Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. Conclusion: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Therapeutic efficacy and safety of initial triple combination of metformin, sitagliptin, and lobeglitazone in drug-naïve patients with type 2 diabetes: initial triple study.

OBJECTIVE: To compare the efficacy and safety of an initial triple therapy using metformin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and thiazolidinedione with a stepwise approach using sulfonylurea and metformin in new-onset, drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Among drug-naïve patients with 9.0%-12.0% glycated hemoglobin (HbA1c) but no hyperglycemic symptoms, 100 subjects who started triple medications (metformin 1000 mg/day, sitagliptin 100 mg/day, and lobeglitazone 0.5 mg/day) were selected as an initial triple therapy group. Age and body mass index-matched subjects (n=100) who started glimepiride (≥2 mg/day with uptitration) and metformin (≥1000 mg/day with uptitration) were selected as a conventional therapy group. We investigated changes in HbA1c level, dynamic indexes for insulin sensitivity and ß-cell function, and hypoglycemia. RESULTS: After 12 months of treatment, HbA1c levels decreased significantly in both groups: from 10.7%±1.0% to 6.7%±1.3% in the triple group, and from 10.5%±1.0% to 7.3%±1.2% in the conventional therapy group. At 12 months, achievement of the HbA1c target (<7.0%) was higher in the triple group than in the conventional group (70% vs 52%, p<0.01). Dynamic indexes related to ß-cell function and insulin sensitivity improved, and albuminuria reduced significantly only in the triple group. Hypoglycemia was more common in the conventional group. CONCLUSIONS: Initial triple combination therapy with the DPP4 inhibitor, metformin, and thiazolidinedione showed a higher achievement of the target HbA1c goal with a lower risk of hypoglycemia, better restoration of ß-cell function, and multiple metabolic benefits, implying durable glycemic control. This strategy may be useful for patients presenting with type 2 diabetes and high HbA1c levels.

Association between Body Fat and Diabetic Peripheral Neuropathy in Middle-Aged Adults with Type 2 Diabetes Mellitus: A Preliminary Report.

BACKGROUND: Previous epidemiologic studies showed that obesity increased the risk of diabetic peripheral neuropathy (DPN). However, there is very limited data about the impact of body fat measured by body composition analysis in DPN. METHODS: Subjects with type 2 diabetes mellitus (T2DM) between 20 to 55 years old were enrolled. DPN was diagnosed using the Michigan Neuropathy Screening Instrument. Body composition was assessed by bio-impedance analysis, and the association between body composition and DPN was investigated. RESULTS: Among 65 subjects, 44.6% were diagnosed with DPN. Subjects with DPN had higher body mass index and waist circumference than subjects without DPN. Body composition data showed that fat mass, fat percent, and visceral fat area were higher in subjects with DPN than in subjects without DPN. Furthermore, the presence of DPN was associated with waist circumference (odds ratio [OR], 1.151; 95% confidence interval [CI], 1.055-1.256; P=0.002), visceral fat area (OR, 1.026; 95% CI, 1.005-1.048; P=0.015), and insulin resistance (OR, 1.673; 95% CI, 1.091-2.565; P=0.018) after adjusting age, sex, diabetes duration, and smoking status. CONCLUSION: Abdominal obesity was associated with DPN. Insulin resistance might mediate obesity and DPN in middle aged subjects with T2DM.

Components of Metabolic Syndrome in Korean Adults: A Hospital-Based Cohort at Seoul National University Bundang Hospital.

