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Background: Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). Methods: Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and β-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. Results: NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no sig nificant difference in insulin resistance. Total islet and β-cell masses were decreased in NAS mice. The number of large islets (≥250 μm) decreased while that of small islets (

Islet transplantation has emerged as a promising treatment for type 1 diabetes mellitus. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, protects beta cells after islet transplantation by improving glycemic control through several mechanisms. In this study, we compared the effects of local pretreatment and systemic treatment with liraglutide on islet transplantation in a diabetic mouse model. Streptozotocin (STZ)-induced diabetic C57BL/6 mice were transplanted with syngeneic islets under the kidney capsule. Isolated islets were either locally treated with liraglutide before transplantation or mice were treated systemically by intraperitoneal injection after islet transplantation. Local pretreatment of islets with liraglutide was more effective in increasing body weight, decreasing hemoglobin A1c levels, and lowering blood glucose levels in STZ-diabetic mice transplanted with islets. Local pretreatment was also more effective in increasing insulin secretion and islet survival in STZ-diabetic mice. Histological analysis of the transplantation site revealed fewer apoptotic cells following local pretreatment compared with systemic injection of liraglutide. These findings indicate that liraglutide administered once locally before transplantation might have superior effects on islet preservation than systemic administration.

Notch1 signaling is an important regulator of embryonic development and cell fate decision. Notch1 signaling is also expressed in adult pancreas but there is no study on the role of Notch1 in glucose homeostasis and islet mass in adult pancreas. Here, we investigated the role of Notch1 in glucose homeostasis and islet mass using Notch1 Antisense Transgenic (NAS) mice. We conducted an IPGTT and IPITT in 8-week-old male NAS mice and C57BL/6 mice (control mice). Insulin secretion capacity was measured by GSIS and perifusion. Morphology of pancreatic islet and β cell was conducted in two groups and transcription factors were evaluated. NAS mice showed higher glucose levels and lower insulin secretion in IPGTT. There was no significant difference in insulin resistance. Total islet and β cell masses were decreased in NAS mice. The number of large islets (≥ 250 μm) decreased while that of small islet (< 250 μm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Our study provides that Notch1 inhibition decreased insulin secretion without any alterations in insulin resistance and decreased islet and β cell mass in the adult pancreas in NAS model. It is thought that Notch1 inhibition early suppresses islet proliferation and induces differentiation of not fully proliferated small islets. In conclusion, the Notch signaling pathway may play an important role in beta cell mass and development of diabetes. Disclosure Y. Eom: None. K. Kim: None. B. Kim: None. Funding Korea Health Technology R&D Project (A101711, HI14C2539); Korean Ministry of Health, Welfare, and Family Affairs

Digital door lock system is a widely used physical security system. It restricts unauthorized accesses and protects assets or private spaces. However, once its password has been exposed to unauthorized people, it becomes useless. In this paper, we propose a novel side channel attack model, which enables a cracking of a digital door lock password. We noted that when people press the key-lock button, irrespective of how careful they are, the generated vibrations differ with the location of the button pressed. Our model uses and analyzes the natural phenomenon of vibration to infer passwords. Under our attack, the ease of password inference depends on the number of distinguishable buttons rather than password length. The results of our experiments contradict the commonly held security principle that a longer password guarantees a higher level of security.

A 1.2 V 1.33Gb/s/pin 8Tb NAND flash memory multi-chip package incorporating 16-die stacked 512-Gb NAND flash memories and F-Chip is presented. To meet the performance requirements of storage devices for higher capacity and faster data throughput, the 2nd generation F-Chip is developed. The F-Chip presents a dual bi-directional transceiver architecture including data retiming and training techniques to adaptively improve signal integrity. Besides, the F-Chip supports 1.2 V I/O for low power storage applications. This work, as a result, shows 33% improvement of eye-opening performances and 41% reduction of I/O power consumption compared to the previous generation.

