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The objective of the study was to investigate the effects of rosiglitazone (RSG), a thiazolidinedione derivative, on body fat distribution and insulin sensitivity in Korean subjects with type 2 diabetes mellitus. This study was a phase IV, multicenter, single-blind, positive-controlled parallel group study. Eighty-nine patients with type 2 diabetes mellitus, aged 30 to 75 years, were enrolled in this study. Their fasting plasma glucose levels ranged from 126 to 270 mg/dL, and subjects had hemoglobin A1c levels of greater than 7.0%. We compared the effect of the treatment with glibenclamide plus RSG 4 mg/d (increased to 8 mg/d after 6 months) with glibenclamide plus placebo on body fat distributions, which were determined by computed tomography scanning and glycemic and insulinemic responses to oral glucose load. During the 12-month treatment period, the difference between the changes in the ratio of the intraabdominal adipose tissue (IAAT) to abdominal subcutaneous adipose tissue areas (SAT) between treatment groups was significant (from 1.13 +/- 0.53 to 1.00 +/- 0.40 in the RSG group and from 0.92 +/- 0.54 to 0.96 +/- 0.62 in the placebo group, P = .0351). The glycemic responses to oral glucose load (area under the curve, millimoles per liter per hour) were improved in the RSG group with 12 months of treatment (from 4.88 +/- 1.10 to 4.38 +/- 1.35 in 1 hour and from 13.78 +/- 2.83 to 12.16 +/- 2.52 in 2 hours), and the difference between the changes of the glycemic response showed statistical significance between groups (RSG group vs placebo group: -0.53 +/- 1.42 vs 0.38 +/- 1.31, difference in 1 hour; -0.76 +/- 2.98 vs 1.43 +/- 2.58, difference in 2 hours). However, there was no difference between insulin responses from baseline to follow-up and no differences in the change in insulin response between groups. In Korean subjects with type 2 diabetes mellitus, 12 months of treatment with RSG may increase SAT, but may have a neutral effect on IAAT, resulting in a decrease in the IAAT:SAT ratio. The RSG treatment improved the glucose control in type 2 diabetes mellitus. However, it is important to determine whether the glucose-lowering effect of RSG occurs mainly through direct enhancement of insulin sensitivity.

Although many studies have reported an association between total white blood cell count and metabolic syndrome, relatively few reports are available on the association between differential white blood cell counts and metabolic syndrome. The medical records of 15,654 subjects (age, median 46, range 14-90 yr; 8,380 men and 7,274 women) who visited the Center for Health Promotion were investigated. It was found that as total white blood cell (WBC) and differential WBC counts increased the frequencies of diabetes, hypertension, obesity, dyslipidemia, and metabolic syndrome also increased. Moreover, these significant relationships persisted after adjusting for age, gender, smoking, alcohol intake, educational background, and household income. The odds ratios (95% CI) for metabolic syndrome was 2.64 (2.30- 3.04) in the highest quartile of total WBC count, with corresponding figures of 2.14 (1.88-2.44) for neutrophils, 2.32 (2.03-2.64) for lymphocytes, 1.56 (1.37-1.78) for monocytes, 1.36 (1.20-1.54) for basophils, and 1.82 (1.59-2.08) for eosinophils versus the lowest quartiles of the appropriate total and differential counts, respectively, after adjusting for the variables mentioned above. These independent associations were also observed by subgroup analyses according to the smoking status. Our data suggest that even within normal ranges, total WBC count and the differential WBC counts are associated with the presence of metabolic syndrome.

The genes coding for two PII-like proteins, GlnB and GlnK, which play key roles in repressing the nitrogenase expression in the presence of ammonium ion, were interrupted from the chromosome of Rhodobacter sphaeroides. The glnB–glnK mutant exhibits the less ammonium ion-mediated repression for nitrogenase compared with its parental strain, which results in more H2 accumulation by the mutant under the conditions. Rhodospirillum rubrum produces H2 by both nitrogenase and hydrogenase. R. rubrum containing the recombinant pRK415 with an insert of hydC coding for its own Fe-only hydrogenase showed twofold higher accumulation of H2 in the presence of pyruvate under photoheterotrophic conditions, which was not observed in the absence of pyruvate. The same was true with R. rubrum containing the recombinant pRK415 cloned with hydA coding for Fe-only hydrogenase of Clostridium acetobutylicum. Thus, Fe-only hydrogenase requires pyruvate as an electron donor for the production of H2.

Delayed heart rate recovery (HRR) following exercise testing, an indicator of decreased autonomic nervous system activity, is associated with an increased risk of cardiovascular events. Because autonomic nervous system function may be associated with fibrinolytic factors, we tested the hypothesis that delayed HRR is associated with elevated fibrinolytic factors.In 547 (mean age 49.4+/-6.9 years) healthy men who underwent exercise treadmill testing and fasting blood analysis for fibrinolytic factors, we calculated HRR as the difference between maximum heart rate during the test and heart rate 1 min after cessation of exercise.HRR was inversely correlated with plasminogen activator inhibitor 1 (PAI-1) activity (r=-0.23, p0.001), tissue plasminogen activator (t-PA) antigen (r=-0.19, p0.001), and fibrinogen (r=-0.11, p0.05). Men in the lowest quartile of HRR had significantly higher PAI-1, t-PA, and fibrinogen than men in the highest quartile of HRR (all p trend0.001). HRR was independently associated with PAI-1 (beta=-0.12, p0.01) and fibrinogen (beta=-0.09, p=0.04) but not t-PA (beta=-0.06, p=0.29) in a multiple regression analysis.These results suggest that delayed HRR after exercise testing is associated with elevated fibrinolytic factors in cross-section. The presence of other CHD risk factors does not explain this association, but further research is needed to identify the direction of the association.

Computer based three-dimensional (3D) reconstruction technique is widely used in clinical practices and its accuracy is still improving due to introducing of high resolution imaging modalities. Practically, two-dimensional X-ray image might be considered as one of major tools in orthopaedics, due to its lower cost and lower dose of radiation than computer tomography (CT).The purpose of the current study is generating 3D model of femoral bone using conventional X-ray images incorporating the anatomical parameters into a referential 3D model. For the 3D reconstruction, the 2D shape and specific parameters of bone were firstly measured from X-ray images. Then, the referential CT model was modified as follows: the axial scaling, shearing transformation and radial scaling. In this study, the 3D reconstruction algorithm was tested using femoral X-ray images from the 28 years old male.The current study showed that the 3D reconstruction technique by using X-ray images can be useful and feasible in clinical practices. It could easily generate 3D femoral model not only with saving time and costs, but also less radiation exposure to the patients.