BACKGROUND: The prevalence of metabolic syndrome is increasing in Korea, particularly among young adults. This trend will increase the incidence of cardiovascular and metabolic diseases in the future. Therefore, it is imperative to detect and prevent metabolic abnormalities early in life. Here, we established a hospital-based biobank cohort to identify the most prevalent dysmetabolic phenotype. The aim of this report was to inform other researchers of our protocol and to share our data for future collaboration. METHODS: The baseline examination comprised health-related questionnaires, anthropometric and handgrip strength measurements, bioelectrical impedance analysis of body composition, and nutritional assessment. Relevant biochemical parameters were measured, and oral glucose tolerance tests were performed. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria with Asian waist circumference criteria. RESULTS: From a total of about 3,000 employees aged 20 to 59 years working at Seoul National University Bundang Hospital, 1,017 were enrolled from 2015 to 2016. The mean age was 34.5±8.4 years for men (n=311, 30.6%) and 30.9±8.5 years for women (n=706, 69.4%). The overall prevalence of metabolic syndrome was 7.6% (17.7% in men and 3.1% in women). Among the five components of metabolic syndrome, high blood pressure was the most prevalent in both men (51.4%) and women (13.8%). CONCLUSION: Although further follow-up data are needed, we expect that more adverse cardiovascular events may occur in men than in women. This hospital-based cohort will serve as the foundation for a comprehensive evaluation of metabolic syndrome and future cardiometabolic disease risk in middle-aged Koreans.

Association between deterioration in muscle strength and peripheral neuropathy in people with diabetes.

AIMS: Diabetic peripheral neuropathy (DPN) is a major risk factor for sarcopenia or frailty in older patients with diabetes. In this study, we investigated the association between DPN and muscle strength in type 2 diabetes. METHODS: DPN was assessed using the Michigan Neuropathy Screening Instrument Questionnaire (MNSI-Q) and Physical Examination (MNSI-PE) in 230 subjects with type 2 diabetes. Handgrip strength (HGS) was measured using an electronic grip strength dynamometer. RESULTS: The prevalence of DPN was 26.4% in men and 34.7% in women. HGS was significantly lower in men with DPN compared with men without DPN (27.0 ±â€¯9.4 vs. 29.7 ±â€¯8.4 kg, p = 0.036). This effect was not seen in women. In men, multivariate regression analysis showed that HGS was negatively associated with the MNSI-Q (ß = -1.200, p = 0.003) and MNSI-PE scores (ß = -0.937, p = 0.046) and resulted in an abnormal 10-gram monofilament test score (ß = -10.895, p < 0.001). However, HGS was not significantly associated with neuropathy in women. CONCLUSIONS: Muscle strength was lower in men with DPN than in those without DPN. Assessment of muscle function may have clinical implications in the prevention of sarcopenia and frailty in men with DPN.

Serum Neopterin Concentration and Impaired Glucose Metabolism: Relationship With ß-Cell Function and Insulin Resistance.

Aim: The purpose of this study was to measure the serum neopterin according to glucose metabolism and to evaluate neopterin as a predictor of type 2 diabetes (T2D) in a hospital-based cohort. Methods: A 75-g oral glucose tolerance test (OGTT) was performed by people who visited the outpatient clinic in Seoul National University Bundang Hospital for suspected abnormal glucose tolerance or a strong family history of T2D. Neopterin was measured using an enzyme-link immunosorbent assay with baseline samples from the OGTT. Results: Neopterin was measured in 184 participants. Indices related to glucose metabolism, such as the HOMA-IR, disposition index, etc. were calculated based on the results of the OGTT. The classifications for the 184 participants were: 24 (13%) had NGT, 89 (48.4%) prediabetes, and 60 (38.6%) T2D. Neopterin increased with deterioration of glucose metabolism (0.55 ± 0.25 vs. 0.58 ± 0.27 vs. 0.67 ± 0.27 ng/ml, p = 0.041; NGT, prediabetes, and T2D, respectively). Neopterin also correlated with fasting plasma glucose, 30-min and 120-min glucose of OGTT and HbA1c (r = 0.251, 0.259, 0.184, and 0.270, all p < 0.05). The HOMA-IR and disposition index correlated with neopterin (r = 0.291 and -0.170, respectively, both p < 0.05). When combined with C-peptide level, neopterin was as powerful as HOMA-IR in predicting future T2D. Conclusion: Serum neopterin appears to be related to impaired insulin secretion and insulin resistance in the development of T2D. Further investigation of the relationship between neopterin and glucose metabolism would be helpful to understand the pathophysiology for the development of T2D.

