PWV. Conclusions:Insulin resistance was independently associated with PWV in normoglycemic normotensive postmenopausal women.

Effects of growth hormone on insulin resistance and atherosclerotic risk factors in obese type 2 diabetic patients with poor glycaemic control

Objective  We aimed to evaluate the combined effects of GH treatment and diet restriction on lipolysis and anabolism, insulin resistance and atherosclerotic risk factors in obese patients with type 2 diabetes mellitus (T2DM).

Effect of pioglitazone on serum concentrations of osteoprotegerin in patients with type 2 diabetes mellitus

Objective Osteoprotegerin (OPG) acts as an important regulatory molecule in atherosclerosis. Recent studies report that thiazolidinediones could affect OPG expression. We investigated the relationship between OPG and inflammatory cytokines and the effects of pioglitazone (a PPARγ (PPARG) agonist) versus metformin on serum OPG levels in type 2 diabetic patients. Design and methods Sixty-seven type 2 diabetic patients were included in this study. They were assigned to pioglitazone (15 mg/day, n=34) or metformin (1000 mg/day, n=33) during 24 weeks. Various anthropometric and metabolic parameters, OPG, interleukin 6 (IL6), C-reactive protein (CRP), adiponectin, and homeostasis model assessment of insulin resistance (HOMA-IR), were measured at baseline and at 6 months of treatment. Results Serum OPG levels correlated significantly with fasting plasma glucose (FPG), HbAlc, HOMA-IR, IL6, and CRP, and inversely correlated with adiponectin after adjusting for age (P<0.05). Multiple regression analysis showed that FPG, HbAlc, and adioponectin were independently correlated with OPG level. After 6 months of treatment, the reduction in FPG and HbAlc levels was similar between the two groups. Pioglitazone treatment significantly increased body mass index (P<0.05) and waist circumference (P<0.05) and decreased triglycerides (P<0.05) and HOMA-IR (P<0.01). The adiponectin concentration was increased (P<0.05), and OPG and CRP levels were decreased in the pioglitazone group (P<0.05), but were unchanged in the metformin group. The changes in serum OPG in the pioglitazone group showed significant correlation with changes in FPG, HbAlc, and adiponectin. Conclusions In type 2 diabetic patients, pioglitazone decreases OPG levels, and this decrease in OPG levels might be associated with the increase in adiponectin.

Usefulness of brachial-ankle pulse wave velocity as a predictive marker of multiple coronary artery occlusive disease in Korean type 2 diabetes patients

Multiple coronary artery occlusive disease (multiple CAOD) is the most fatal and frequently observed coronary artery disease in type 2 diabetes patients, but no simple, non-invasive screening tool is available yet. The aim of this study is to evaluate the arterial stiffness in type 2 diabetes patients using brachial-ankle pulse wave velocity (baPWV), to demonstrate the correlation between arterial stiffness and multiple CAOD, and to suggest the cutoff point of baPWV for predicting multiple CAOD in Korean type 2 diabetes patients. One hundred and eighty-one diabetes and 262 non-diabetes patients were enrolled in the study. Routine anthropometric and serologic data were collected. baPWV was measured the day before coronary angiography, and the severity of CAOD was assessed with Gensini score after angiography. baPWV and Gensini score were significantly increased in diabetes patients and Gensini score had a positive correlation with baPWV. Subjects in the highest tertile of baPWV showed odds ratio of 3.06 for multiple CAOD compared to the lowest tertile. In ROC curve, baPWV at 1635 cm/s showed 73% sensitivity and 75% specificity with AUC 0.76 in diabetes patients in detecting multiple CAOD. Therefore, baPWV may be utilized a screening tool for predicting multiple CAOD, especially in type 2 diabetes patients.

Coping strategies and their relationship to psychopathologies in people at ultra high-risk for psychosis and with schizophrenia.

This studys aim was to investigate coping strategies and their relationship to symptoms in people at ultra high risk (UHR) for psychosis compared with recent-onset schizophrenia (SPR) and healthy controls. Thirty-three UHR participants, 22 SPR patients, and 33 healthy controls completed the Ways of Coping Questionnaire and other clinical measures. People at UHR for psychosis showed significantly more reliance on tension-reduction and less reliance on problem-focused coping than healthy controls. The SPR group showed more reliance on tension-reduction coping than healthy controls at a trend level. Maladaptive coping patterns were associated with higher levels of negative symptoms, depression, and anxiety in both the UHR and SPR groups. These findings suggest that maladaptive coping strategies might have already emerged in the (putative) prodromal stage and could influence symptom severities.

Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression.