Slow heart rate recovery (HRR) after exercise is an estimate of impaired parasympathetic tone and predictor of all-cause and cardiovascular mortality. Carotid atherosclerosis is associated with high risk of developing coronary heart disease (CHD) and stroke. We tested the hypothesis that slow HRR is associated with carotid atherosclerosis in a cross-sectional study of 12,712 middle-aged men (age 49.1+/-8.9 years).Carotid atherosclerosis was measured using B-mode ultrasonography and defined as stenosis25% and/or intima-media thickness1.2mm. HRR was calculated as the difference between peak heart rate during a graded exercise treadmill test and heart rate 2 min after cessation of exercise.The prevalence of carotid atherosclerosis was 8.4%. The prevalence of atherosclerosis was significantly higher among subjects in the lowest (44 bpm) versus the highest (61 bpm) quartile of HRR (14.4% versus 4.1%, p0.001). In multivariable logistic regression models adjusted for established CHD risk factors, inflammatory markers, and exercise capacity, subjects in the lowest quartile of HRR (44 bpm) were 1.50 times (95% CI: 1.13-2.00) more likely to have carotid atherosclerosis than subjects in the highest quartile (HRR61 bpm).Slow heart rate recovery after exercise, an index of decreased parasympathetic activity, is associated with carotid atherosclerosis independent of established risk factors in middle-age men.

Advertisement signboards on the buildings have functionally a visual value as factor of urban and building design. But it is not easy to find any reasonable principles and regulations, how well the signboards deliver the information of stores to the customers, and how they contribute the visual amenity from the sight of urban landscape. Under this context, this study tries to analyze the information delivery power of signboards in relation to the visual cognition. The analysis method is the Two-Way ANOVA (Analysis of Variance) evaluation with factors, such as scale, amount and arrangement of signboards. The scale of letters or figures at Signboards is specified in 3 different sizes such as big, medium and small. The amount is classified into 5 grades from 100% to 20% installation. And the arrangement is divided into orderly and disorderly installation. As the results of the Two-Way ANOVA, the identical scale of signboards is much better for the awareness. And the orderly arrangement shows also the same result. Above all, including these two results, the 80% of installation showed the biggest different result of awareness.

OBJECTIVE—We have reported important roles for signal transducer and activator of transcription-1 (STAT1) in pancreatic β-cell death by cytokines in vitro. However, in vivo evidence supporting the role for STAT1 in natural type 1 diabetes has not been reported. We studied whether STAT1 plays an important role in the development of natural type 1 diabetes.RESEARCH DESIGN AND METHODS—We produced nonobese diabetic (NOD)/STAT1−/− mice by backcrossing and studied the in vivo role of STAT1 in β-cell death and type 1 diabetes.RESULTS— STAT1 −/− islet cells were resistant to death by interferon (IFN)-γ/tumor necrosis factor (TNF)-α or IFN-γ/interleukin (IL)-1β combination. Cytochrome c translocation by IFN-γ/TNF-α was abrogated in STAT1−/− islet cells. The induction of X-linked inhibitor of apoptosis protein by TNF-α was inhibited by IFN-γ in STAT1+/− islet cells but not in STAT1−/− islet cells. Inducible nitric oxide (NO) synthase induction and NO production by IFN-γ/IL-1β were impaired in STAT1−/− islet cells. Strikingly, diabetes and insulitis were completely abrogated in NOD/STAT1−/− mice. Development of diabetes after CD4+ diabetogenic T-cell transfer was inhibited in those mice. STAT1−/− neonatal pancreata were not destroyed when grafted into diabetic NOD/BDC2.5 mice that developed CD4+ T-cell–dependent islet cell death. In NOD/STAT1−/− mice, autoreactive T-cell priming was not impaired, but Th1 differentiation was impaired. A janus kinase (JAK) 2 inhibitor upstream of STAT1 attenuated islet cell death by IFN-γ/TNF-α or IFN-γ/IL-1β and delayed diabetes onset in NOD/BDC2.5-SCID mice.CONCLUSIONS—These data demonstrate a critical role for STAT1 in β-cell death, T-cell immunoregulation, and type 1 diabetes in vivo and suggest potential therapeutic values of STAT1 or JAK inhibitors in the treatment/prevention of type 1 diabetes.

Background: Several studies have shown that metabolic syndrome contributed to the development of incident chronic kidney disease in the general population. We evaluated the cross-sectional association between metabolic syndrome and microalbuminuria in patients with type 2 diabetes. We excluded patients with hypertension to distinguish the effects of metabolic syndrome from those of hypertension. Methods: A total of 642 non-hypertensive patients with type 2 diabetes were recruited. Metabolic syndrome was assessed according to the NCEP Guidelines and Asian-Pacific criteria for abdominal obesity. Results: Among all patients, 37.2% were diagnosed as having metabolic syndrome, and these patients had a higher prevalence of microalbuminuria than those without metabolic syndrome (19.7 vs. 13.6%, p = 0.044). There was a graded association between metabolic score and the prevalence of microalbuminuria (p = 0.006 for trend). After adjustment for sex, age, smoking status, C-reactive protein, and HbA1c, patients with metabolic syndrome had increased odds of 1.58 (95% CI 1.01–2.47) for microalbuminuria. An increment in metabolic score was found to increase the risk of microalbuminuria by 1.34-fold (95% CI 1.07–1.66, p = 0.008). Conclusion: This study demonstrated that metabolic syndrome was associated with an increased risk of microalbuminuria in non-hypertensive patients with type 2 diabetes.

The indentation test has been in the spotlight due to easy and non-destructive testing characteristics. However, there are little studies for the indentation test of porous materials in the evaluation aspect of methodology. The goal of this study was to evaluate a spherical indentation test in the aspect of indenter-size and indentation depth by measuring elastic modulus of porous materials such as a cancellous bone using a FEM. We developed a microstructure-based FE model of cancellous bone with apparent density 0.2~0.8 g/cm3 in order to simulate uniaxial compression test and indentation test in the light of anatomical observation with a scanning electron microscope (SEM). We obtained a load-displacement curve through the indentation simulation and calculated the Young’s modulus of cancellous structure based on Pharr's hypothesis. The result indicated that indenter diameter has to be more than five times of pore size and indentation depth should be about 8% of indenter diameter at least to obtain the appropriate result of the indentation test. It is expected that this result may guide to the design and the simulation of indentation test for porous materials