Clinical Feasibility of Monitoring Resting Heart Rate Using a Wearable Activity Tracker in Patients With Thyrotoxicosis: Prospective Longitudinal Observational Study.

BACKGROUND: Symptoms and signs of thyrotoxicosis are nonspecific and assessing its clinical status is difficult with conventional physical examinations and history taking. Increased heart rate (HR) is one of the easiest signs to quantify this, and current wearable devices can monitor HR. OBJECTIVE: We assessed the association between thyroid function and resting HR measured by a wearable activity tracker (WD-rHR) and evaluated the clinical feasibility of using this method in patients with thyrotoxicosis. METHODS: Thirty patients with thyrotoxicosis and 10 controls were included in the study. Participants were instructed to use the wearable activity tracker during the study period so that activity and HR data could be collected. The primary study outcomes were verification of changes in WD-rHR during thyrotoxicosis treatment and associations between WD-rHR and thyroid function. Linear and logistic model generalized estimating equation analyses were performed and the results were compared to conventionally obtained resting HR during clinic visits (on-site resting HR) and the Hyperthyroidism Symptom Scale. RESULTS: WD-rHR was higher in thyrotoxic patients than in the control groups and decreased in association with improvement of thyrotoxicosis. A one standard deviation-increase of WD-rHR of about 11 beats per minute (bpm) was associated with the increase of serum free T4 levels (beta=.492, 95% CI 0.367-0.616, P<.001) and thyrotoxicosis risk (odds ratio [OR] 3.840, 95% CI 2.113-6.978, P<.001). Although the Hyperthyroidism Symptom Scale showed similar results with WD-rHR, a 1 SD-increase of on-site rHR (about 16 beats per minute) showed a relatively lower beta and OR (beta=.396, 95% CI 0.204-0.588, P<.001; OR 2.114, 95% CI 1.365-3.273, P<.001) compared with WD-rHR. CONCLUSIONS: Heart rate data measured by a wearable device showed reasonable predictability of thyroid function. This simple, easy-to-measure parameter is clinically feasible and has the potential to manage thyroid dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT03009357; https://clinicaltrials.gov/ct2/show/NCT03009357 (Archived by WebCite at http://www.webcitation.org/70h55Llyg).

Validity and Reliability of the Korean Version of the Hyperthyroidism Symptom Scale.

BACKGROUND: Thyrotoxicosis is a common disease resulting from an excess of thyroid hormones, which affects many organ systems. The clinical symptoms and signs are relatively nonspecific and can vary depending on age, sex, comorbidities, and the duration and cause of the disease. Several symptom rating scales have been developed in an attempt to assess these symptoms objectively and have been applied to diagnosis or to evaluation of the response to treatment. The aim of this study was to assess the reliability and validity of the Korean version of the hyperthyroidism symptom scale (K-HSS). METHODS: Twenty-eight thyrotoxic patients and 10 healthy subjects completed the K-HSS at baseline and after follow-up at Seoul National University Bundang Hospital. The correlation between K-HSS scores and thyroid function was analyzed. K-HSS scores were compared between baseline and follow-up in patient and control groups. Cronbach's α coefficient was calculated to demonstrate the internal consistency of K-HSS. RESULTS: The mean age of the participants was 34.7±9.8 years and 13 (34.2%) were men. K-HSS scores demonstrated a significant positive correlation with serum free thyroxine concentration and decreased significantly with improved thyroid function. K-HSS scores were highest in subclinically thyrotoxic subjects, lower in patients who were euthyroid after treatment, and lowest in the control group at follow-up, but these differences were not significant. Cronbach's α coefficient for the K-HSS was 0.86. CONCLUSION: The K-HSS is a reliable and valid instrument for evaluating symptoms of thyrotoxicosis in Korean patients.