Low-density lipoprotein receptor-related protein 1 (LRP1) binds to apolipoprotein E and serves as a receptor for remnant lipoproteins in the liver, thus playing an important role in clearing these atherogenic particles. In this study, we investigated the effect of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, on hepatic LRP1 expression. We used HepG2 and Hep3B cells for in vitro study, and Otsuka Long-Evans Tokushima fatty and Sprague-Dawley rats for in vivo study. We used relatively high pharmacologic dose of atorvastatin in this study (in vitro, 0.5 μmol/L in culture media, for 48 hours; in vivo, 20 mg/[kg d], for 6 weeks). Atorvastatin increased LRP1 and low-density lipoprotein (LDL) receptor expression in HepG2 and Hep3B cells and induced hepatic LRP1 and LDL receptor expression in chow diet-fed Sprague-Dawley rats and high-fat diet-fed Otsuka Long-Evans Tokushima fatty rats. Atorvastatin decreased intracellular sterol level and increased the amount of the nuclear form of sterol response element-binding protein-2 (SREBP-2) in both HepG2 and Hep3B cells as well as in two animal models. Treatment of HepG2 cells with LDL increased intracellular sterol level and reduced LRP1, LDL receptor, and SREBP-2. When SREBP-2 in HepG2 cells was knocked down by small interfering RNA, the induction of LRP1 expression by atorvastatin did not take place. In conclusion, up-regulation of hepatic LRP1 might be a novel mechanism by which statin treatment decreases remnant lipoproteins. In addition, SREBP-2 acts as a mediator of atorvastatin-induced up-regulation of hepatic LRP1. Future studies using standard doses of atorvastatin in humans are needed to elucidate clinical relevance of these findings.

Comparison of the Efficacy of Glimepiride, Metformin, and Rosiglitazone Monotherapy in Korean Drug-Naïve Type 2 Diabetic Patients: The Practical Evidence of Antidiabetic Monotherapy Study

Background Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated. Methods We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels. Results HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group. Conclusion The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information.

Relationships between serum uric acid, adiponectin and arterial stiffness in postmenopausal women

OBJECTIVES Cardiovascular disease (CVD) is a leading cause of death in postmenopausal women. Elevated serum uric acid levels, hypoadiponectinemia and arterial stiffness are strongly associated with cardiovascular diseases. We investigated the relationships among uric acid, adiponectin and arterial stiffness in postmenopausal women. STUDY DESIGN 9555 subjects who had the routine health check-ups, 841 postmenopausal women aged 50 years or older who had not had a menstrual period for more than 12 consecutive months were included in this study. MAIN OUTCOME MEASURES BMI, WC, and serum concentrations of uric acid, adiponectin, glucose, lipids (total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) were measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Pulse wave velocity (PWV) was evaluated to assess arterial stiffness. RESULTS The subjects were stratified into three groups according to uric acid values. PWV values gradually increased and adiponectin level decreased with uric acid tertiles. Serum uric acid levels in postmenopausal women correlated significantly with age, BMI, WC, TG, HDL-C, insulin, HOMA-IR, adiponectin and PWV. Multiple regression analysis showed that WC (β=0.141, P<0.01), HOMA (β=0.137, P<0.01), adiponectin (β=-0.104, P<0.01), and PWV (β=0.129, P<0.01) were independently correlated with uric acid levels. In multiple logistic regression analysis after adjusting for risk factors, uric acid was a significant contributor to increased PWV. CONCLUSIONS These findings indicate that serum uric acid is independently associated with adiponectin and arterial stiffness in postmenopausal women.

The activation of NF-κB and AP-1 in peripheral blood mononuclear cells isolated from patients with diabetic nephropathy

We evaluated the role of oxidative stress in diabetic nephropathy by measuring intracellular reactive oxygen species (ROS) and redox-sensitive transcription factors in isolated peripheral mononuclear cells (PBMC) in 66 diabetic patients with or without diabetic nephropathy (Groups III and II, respectively) and 49 normal controls (Group I). Stimulated ROS was significantly higher in Group III compared to Group II (increment of H(2)O(2)-induced ROS production: 21.8+/-2.2% vs. 11.1+/-2.0%; increment of PMA-induced ROS production 23.5+/-4.5% vs. 21.6+/-2.2%; both respectively), and the activity of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1), but not specificity protein 1 (Sp1) was significantly higher in Group III than in Group II (2.53-fold vs. 2.0-fold vs. 1.43-fold, respectively). Both PBMC- and urinary TGF-beta1 levels were higher in Group III than Group II (3.23+/-0.39 ng/g vs. 1.99+/-0.68 ng/g in PBMCs, 16.88+/-6.84 (ng/g Cr) vs. 5.61+/-1.57 (ng/g Cr) in urine, both respectively), and they correlated with the activity of NF-kappaB and AP-1 and 24-h urine albumin excretion (UAE). Increased intracellular ROS generation in PBMCs of diabetic patients is involved in the pathogenesis of diabetic nephropathy via activation NF-kappaB and AP-1 and an increased expression of TGF-beta1.