In the area of biomaterials, the structures with negative Poisson’s ratio are able to be applied to the polymer component of prosthesis, artificial blood-vessel and catheter. To induce its characteristic, previous studies postulated many structural shapes such as non-convex shape with reentrant corners and re-entrant honeycomb. In this study, we proposed the rotational particle structures and investigated the Poisson’s ratio and the ratio (Ee/E) of the elastic modulus of these structures based on structural design variables using finite element method. The auto-meshing preprocessor was coded using MATLAB in order to construct numerical models as design variables and perform finite element analysis (FEA) effectively. Three selected design variables were the ratio of fibril’s length to particle’s diameter (0.2~2.0), the ratio of fibril’s length to its width (0.02~0.2) and the angle of fibril about horizontal axis (0 degree ~ tangential angle). Finite element model has 2D plain stress quadratic element and composed of 515 particles and 6-linked fibrils per each particle. For all of 213 cases, one side of each model is applied a tension, 0.1% strain and analyze Poisson’s ratio and the ratio (Ee/E) of the elastic modulus. As the ratio of fibril’s length to particle’s diameter increased and the ratio of fibril’s diameter to fibril’s length decreased fixing the fibril’s angle with 45 degree, the negative Poisson effect of rotational particle structures increased. The ratio of elastic modulus of these structures decreased with Poisson’s ratio. The results show the reasonable values as compared with the previous analytical results.

The shortage of islets for transplantation has led to find alternative insulin producing cells. Pancreatic progenitor cells in the duct have the potential to grow and differentiate into endocrine cells. In this study, we examined whether activin A can promote the expansion and/or differentiation of ductal cells into insulin-producing cells.Pancreatic ductal cells were treated with activin A for differentiation into endocrine cells, and transplanted into the renal subcapsular space of streptozotocin (STZ)-induced diabetic rats. The identity of the endocrine cells was confirmed by immunostaining and analysis of the expression of transcription factors and endocrine genes by reverse-transcriptase polymerase chain reaction.Activin A treatment significantly increased the DNA synthesis and the expression of insulin I, insulin II, PDX-1, Nkx 6.1, Glut-2, Pax-4, Pax-6, and Ngn-3. De novo synthesis of insulin in activin A-treated ductal cells was observed by the immunocytochemical detection of C-peptide and the differentiated ductal cells secreted significantly increased amount of insulin compared to nontreated ductal cells in response to glucose stimulation. When activin A-treated ductal cells were transplanted on STZ-induced diabetic rats, blood glucose levels were normalized and the removal of the transplanted kidney resulted in return to hyperglycemia.The pancreatic ductal cells could be efficiently differentiated into insulin secreting cells by activin A treatment in vitro and normalize hyperglycemia in vivo.

In modelling automated storage/retrieval systems, the assumption of random storage has been widely used to approximate the activity of the closest open location rule. Considering that the closest open location rule is so popular in practice, it is significant to validate the assumption, or identify under what conditions the assumption could be justified. In this study we show how the “true” activity distribution of the closest open location rule can be approximated by a “modified” uniform distribution. The modified distribution is then used to approximate the expected travel distance, which is simple to use yet accurate enough for practical purposes. We also show that the uniform approximation is valid even for different streams of demand and batch arrivals.

The plasma ghrelin has been reported to be elevated in Prader-Willi syndrome (PWS) and modulated by insulin. It was hypothesized that insulin might have a more pronounced effect on reducing plasma ghrelin in PWS patients, which would influence appetite. This study investigated the degree of ghrelin suppression using an euglycemic hyperinsulinemic clamp in children with PWS (n=6) and normal children (n=6). After a 90-min infusion of insulin, the plasma ghrelin level decreased from a basal value of 0.86+/-0.15 to 0.58+/-0.12 ng/mL in the controls, and from 2.38+/-0.76 to 1.12+/-0.29 ng/mL in children with PWS (p=0.011). The area under the curve below the baseline level over the 90 min insulin infusion was larger in children with PWS than in controls (-92.82+/-44.4 vs. -10.41+/-2.87 ng/mL/90 min) (p=0.011). The insulin sensitivity measured as the glucose infusion rate at steady state was similar in the two groups (p=0.088). The decrease in the ghrelin levels in response to insulin was more pronounced in the children with PWS than in the controls. However, the level of ghrelin was always higher in the children with PWS during the clamp study. This suggests that even though insulin sensitivity to ghrelin is well maintained, an increase in the baseline ghrelin levels is characteristic of PWS.

This study was conducted to test the hypothesis that slow and abnormal heart rate recovery (HRR), an indicator of decreased autonomic nervous system activity, after exercise is associated with inflammatory markers. Subjects who underwent exercise treadmill testing (n = 5,527, mean age 50.4 +/- 8.5 years) were studied in a cross-sectional design. HRR was calculated as the difference between maximum heart rate during the test and heart rate 1 minute after the cessation of exercise. Abnormal HRR was defined asor =12 beats/min. Subjects with abnormal HRR had higher levels of log C-reactive protein (CRP; 1.38 +/- 0.6 vs 1.11 +/- 0.4 mg/dl, p0.001) and higher white blood cell counts (6.9 +/- 2.1 vs 6.2 +/- 1.7 x 10(9) cells/L, p0.001) than those with normal HRR. HRR was associated with CRP (r = -0.21, p0.001) and white blood cell count (r = -0.19, p0.001). HRR was independently associated with CRP (beta = -0.13, p = 0.001) in a stepwise multiple regression. In a logistic multivariate model, the group within the highest quartile of CRP (odds ratio 1.54, 95% confidence interval 1.05 to 2.27) was more likely to have abnormal HRR than those within the lowest quartile. In conclusion, slow and abnormal HRR after exercise testing is associated with inflammatory markers, which could contribute to the high incidence of cardiovascular disease in these subjects.

A 42-year old woman presented with headache, palpitation and facial flushing. Ultrasonograms and computed tomograms revealed tumors in both of the adrenal glands, anterior aspect of the inferior vena cava, and the right lobe of the thyroid gland. Fine needle aspiration biopsy of the thyroid nodule revealed papillary thyroid carcinoma. Serum calcitonin, CEA, intact PTH and calcium levels were within normal limits. Markedly elevated levels of urinary normetanephrine and vanillylmandelic acid, and the result of 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy indicated that both adrenal masses were pheochromocytoma. Bilateral adrenalectomy, paracaval mass removal and total thyroidectomy together with central lymph node dissection were performed. The final pathological diagnosis was bilateral adrenal pheochromocytoma, paraganglioma, papillary thyroid carcinoma and either parathyroid adenoma or hyperplasia. Analysis of the RET proto-oncogene mutation, von Hippel Lindau mutation, succinate dehydrogenase subunit B mutation, and succinate dehydrogenase subunit D mutation yielded negative results. The relationship of these lesions could not be determined. This is the first report of a combination of bilateral pheochromocytoma, abdominal paraganglioma, papillary thyroid carcinoma and either parathyroid adenoma or hyperplasia without hyperparathyroidism.