Clinical Feasibility of Continuously Monitored Data for Heart Rate, Physical Activity, and Sleeping by Wearable Activity Trackers in Patients with Thyrotoxicosis: Protocol for a Prospective Longitudinal Observational Study.

BACKGROUND: Thyrotoxicosis is a common disease caused by an excess of thyroid hormones. The prevalence of thyrotoxicosis about 2% and 70-90% of thyrotoxicosis cases are caused by Graves' disease, an autoimmune disease, which has a high recurrence rate when treated with antithyroid drugs such as methimazole or propylthiouracil. The clinical symptoms and signs of thyrotoxicosis include palpitation, weight loss, restlessness, and difficulty sleeping. Although these clinical changes in thyrotoxicosis can be detected by currently available wearable activity trackers, there have been few trials of the clinical application of wearable devices in patients with thyrotoxicosis. OBJECTIVE: The aim of this study is to investigate the clinical applicability of wearable device-generated data to the management of thyrotoxicosis. We are analyzing continuously monitored data for heart rate, physical activity, and sleep in patients with thyrotoxicosis during their clinical course after treatment. METHODS: Thirty thyrotoxic patients and 10 control subjects were enrolled in this study at Seoul National University Bundang Hospital. Heart rate, physical activity, and sleep are being monitored using a Fitbit Charge HR or Fitbit Charge 2. Clinical data including anthropometric measures, thyroid function test, and hyperthyroidism symptom scale are recorded. RESULTS: Study enrollment began in December 2016, and the intervention and follow-up phases are ongoing. The results of the data analysis are expected to be available by September 2017. CONCLUSIONS: This study will provide a foundational feasibility trial of the clinical applications of biosignal measurements to the differential diagnosis, prediction of clinical course, early detection of recurrence, and treatment in patients with thyrotoxicosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03009357; https://clinicaltrials.gov/ct2/show/NCT03009357 (Archived by WebCite at http://www.webcitation.org/6wh4MWPm2).

Comparisons of TBS and lumbar spine BMD in the associations with vertebral fractures according to the T-scores: A cross-sectional observation.

Trabecular bone score (TBS) is a parameter of bone quality that has been shown to be related to vertebral fractures. This study aimed to analyze the difference in discriminatory power of TBS for vertebral fractures according to the bone mineral density (BMD) T-score. Areal BMD at the lumbar spine (LS, L1-L4), femur neck (FN) and total hip were assessed using dual x-ray absorptiometry (Discovery W, Hologic, Bedford, MA) in 929 women aged 50years or older. TBS was analyzed using iNsight software (Med-Imaps, Pessac, France). Vertebral fractures were identified on lateral X-ray films of the thoracic and lumbar spine using a semi-quantitative method. The study subjects consisted of 158 subjects (17.0%) with normal BMD, 461 (49.6%) with osteopenia and 310 (33.4%) with osteoporosis. The incident vertebral fractures were observed in 92 (9.9%) subjects, including 59 fractures in osteoporosis, 29 fractures in osteopenia, and only 4 fractures in normal BMD. We stratified study subjects into two groups according to their BMD T-scores, osteoporosis or osteopenia/normal BMD. The logistic regression model showed that LS BMD values per each 1 standard deviation (SD) decrease were significantly associated with increased risk of vertebral fracture in both osteoporosis and osteopenia/normal BMD group with stronger association in osteoporosis group. However, a TBS value that was lower by 1SD was significantly associated with vertebral fracture risk only in the osteopenia/normal BMD group. The TBS use in addition to FN BMD and age also showed significantly better discriminatory power for vertebral fracture only in the osteopenia/normal BMD group, but not osteoporosis group. In conclusion, TBS is significantly associated with vertebral fractures in subjects with osteopenia/normal BMD levels. Additional assessment of bone microarchitecture using TBS is better able to identify women at risk of fracture, in particular, those with relatively higher BMD.

Association of angiotensin-II levels with albuminuria in subjects with normal glucose metabolism, prediabetes, and type 2 diabetes mellitus.

OBJECTIVES: The relationship between the renin-angiotensin system (RAS) and diabetes has been studied for many years. However, studies that assessed RAS components comprehensively were limited. We hypothesized that serum RAS components, especially the effector peptide angiotensin-II, might be closely associated with glucose metabolism status and diabetic complications. METHODS: We investigated the association of individual RAS component with albuminuria in 407 subjects with normal glucose metabolism (NGM), prediabetes, or type 2 diabetes mellitus (T2DM). Anthropometric and biochemical parameters, including glucose homeostasis, albuminuria, and RAS-related parameters such as plasma renin activity (PRA), aldosterone, angiotensin-converting enzyme (ACE), and angiotensin-II levels, were measured. RESULTS: The mean±standard deviation (SD) age and body mass index were 57.1±11.1years and 24.7±3.3kg/m2, respectively. There were 54 subjects with NGM, 102 with prediabetes, and 251 with T2DM. The mean±SD angiotensin-II levels in these groups were 9.32±6.89, 12.89±10.39, and 17.00±15.28pg/mL, and the respective urinary albumin-to-creatinine ratios (ACRs) were 8.1±5.3, 13.3±17.3, and 30.7±51.9mg/g, which were significantly different among the groups. The serum angiotensin-II levels were correlated with levels of PRA, insulin resistance, C-reactive protein, and urinary ACR. Among RAS-related parameters, only the angiotensin-II level was significantly associated with urinary ACR after adjusting for relevant risk factors. CONCLUSIONS: Angiotensin-II may play an important role in the development of albuminuria, particularly in subjects with impaired glucose metabolism.

Erratum: Correction of Figure. Clinical Implications of Various Criteria for the Biochemical Diagnosis of Insulinoma.

This corrects the article on p. 498 in vol. 29, PMID: 25325272.

Effect of sarpogrelate, a selective 5-HT2A receptor antagonist, on characteristics of coronary artery disease in patients with type 2 diabetes.

BACKGROUND AND AIMS: Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is a potential antiplatelet agent. We performed a randomized study to evaluate the effect of sarpogrelate on vascular health in Korean patients with diabetes. METHODS: Forty diabetic patients aged 58.6 ± 6.8 years with 10-75% coronary artery stenosis, as assessed by coronary computed tomography angiography, were randomly assigned to sarpogrelate 300 mg/day plus aspirin 100 mg/day (SPG + ASA group) or aspirin 100 mg/day alone (ASA group) for 6 months. The primary endpoint of this study was the change in coronary artery disease including the calcium score (CACS), maximal stenosis, and plaque volume (calcified vs. noncalcified). The secondary endpoints were changes in biochemical parameters related to glucose and lipid metabolism, and in subclinical atherosclerosis assessed by ankle-brachial index and pulse wave velocity. RESULTS: After 6-month treatment, there was no significant difference in the changes in CACS, coronary stenosis, ankle-brachial index, and pulse wave velocity, between groups. The total plaque volume decreased from 82.4 ± 14.5 mm3 to 74.6 ± 14.4 mm3 in the SPG + ASA group, but increased from 64.9 ± 16.0 mm3 to 68.6 ± 16.3 mm3 in the ASA group (p < 0.05), mainly driven by changes in the noncalcified component (SPG + ASA group 15.6 ± 4.6 mm3 to 11.2 ± 3.7 mm3vs. ASA group 21.2 ± 6.2 mm3 to 22.8 ± 6.6 mm3, p < 0.01). Serum C-reactive protein levels and homeostasis model assessment of insulin resistance tended to decrease in the SPG + ASA group, but they were not altered in the ASA group. CONCLUSIONS: The present study demonstrated that sarpogrelate treatment may decrease coronary artery plaque volume, particularly the noncalcified portion, in patients with diabetes.

Comprehensive assessment of lipoprotein subfraction profiles according to glucose metabolism status, and association with insulin resistance in subjects with early-stage impaired glucose metabolism.