Upstream stimulatory factor (USF) has a negative effect on the cell proliferation in some cell types. However, its effect on thyrocytes is not clear. Therefore, we investigated the effects of USF on the proliferation and function of thyroid follicular cells. Complementary DNAs of the USF-1 and USF-2 were synthesized using RT-PCR from FRTL-5 cells, and each was transfected to FRTL-5 cells and papillary thyroid carcinoma cell lines. Cyclic AMP (cAMP) production and [methyl-3H] thymidine uptake after thyroid stimulating hormone (TSH) treatment were measured in FRTL-5 cells. In the carcinoma cell lines, 5-bromo-2'-deoxyuridine (BrdU) uptake was assayed to evaluate cell proliferation. Apoptosis was tested by Hoechst staining and cell cycle analysis was done using a fluorescence activated cell sorting. Expression of cell cycle regulating genes was evaluated by Northern and Western blotting. Overexpression of USF-1 and USF-2 significantly suppressed TSH-stimulated [methyl-3H] thymidine uptake (p

In our previous study, the neuroprotective effect of calcitriol was confirmed in SH-SY5Y cells. In this article, we explored whether calcitriol showed neuroprotection in a subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease. After mice were treated with MPTP alone or cotreated with MPTP and calcitriol, the substantia nigra pars compacta was dissected, and related protein levels were detected by western blot. Our results suggest that the MPTP-injected mice treated with calcitriol had attenuated tyrosine hydroxylase expression and increased LC3-II conversion compared with those that were not. Above all, calcitriol showed neuroprotection in the MPTP mouse model.

Dysphagia is an important issue in the prognosis of Parkinson’s disease (PD). Although several studies have reported that oropharyngeal dysphagia may be associated with cognitive dysfunction, the exact relationship between cortical function and swallowing function in PD patients is unclear. Therefore, we investigated the association between an electrophysiological marker of central cholinergic function, which reflected cognitive function, and swallowing function, as measured by videofluoroscopic studies (VFSS). We enrolled 29 early PD patients. Using the Swallowing Disturbance Questionnaire (SDQ), we divided the enrolled patients into two groups: PD with dysphagia and PD without dysphagia. The videofluoroscopic dysphagia scale (VDS) was applied to explore the nature of the dysphagia. To assess central cholinergic dysfunction, short latency afferent inhibition (SAI) was evaluated. We analyzed the relationship between central cholinergic dysfunction and oropharyngeal dysphagia and investigated the characteristics of the dysphagia. The SAI values were significantly different between the two groups. The comparison of each VFSS component between the PD with dysphagia group and the PD without dysphagia group showed statistical significance for most of the oral phase components and for a single pharyngeal phase component. The total score on the VDS was higher in the PD with dysphagia group than in the PD without dysphagia group. The Mini-Mental State Examination and SAI values showed significant correlations with the total score of the oral phase components. According to binary logistic regression analysis, SAI value independently contributed to the presence of dysphagia in PD patients. Our findings suggest that cholinergic dysfunction is associated with dysphagia in early PD and that an abnormal SAI value is a good biomarker for predicting the risk of dysphagia in PD patients.

Background It is presently unclear whether glycemic variability is associated with diabetic cardiovascular autonomic neuropathy (CAN). The aim of this study was to examine whether short- and/or long-term glycemic variability (GV) contribute to CAN. Methods A total of 110 patients with type 2 diabetes who underwent three-day continuous glucose monitoring (CGM) completed five standardized autonomic neuropathy tests. Short-term GV was measured by the standard deviation (SD), coefficient of variation (CV) of glucose, and the mean amplitude of glycemic excursions (MAGE) in CGM. HbA1c variability was calculated from the intrapersonal SD, adjusted SD, and CV of serial HbA1c over 2-year period. CAN was defined as the presence of at least two abnormal parasympathetic function tests. The severity of CAN was evaluated by total scores of five autonomic function tests. Results In univariate analysis, not only SD and CV in CGM but also all parameters of HbA1c variability were significantly higher in the patients with CAN (n = 47, 42.7 %) than in those without CAN. In multivariate analysis, CV (Odds ratio [OR] 1.07, 95 % confidence interval [CI] 1.01–1.13; p = 0.033), but neither SD nor MAGE in CGM, independently correlated with the presence of CAN. All parameters of HbA1c variability, such as SD of HbA1c (OR 12.10 [95 % CI 2.29–63.94], p = 0.003), adjusted SD of HbA1c (OR 17.02 [95 % CI 2.66–108.86], p = 0.003), and log CV of HbA1c (OR 24.00 [95 % CI 3.09–186.48], p = 0.002), were significantly associated with the presence of CAN. The patients with higher HbA1c variability had an increased risk of advanced CAN. Conclusion CV in CGM and all parameters of HbA1c variability were independently associated with the presence of CAN in patients with inadequately controlled type 2 diabetes requiring CGM. Electronic supplementary material The online version of this article (doi:10.1186/s12933-015-0233-0) contains supplementary material, which is available to authorized users.

The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naive patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

This paper deals with the problem of generating 2D cutting paths for a stock plate nested with a set of regular and/or irregular parts. The objective of the problem is to minimize the total non-productive traveling distance of a cutter starting from a known depot, then cutting all the given parts, and returning back to the depot. A cutting path consists of the depot and piercing points, each of which is to be specified for cutting a part. The cutting path optimization problem is shown to be formulated as a generalized version of the standard traveling salesman problem. To solve the problem, a two-step genetic algorithm combining global search for piercing point optimization and local search for part sequencing is proposed. Traditional genetic operators developed for continuous optimization problems are modified to effectively deal with the continuous nature of piercing-point positions. A series of computational results are provided to illustrate the validity of the proposed algorithm.