BACKGROUND: Early detection of atherogenic dyslipidemia is crucial. We investigated lipoprotein subfraction parameters according to glucose metabolism status. METHODS: We recruited 1255 lipid-lowering drug-naïve subjects with normal fasting glucose (NFG; n=200, 15.9%), impaired fasting glucose (IFG; n=443, 35.3%), or type 2 diabetes (T2D; n=612, 48.8%). Lipoprotein subfractions (1-7) were determined by polyacrylamide gel electrophoresis, separating low-density lipoprotein (LDL) into large buoyant LDL (lbLDL, LDL1-2) and small dense LDL (sdLDL, LDL3-7). Lipoprotein subfraction parameters including the sdLDL% (LDL3-7/LDL1-7), the sdLDL/lbLDL ratio (LDL3-7/LDL1-2), and weighted LDL subfraction (LDLSF) scores, were compared between groups. Their associations with insulin resistance, estimated using the homeostasis model assessment of insulin resistance, were examined. RESULTS: The concentrations of sdLDL particles were significantly higher in subjects with T2D and IFG than in those with NFG (15.78±13.47mg/dl and 14.60±14.33mg/dl, respectively, vs. 12.22±12.31mg/dl). Compared with those with NFG, subjects with IFG or T2D had significantly a higher sdLDL% (15.98±15.26% vs. 19.50±16.21% or 21.46±16.81%, respectively), a higher sdLDL/lbLDL ratio (0.24±0.30 vs. 0.31±0.37 or 0.35±0.39), and a higher LDLSF score (2.08±0.91 vs. 2.30±1.14 or 2.36±1.17). These lipoprotein subfraction parameters had stronger associations with insulin resistance compared to conventional lipid profiles in the IFG and T2D groups. CONCLUSIONS: Atherogenic dyslipidemia is initiated in an early stage of impaired glucose metabolism, when early intervention might be required.

Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis.

OBJECTIVE: The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is a key factor in adipogenesis, insulin sensitivity, and cell cycle regulation. Activated PPARγ might also have anti-inflammatory and antiatherogenic properties. We tested whether lobeglitazone, a new PPARγ agonist, might protect against atherosclerosis. METHODS: A rat model of balloon injury to the carotid artery, and high-fat, high-cholesterol diet-fed apolipoprotein E gene knockout (ApoE(-/-)) mice were studied. RESULTS: After the balloon injury, lobeglitazone treatment (0.3 and 0.9 mg/kg) caused a significant decrease in the intima-media ratio compared with control rats (2.2 ± 0.9, 1.8 ± 0.8, vs. 3.3 ± 1.2, P < 0.01). Consistent with this, in ApoE(-/-) mice fed a high-fat diet, lobeglitazone treatment (1, 3, and 10 mg/kg) for 8 weeks reduced atherosclerotic lesion sizes in the aorta compared with the control mice in a dose-dependent manner. Treatment of vascular smooth muscle cells with lobeglitazone inhibited proliferation and migration and blocked the cell cycle G0/G1 to S phase progression dose-dependently. In response to lobeglitazone, tumor necrosis factor alpha (TNFα)-induced monocyte-endothelial cell adhesion was decreased by downregulating the levels of adhesion molecules. TNFα-induced nuclear factor kappa-B (NF-κB) p65 translocation into the nucleus was also blocked in endothelial cells. Insulin resistance was decreased by lobeglitazone treatment. Circulating levels of high sensitivity C-reactive protein and monocyte chemoattractant protein-1 were decreased while adiponectin levels were increased by lobeglitazone in the high-fat diet-fed ApoE(-/-) mice. CONCLUSION: Lobeglitazone has antiatherosclerotic properties and has potential for treating patients with diabetes and cardiovascular risk.

Clinical implications of various criteria for the biochemical diagnosis of insulinoma.