The cause of continued suppression of serum thyroid-stimulating hormone (TSH) levels during antithyroid drug therapy in some Graves' patients is unclear. Recently, there has been a notable explanation involving the direct inhibition of TSH receptor antibody (TRAb) on TSH secretion in the pituitary gland. The purpose of this study is to verify the relation between TRAb or other clinical parameters and the continued suppression of serum TSH level during antithyroid drug therapy in patients with Graves' disease. We reviewed the medical records of patients with Graves' disease between 1995 and 2002 at Samsung Medical Center. We selected 167 Graves' patients who had been euthyroid for at least 12 months after recovery of serum T3 and T4 levels during the antithyroid drug therapy. We analyzed the correlation of the interval until recovery of serum TSH with the pretreatment clinical parameters. We compared the recovery rates of suppressed TSH levels between pretreatment thyrotrophin-binding inhibitory immunoglobulin (TBII)-positive (>15%) and TBII-negative patients. We also compared the clinical parameters between two groups at the time of diagnosis and after recovery of thyroid hormone. Pretreatment serum T3 level, (131)I uptake, TBII activity, and the time to recovery of T3 or T4/free T4 level showed significant positive correlations with the interval until recovery of serum TSH level ( p < 0.05). Recovery rates of serum TSH levels at 3 months after recovery of thyroid hormone were significantly lower in pretreatment TBII-positive patients than those in TBII-negative patients ( p < 0.01). Serum TSH levels were significantly lower in TBII-positive patients at 3 months after recovery of thyroid hormone ( p < 0.05). TBII activities inversely correlated only with serum TSH levels at 3months after recovery of thyroid hormone ( p < 0.001). In conclusion, continued suppression of serum TSH level may be attributed to TRAb activity as well as the pretreatment severity of thyrotoxicosis and the time to recovery of thyroid hormone in patients with Graves' disease during antithyroid drug therapy.

An exaggerated blood pressure (EBP) response to exercise has been shown to be a predictor of future hypertension and risk of cardiovascular mortality. Although EBP is associated with endothelial dysfunction and increased left ventricular hypertrophy, the underlying mechanisms are not fully understood. Inflammatory markers, C-reactive protein (CRP) and white blood cells (WBCs), were predictive of future hypertension. The objective of this study was to examine the hypothesis that increasing levels of CRP and WBCs would be related to an EBP response during exercise.Inflammatory markers were compared in 43 males with an EBP (systolic blood pressure [SBP]or=210 mm Hg) response during maximal treadmill testing to an age and resting SBP-matched group of 42 males with a normal blood pressure response to exercise.There were significant group differences in maximal SBP and diastolic blood pressure (DBP), exercise induced increases in SBP and DBP (P.01), and WBCs (P.01), but CRP did not differ between groups (P =.39). White blood cells were significantly associated with maximal SBP (r = 0.31), and the exercise-induced increase in SBP (r = 0.34). However, CRP did not correlate with the maximal blood pressure response to exercise (r = 0.11, P =.33). In a stepwise multiple regression analysis, WBC was independently associated with the exercise-induced increase in SBP (beta = 0.256, P =.011).These results suggest that inflammation may be associated with an EBP response during exercise testing.

Although an exaggerated systolic blood pressure (SBP) response to exercise is a predictor of future hypertension and cardiovascular mortality, the underlying mechanisms are not fully understood. We tested the hypothesis that an exaggerated SBP response is associated with carotid atherosclerosis in a cross-sectional study of 9073 healthy men (aged 47.8 +/- 8.8 years).Exaggerated SBP response was defined as an SBP of 210 mmHg or greater during a maximal treadmill test. Carotid atherosclerosis was defined as stenosis greater than 25% or intima-media thickness greater than 1.2 mm using B-mode ultrasonography.An exaggerated SBP response was present in 375 men (4.1%). The proportion of individuals with carotid atherosclerosis in the group with an exaggerated SBP response to exercise was higher than in the group with a normal SBP response (14.4 versus 5.3%, P0.001). In a multivariable logistic regression model, individuals with an exaggerated SBP (or= 210 mmHg) response to exercise had a 2.02 times [95% confidence interval (CI) 1.33-3.05] increased risk of carotid atherosclerosis compared with individuals with an SBP response of less than 210 mmHg. The highest quartile (61 mmHg) group of relative exercise-induced increases in SBP showed a 1.57 (95% CI 1.18-2.08) greater risk of carotid atherosclerosis compared with individuals in the lowest quartile (38 mmHg) in the adjusted model.These results suggest that an exaggerated SBP response to exercise is strongly associated with carotid atherosclerosis, independent of established risk factors in healthy men. It may be an important factor in evaluating hypertension related to target-organ damage.

To investigate the pathogenesis of distal pancreatectomy (d-Px)-induced diabetes in Korean patients, we investigated insulin secretory and sensitivity indexes obtained by oral glucose tolerance testing in 20 patients that had received d-Px (10 with d-Px-induced diabetes and 10 with normal glucose tolerance with d-Px [NGT d-Px]) and in 164 control subjects (77 with type 2 diabetes mellitus and 87 with NGT) that did not receive d-Px. The pancreatectomized subjects had lower fasting serum insulin, homeostasis model assessment of pancreatic beta-cell function (HOMA-beta) levels, and insulinogenic indices than the NGT controls. The HOMA-beta values of nonobese NGT d-Px- and d-Px-induced diabetic subjects were 73.7% and 38.7% of those for nonobese NGT controls, respectively, and HOMA-beta was significantly lower only for d-Px-induced diabetic subjects (P.01). In obese subjects, the HOMA-beta values of obese d-Px-induced diabetic subjects were significantly lower than those of obese NGT controls (P.05). The insulin sensitivity was significantly lower in nonobese type 2 diabetes mellitus controls than in nonobese NGT d-Px or in nonobese d-Px-induced diabetic subjects (P.001 and .05, respectively). These results show that a reduced insulin secretory function is a typical feature of glucose homeostasis in distal pancreatectomized patients and that insulin secretory defect plays a major role in the development of diabetes in these patients. In addition, the study suggests that pancreatic resections of 60% or less and body mass index are not the main causes of diabetes onset after d-Px in this study.

Objective: To investigate the heterogeneity of early-onset and ketosis-resistant diabetes and to define a not-arbitrary cut-off age for early-onset diabetes based on its clinical and metabolic characteristics, and diabetes complications. Methods: We classified 1015 early-onset diabetes subjects aged 21–40 into four groups (group I, age at diagnosis 21–25 years; group II, 26–30; group III, 31–35; group IV, 36–40). Familial and diabetic history, statue of insulin secretion, metabolic parameters, and diabetes complications were analyzed. Results: No significant difference in family history or the rate of diabetic complication was found in the four groups. Subjects with a 21 to a 25-year-old diabetes onset had the lowest serum C-peptide levels, with 50% of the cumulative 24-h urine C-peptide levels of the other three groups ( p < 0.0001). This group also had the lowest prevalence of hyperlipidemia and arterial hypertension ( p < 0.01 and

Objective: To investigate the clinical characteristics and predisposing metabolic abnormalities in the development of glucose intolerance and diabetes mellitus in obese and non-obese Korean subjects. Methods: Four hundred Korean subjects were classified into five groups according to degree of glucose tolerance by OGTT: NGT, IGT alone, IFG alone, IFG + IGT, and DM. The groups were also subdivided into obese and non-obese group according to body mass index. Insulin resistance was assessed by using homeostasis model assessment of insulin resistance (HOMA-R), and insulinogenic index was used as an index of early-phase insulin secretion. Results: Impaired early-phase insulin secretion was seen in non-obese IGT alone, IFG alone, and IFG + IGT, though more profound secretory defects were noted in IFG + IGT and DM. No significant difference were found in HOMA-R among non-obese IGT alone, IFG alone, or IFG + IGT, or in terms of early-phase insulin secretion in obese IGT alone, IFG alone, or IFG + IGT. However, the magnitude of insulin resistance differed in the obese group, IFG + IGT and DM being more insulin resistant than IGT alone or IFG alone. Conclusions: These results suggest that the predisposing metabolic abnormality in non-obese subjects with IGT alone or IFG alone and in progression to IFG + IGT might be deterioration of early phase insulin secretion, whereas insulin resistance might be the major contributory factor in obese subjects. The predisposing metabolic abnormality leading to diabetes in both obese and non-obese groups was deterioration of early-phase insulin secretion.

Background Cystic neoplasms of the pancreas are an increasingly diagnosed entity, and surgical resection of the pancreas is advocated. Islet autotransplantation is a therapeutic approach used to prevent diabetes in cases of pathologically benign neoplasm after major pancreatectomy. Methods A total of 10 patients underwent pancreatectomy with islet autotransplantation. To evaluate islet transplantation efficiency, the authors compared 23 subjects who did not undergo islet transplantation after partial pancreatectomy with 87 subjects with normal glucose tolerance and with 77 diabetic subjects that did not undergo pancreatectomy. Results Ten female patients with nine cystic neoplasms and one patient with pancreatic injury underwent transplantation. Their mean islet equivalents (IEQ) was 3,159 IEQ/kg. During follow-up, two recipients required insulin or oral agents. At the 12-month follow-up, homeostasis model assessment (HOMA)-beta was 77.36+/-17.68, the insulinogenic index (INSindex) was 0.49+/-0.11, and fasting C-peptide and hemoglobin A1c were 1.28+/-0.18 ng/mL and 5.73+/-0.26%, respectively. Islet replacement was found to increase HOMA-beta by approximately 17% compared with distal pancreatectomy in normal glucose tolerance subjects without islet autotransplantation and by 46% compared with distal pancreatectomy diabetes subjects without islet autotransplantation. Factors different in the two insulin and oral hypoglycemic agent (OHA)-requiring recipients and the eight insulin- and OHA-free recipients were pancreatectomy extent, preoperative glucose metabolism insufficiency, age, and underlying cystic neoplasm disease. Conclusions Even partial islet graft function can have a beneficial metabolic effect on the recipient in terms of metabolic parameters such as HOMA-beta and INSindex. This study suggests that islet replacement should be considered for experimental procedures in benign pancreatic conditions.

The problem of the determination of the space requirements for warehouse systems operating under a dedicated storage policy, full turnover-based storage, is investigated. Space shortage occurs when demand exceeds the warehouse storage capacity. The additional space requirement is satisfied by considering a leased storage space. The warehouse storage capacity problem is then formulated as a non-linear programming model to minimize the total cost of owned and leased storage space. An iterative search procedure, which always generates the optimal solution, is developed. Illustration of the approach for systems operating under the standard economic-order-quantity inventory model is provided. The results obtained using the optimization approach presented can be used for determining bounds or approximations for the first-cut design of the storage space requirements.

High-resolution ultrasonography (US) has made possible the detection of asymptomatic small thyroid nodules. Thyroid incidentalomas have created a clinical dilemma as to how to properly manage such incidental findings. We investigated the prevalence, the clinical and US characteristics, and optimal diagnostic approach to incidentally detected benign and malignant thyroid nodules1.5 cm. Retrospective review was done on 1475 patients who had visited Samsung Medical Center, Soul Korea from January 1999 to December 2000. The prevalence of thyroid incidentalomas was 13.4%. The malignancy rate within thyroid incidentalomas was 28.8%. There were no significant differences in age, nodule size and number, thyroid function test, and Tc99m thyroid scan between benign and malignant incidentalomas. US characteristics of solid echostructure, irregular margin, and calcification showed meaningful diagnostic value in detecting malignancy in thyroid incidentalomas (p0.05). Most malignant incidentalomas were low stage. In conclusion, occult thyroid cancers are a fairly common finding. There were no significant differences in clinical and laboratory parameters between benign and malignant thyroid nodules1.5 cm; however, US findings can be used in the decision of optimal management strategies.

Recent studies incriminating tumor necrosis factor (TNF)-alpha as the final effector in pancreatic beta-cell death in type 1 diabetes underscore the potential role of TNF-alpha-dependent NF-kappaB activation as an important modulator of pancreatic beta-cell death in autoimmune diabetes. Although nuclear factor (NF)-kappaB activation has been implicated in the protection of target cells against apoptosis by a variety of death effectors, its role in pancreatic islet cell death is not clear. We studied the role of NF-kappaB activation in pancreatic islet cell death by using a gamma-interferon (IFN-gamma)/TNF-alpha synergism model we had previously reported. TNF-alpha induced inhibitor of kappaB (IkappaB) degradation and p65 translocation from cytoplasm to nuclei in MIN6N8 insulinoma cells. The NF-kappaB DNA-binding nuclear complex activated by TNF-alpha contained both the p65 and p50 subunit. IFN-gamma pretreatment did not affect TNF-alpha-induced NF-kappaB activation. Treatment with a proteasome inhibitor blocked p65 translocation and induced susceptibility to TNF-alpha in otherwise resistant insulinoma cells or primary pancreatic islet cells. Specific inhibition of NF-kappaB activation by adenoviral transduction of IkappaB "superrepressor" also sensitized insulinoma cells and primary islet beta-cells to TNF-alpha-induced apoptosis. These results suggest the protective role of NF-kappaB activation against cytokine-mediated pancreatic beta-cell death, contrary to previous reports implicating NF-kappaB as a mediator of pancreatic islet cell death.

Mutations in the CYP17 gene impair steroid biosynthesis in the adrenals and gonads and often cause 17α-hydroxylase/17,20-lyase deficiency, leading to amenorrhea, sexual infantilism, and hypokalemic low aldosterone hypertension. Several CYP17 mutations resulting in 17α-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we found a novel CYP17 mutation from the molecular analysis of a Korean patient with primary amenorrhea with a 46,XX karyotype, and hypokalemic hypertension. We sequenced all 8 exons of the CYP17 gene that were amplified from patient's genomic DNA using polymerase chain reaction (PCR) and found a compound heterozygous mutation in the CYP17 structural gene; a 1-base deletion and a 1-base transversion (TAC→AA) at codon 329, leading to the production of a truncated protein (1-417 amino acids), and a 3-base deletion (TCC, either 350-351 or 351-352 codon) in the other allele. Restriction enzyme digestion analysis of patient's and parental DNA showed that the 1-base deletion and the 3-base deletion are inherited from mother and father, respectively. Here we conclude that these novel compound heterozygous mutations might account for the patient's clinical manifestations of 17α-hydroxylase/17,20-lyase deficiency. Copyright 2003 Elsevier, Inc. All rights reserved.