BACKGROUND: Among the various diagnostic criteria for insulinoma, the ratio criteria have been controversial. However, the amended insulin-glucose ratio exhibited excellent diagnostic performance in a recent retrospective cohort study, although it has not yet been validated in other patient cohorts. We examined the diagnostic performance of the current criteria of the Endocrine Society, insulin-glucose ratio, C-peptide-glucose ratio, and amended ratios in terms of differentiating insulinomas. METHODS: We reviewed the medical records of patients who underwent evaluation for hypoglycemia from 2000 to 2013. Fourteen patients with histopathologically confirmed insulinoma and 18 patients without clinical evidence of insulinoma were included. The results of a prolonged fast test were analyzed according to the abovementioned criteria. RESULTS: Fulfilling all three Endocrine Society criteria-plasma levels of glucose (<3.0 mmol/L), insulin (≥8 pmol/L), and C-peptide (≥0.2 nmol/L)-exhibited 100% sensitivity and 89% specificity. Fulfilling the glucose and C-peptide criteria showed 100% sensitivity and 83% specificity, while fulfilling the glucose and insulin criteria showed 100% sensitivity and 72% specificity. Among the ratio criteria, the insulin-glucose ratio [>24.0 (pmol/L)/(mmol/L)] gave the highest area under the receiver operating characteristic curve, with 93% sensitivity and 94% specificity. CONCLUSION: Fulfilling the glucose, insulin, and C-peptide criteria of the Endocrine Society guidelines exhibited the best diagnostic performance for insulinoma. Nonetheless, the insulin-glucose ratio may still have a role in the biochemical diagnosis of insulinoma.

A novel mutation in the von hippel-lindau tumor suppressor gene identified in a patient presenting with gestational diabetes mellitus.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited, multisystemic tumor syndrome caused by mutations in the VHL gene. To date, more than 1,000 germline and somatic mutations of the VHL gene have been reported. We present a novel mutation in the VHL tumor suppressor gene that presented with gestational diabetes mellitus. METHODS: A 30-year-old woman presented with gestational diabetes mellitus. She sequentially showed multiple pancreatic cysts, spinal cord hemangioblastoma, cerebellar hemangioblastoma, and clear cell type renal cell carcinomas. Also, her father and brother had brain hemangioblastomas. Each of the three exons of the VHL gene was individually amplified by polymerase chain reaction and direct sequencing was performed using an ABI 3730 DNA analyzer. RESULTS: DNA sequence analysis to determine the presence of VHL mutation in her family revealed del291C, a novel frameshift mutation. CONCLUSION: We found a novel mutation in the VHL tumor suppressor gene that presented with gestational diabetes mellitus.

KST5468, a new T-type calcium channel antagonist, has an antinociceptive effect on inflammatory and neuropathic pain models.

The T-type Ca(2+) channel is a low-voltage-activated Ca(2+) channel related to nociceptive stimuli. Increases in Ca(2+) due to calcium channel activation enhance pain sensitivity through both peripheral and central pain pathways. We have developed a novel compound, KST5468, which is a T-type calcium channel antagonist. The new synthetic compound may have an antinociceptive effect, and thus we evaluated KST5468 as a putative analgesic in a hot plate test, a formalin test, and two neuropathic pain models. KST5468 caused a significant increase in latency in the hot plate test at 30min after a 10mg/kg peritoneal injection of the compound. Interestingly, in the second phase of formalin test, KST5468 decreased pain behaviors in a dose-dependent manner. Moreover, in two neuropathic pain models induced by chronic constriction and spared nerve injury, KST5468 significantly increased the mechanical pain threshold. Using immunohistochemistry, expression of two well known pain-related molecular markers, c-Fos and calcitonin gene-related peptide (CGRP), and phosphorylated extracellular signal-related kinase (p-ERK) were found to be decreased in the laminae I-II layers of the ipsilateral L4-L5 spinal dorsal horn in KST5468 treated mice. Taken together, the results of this study suggest that KST5468 may be an effective antinociceptive agent for neuropathic pain.

Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers.

T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.