Objective To evaluate plasma apolipoprotein B (ApoB)-48 concentrations among Korean diabetic subjects with normal to moderately high levels of low-density-lipoprotein cholesterol (LDL-C). Methods This multicenter, cross-sectional study included subjects with LDL-C levels between 100 and 160mg/dL who had not been treated with a lipid-lowering agent for over 6weeks prior to baseline. Blood tests to assess lipid-profile parameters were conducted in both fasting and postprandial states. This study compared ApoB-48 and other lipid-profile parameters in diabetic and nondiabetic subjects. Results Of the 93 subjects enrolled, 88 (42 diabetic; 46 nondiabetic) completed the study. Significantly higher mean incremental area under curve (0–6h; iAUC 0–6h ) of postprandial ApoB-48 levels was noted among diabetic subjects than nondiabetic subjects ( p =0.0078). The mean postprandial ApoB-48 peak level was higher in diabetic subjects; however, the difference was not statistically significant. The fasting ApoB-48 level was similar in both groups: 5.9 (3.5) in diabetics and 7.3 (5.8) in nondiabetics ( p =0.18). The iAUC 0–6h of postprandial total cholesterol (TC), triglyceride (TG), LDL-C, non–high-density-lipoprotein cholesterol (non-HDL-C), ApoB-100, and remnant cholesterol was similar in both groups. The ApoB-48 level was moderately correlated with TG and non-HDL-C for both groups ( p Conclusion Without lipid-lowering treatment, the postprandial increment in ApoB-48 level was significantly higher in Korean diabetic subjects compared with nondiabetic subjects, irrespective of similar LDL-C levels.

Troglitazone (TGZ) is an antidiabetic agent of the thiazolidinedione (TZD) class that potentiates insulin action. In addition to its effects on insulin action, TGZ has an antiproliferative effect on vascular smooth muscle cells (VSMCs), of which proliferation is a prominent feature of retenosis after balloon injury, as well as atherosclerosis. Therefore, we investigated the effects of TGZ on intimal formation and blood flow after balloon injury in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats to see whether the decrease in insulin resistance could minimize VSMC proliferation and could maintain blood flow. OLETF rats, an animal model of type 2 diabetes, develop spontaneous hyperglycemia after the age of 24 weeks. Balloon injury was applied to the left common carotid arteries of the rats with a 2F Fogarty catheter. Two weeks after the balloon injury, blood flow velocity was measured with Doppler ultrasonography, and histomorphometric analyses of the common carotid arteries were performed. The neointimal formation caused by VSMC proliferation was inhibited by TGZ treatment by as much as 80% (0.197 +/- 0.013 mm(2) v 0.157 +/- 0.011 mm(2), P

Catecholamines play a central role in the regulation of energy expenditure, in part stimulating lipid mobilization through lipolysis in fat cells. The [beta ] 2 -adrenergic receptor (ADRB2) is a major lipolytic receptor in human fat cells, and a recent study has shown that common polymorphisms occurring in codons 16 and 27 of the ADRB2 gene are significantly associated with obesity and lipolytic ADRB2 function in adipose tissue. We investigated whether previously described human ADRB2 gene polymorphisms are associated with obesity and diabetes in Korean subjects. According to the World Health Organization (WHO) criteria for oral glucose tolerance testing, 57 subjects had normal glucose tolerance (NGT), 32 had impaired glucose tolerance (IGT), and 106 had diabetes mellitus. The nondiabetic group (including NGT and IGT) consisted of 46 obese (defined as those with body mass index [BMI] of [ge ] 27 kg/m 2 ) and 43 nonobese subjects (BMI [lt ] 27 kg/m 2 ). The subjects with diabetes consisted of 62 obese and 44 nonobese subjects. There was no significant difference between nonobese and obese subjects in the allele frequency of ADRB2 gene polymorphisms at codons 16 and 27. There were no significant differences in BMI, percentage body fat, waist[ndash ]to-hip ratio (WHR), systolic blood pressure, diastolic blood pressure and concentrations of fasting plasma glucose, fasting serum insulin, serum low-density lipoprotein (LDL)-cholesterol, serum high-density lipoprotein (HDL)-cholesterol, serum triglyceride, and serum free fatty acids, according to ADRB2 gene polymorphisms at codons 16 and 27. The frequency of the Glu27 homozygote was 1.1%. These findings suggest that genetic variability in the ADRB2 gene may not be a major determinant for the development of obesity and diabetes in Koreans.

Over the past 20 years, allo-transplantation of islet or whole pancreas for reaching and sustaining near-normoglycemia, as close as possible to the physiological model, have been undertaken. As previously known, even though islet transplantation is possible as a safe re-transplant, it is not well known whether re-transplantation of islets is suitable for patients who have lost the grafted islet function. We have performed a human islet allo-transplantation and re-transplantation on an IDDM patient for the first time in Asia and Korea. The recipient was a 32-year-old male and his insulin requirement was 75–85 U per day. After islet transplantation, the basal C-peptide increased from 0.6 to 2.1 ng/ml and insulin requirement decreased from 80 to 36 U per day, indicating that the grafted islets were functional. However, the grafted islets lost function 70 days after the transplantation. So, we performed re-transplantation of the islets. After the re-transplantation, the glucose profile became more stable and frequent episodes of severe hypoglycemia completely disappeared. His severe neuropathic pain improved dramatically and he could engage his ordinary daily life without any antineuropathic drugs. The success of this re-transplantation is one step closer to becoming a viable alternative for the millions of individuals who are suffering from diabetes.

The aim of the present 24-week multicentre randomized non-inferiority trial was to compare the efficacy and safety of two insulin intensification strategies in uncontrolled type 2 diabetes despite optimized basal insulin therapy.Patients with fasting plasma glucose (FPG)130 mg/dL and HbA1c 7.0%-10.0% while on insulin glargine were randomized to a basal-prandial group (stepwise addition of insulin glulisine) or a premixed insulin group (insulin aspart/insulin aspart protamine 30/70 starting with 6 IU twice daily). The primary endpoint was the change in HbA1c after 24 weeks (non-inferiority margin 0.4%).At Week 24, the adjusted mean change from baseline HbA1c was -0.94 ± 0.09% and -1.04 ± 0.09% in basal-prandial and premixed insulin groups, respectively, with a mean difference of -0.09% (95% confidence interval [CI] -0.35, 0.16). A lower rate of hypoglycemia with a similar reduction in HbA1c was observed during stabilization of the total daily insulin dose in the premixed insulin group (Weeks 0-12). After stabilization of the total daily insulin dose, the rate of hypoglycemia and the total daily insulin dose were similar in the two groups.The efficacy and safety of the two intensifying regimens were similar after stabilization of the total daily insulin dose when oral agents were maintained. Starting with a lower total daily insulin dose with a gradual change in the treatment regimen was helpful in reducing the rate of hypoglycemia during initial stabilization of the total daily insulin dose.

OBJECTIVE We aimed to evaluate the effects of carnitine-orotate complex in patients with nonalcoholic fatty liver disease (NAFLD) and diabetes. RESEARCH DESIGN AND METHODS Eight hospitals in Korea participated in this randomized, controlled, double-blind trial of patients with diabetes and NAFLD. Seventy-eight patients were randomly assigned in a 1:1 ratio to receive carnitine-orotate complex (824 mg, three times daily) or matching placebo. The primary study outcome was decline in alanine aminotransferase (ALT) to the normal range. Secondary study outcomes were change in ALT, radiological hepatic steatosis, parameters for anthropometry, liver function, lipid profiles, and glycemic control. Hepatic steatosis was assessed using Hounsfield units on noncontrast computed tomography (CT) imaging with hepatic attenuation. RESULTS After 12 weeks of treatment, compared with placebo group, carnitine-orotate complex–treated participants had a significantly higher rate of normalization of serum ALT level (17.9% vs. 89.7%, P < 0.001). On hepatic CT analysis, participants treated with carnitine-orotate complex showed an increased liver attenuation index (0.74 ± 8.05 vs. 6.21 ± 8.96, P < 0.008). A significant decrease in HbA1c was observed in the carnitine-orotate complex group (−0.33 ± 0.82% [−3.6 ± 9.0 mmol/mol], P = 0.007), but no significant change was seen in the placebo group. CONCLUSIONS Treatment with carnitine-orotate complex improves serum ALT and may improve hepatic steatosis as assessed by CT in patients with diabetes and NAFLD. Further studies using more advanced magnetic resonance imaging and liver histology as an end point are needed to assess its efficacy in NAFLD.

We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add-ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28-week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was −0.74% for the lobeglitazone group and −0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, −0.16 to 0.18]. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add-on to metformin in terms of their efficacy and safety.

ObjectiveThis study was carried out to determine whether serum TSH levels improve the prediction of cardiovascular risk in addition to common clinical risk scores, given the association between subclinical hypothyroidism (SCH) and cardiovascular disease (CVD).DesignWe carried out an observational study in a prospective cohort.MethodsThe study included a total of 344 SCH and 2624 euthyroid participants aged over 40 years and who were without previously recorded CVDs were included in this study analysis. We measured thyroid function and traditional risk factors at baseline and estimated the 10-year cumulative incidence of CVD in a gender-stratified analysis.ResultsDuring 10 years of follow-up, 251 incident cardiovascular events were recorded. The elevation of serum TSH levels significantly increased the CV risk independent of conventional risk factors in men. In the atherosclerotic CVD (ASCVD) risk score or the Reynolds risk score (RRS) model, the addition of serum TSH levels had no effect on model discrimination as measured by the area under the curve in either women or men. Adding serum TSH did not improve the net reclassification improvement in either women (3.48% (P=0.29) in the ASCVD, −0.89% (P=0.75) in the RRS, respectively) or men (−1.12% (P=0.69), 3.45% (P=0.20), respectively) and only mildly affected the integrated discrimination Improvement in the ASCVD-adjusted model (0.30% in women and 0.42% in men, both P=0.05).ConclusionsIn the context of common risk scoring models, the additional assessment of serum TSH levels provided little incremental benefit for the prediction of CV risk.

Islet transplantation has been hampered by the shortage of islet donors available for diabetes therapy. However, pluripotent stem cells (PSCs) can be an alternative source of insulin-producing cells (IPCs) because of their capacity for self-renewal and differentiation. We described a method to efficiently differentiate PSCs into IPCs by co-culturing mature islets with directed-differentiated pancreatic endoderm (PE) cells from mouse and human PSCs. PE cells co-cultured with islet cells or islet cell-derived conditioned medium (CM) showed increased expression levels of β-cell markers; significantly higher levels of proinsulin- and Newport Green (NG)-positive cells, which revealed the characteristics of insulin producing cells; and increased insulin secretion upon glucose stimulation. Co-culturing human PE cells with islet cells was also effective to differentiate PE cells into IPCs. Diabetic nude mice transplanted with co-cultured cells exhibited restored euglycemia, human C-peptide release, and improved glucose tolerance. Immunohistochemistry revealed that insulin+/C-peptide + cells existed in the grafted tissues. These results suggest that mature islet cells can increase the differentiation efficiency of PE cells into mature IPCs via paracrine effects.

Dysregulation of the autophagy pathway has been suggested as an important mechanism in the pathogenesis of Parkinson's disease (PD). Therefore, modulation of autophagy may be a novel strategy for the treatment of PD. Recently, an active form of vitamin D₃ has been reported to have neuroprotective properties. Therefore, we investigated the protective, autophagy-modulating effects of 1,25-dyhydroxyvitamin D₃ (calcitriol) in an in vitro model of Parkinson's disease.An in vitro model of Parkinson's disease, the rotenone-induced neurotoxicity model in SH-SY5Y cells was adapted. We measured cell viability using an MTT assay, Annexin V/propidium iodide assay, and intracellular reactive oxygen species levels and analyzed autophagy-associated intracellular signaling proteins by Western blotting.Rotenone treatment of SH-SY5Y cells reduced their viability. This treatment also increased reactive oxygen species levels and decreased levels of intracellular signaling proteins associated with cell survival; simultaneous exposure to calcitriol significantly reversed these effects. Additionally, calcitriol increased levels of autophagy markers, including LC3, beclin-1, and AMPK. Rotenone inhibited autophagy, as indicated by decreased beclin-1 levels and increased mTOR levels, and this effect was reversed by calcitriol treatment.Calcitriol protects against rotenone-induced neurotoxicity in SH-SY5Y cells by enhancing autophagy signaling pathways such as those involving LC3 and beclin-1. These neuroprotective effects of calcitriol against rotenone-induced dopaminergic neurotoxicity provide an experimental basis for its clinical use in the treatment of PD.