Background: The aim of this study was to assess the clinical differences between acromegalic patients with microadenoma and pa- tients with macroadenoma, and to evaluate the predictive value of growth hormone (GH) levels for early detection of macroadenoma. Methods: We performed a retrospective analysis of 215 patients diagnosed with a GH-secreting pituitary adenoma. The patients were divided into two groups: the microadenoma group and the macroadenoma group, and the clinical parameters were compared between these two groups. The most sensitive and specific GH values for predicting macroadenoma were selected using receiver operating characteristic (ROC) curves. Results: Compared with the microadenoma group, the macroadenoma group had a significantly younger age, higher body mass in- dex, higher prevalence of hyperprolactinemia and hypogonadism, and a lower proportion of positive suppression to octreotide. How- ever, there were no significant differences in the gender or in the prevalence of diabetes between the two groups. The tumor diameter was positively correlated with all GH values during the oral glucose tolerance test (OGTT). All GH values were significantly higher in the macroadenoma group than the microadenoma group. Cut-off values for GH levels at 0, 30, 60, 90, and 120 minutes for optimal discrimination between macroadenoma and microadenoma were 5.6, 5.7, 6.3, 6.0, and 5.8 ng/mL, respectively. ROC curve analysis revealed that the GH value at 30 minutes had the highest area under the curve. Conclusion: The GH level of 5.7 ng/mL or higher at 30 minutes during OGTT could provide sufficient information to detect mac- roadenoma at the time of diagnosis.

Background The aim of this study was to investigate whether adjusting diabetic treatment regimens according to the information obtained from a continuous glucose monitoring system (CGMS) might lead to improved glycemic control in patients with type 2 diabetes. Methods We reviewed the medical charts of 172 patients who used the CGMS for 1 year starting in December 2008 and the records of 1,500 patients who visited their regular outpatient clinics during December 2008. Of these patients, a total of 65 CGMS patients and 301 regular outpatients (control group) were enrolled in the study after propensity score matching. There were no differences in baseline glycated hemoglobin (HbA1c), age, and duration of diabetes between the CGMS and the control groups after propensity score matching. The changes in the HbA1c levels from baseline to 6 months were calculated. Results The CGMS group showed a significant improvement in the HbA1c level compared to the control group at 3 months (7.9%±1.6% vs. 7.4%±1.2%, P=0.001) and at 6 months (7.4%±1.2% vs. 7.9%±1.6%, P=0.010). There were significant differences in the treatment modality changes between the CGMS group and the control group. Conclusion Using a 3-day CGMS was advantageous for improving glucose control in patients with type 2 diabetes and may help these patients to optimize glycemic control in clinical practice.

Role of impaired suppression of glucagon secretion in the pathogenesis of pancreatic cancer-associated diabetes has been suggested. We examined the correlation between glucagon/insulin ratio (G/I) after glucose challenge and hemoglobin A1C (A1C) in subjects with and without pancreatic cancer. Data were gathered from a preoperative screening 75-g oral glucose tolerance test in patients who would eventually undergo pancreatic resection. A multiple linear regression analysis was conducted using the following covariates: age, body mass index, hemoglobin, glucose and insulin levels at the corresponding time points, indices of insulin resistance, duration of diabetes, insulinogenic index, and use of glucose-lowering drugs. In subject group with pancreatic cancer (n = 45), but not in subject group without pancreatic cancer (n = 101), participants with A1C ≥6.5 % had significantly higher glucagon levels, lower insulin levels, and higher G/I ratios after the glucose challenge than those of the subjects with A1C

Background The ratio of apolipoprotein B (apoB) to apolipoprotein A1 (apoA1) has been reported to be associated with metabolic syndrome (MetS) and insulin resistance (IR). Non-HDL-C is regarded as a surrogate marker for apoB in routine clinical practice. However, it is unclear whether the ratio of non-HDL-C to HDL-C is an equal or a better predictor than the apoB/apoA1 ratio for the identification of MetS and IR. Methods We performed a retrospective study of 41,821 Korean adults who participated in a routine health screening examination. Anthropometry, fasting glucose, fasting insulin, HOMA-IR, CRP, lipid profiles, apoB, and apoA1 were measured. Results To compare the predictive value for MetS between different lipid ratios, we analyzed the ROC curves of apoB/apoA1 and non-HDL-C/HDL-C ratios. ROC analysis showed that the AUCs of non-HDL-C/HDL-C (0.75 [95% CI=0.74–0.76] in men and 0.84 [95% CI=0.83–0.85] in women) were significantly higher than those of apoB/apoA1 (0.66 [95% CI=0.65–0.67] in men and 0.77 [95% CI=0.76–0.78] in women). The non-HDL-C/HDL-C ratio also showed a significantly stronger association with HOMA-IR than the apoB/apoA1 ratio. The optimal cutoff value of the non-HDL-C/HDL-C ratio for detection of MetS in men was 3.39, with a sensitivity of 66.7% and a specificity of 71.8%, whereas the optimal ratio cutoff value in women was 2.89, with a sensitivity of 75.7% and a specificity of 78.1%. Conclusions Our findings indicate that the non-HDL-C/HDL-C ratio is a better marker than the apoB/apoA1 ratio for identifying IR and MetS in Koreans.

Aims/Introduction The goal of the present study was to evaluate predictive factors for good efficacy and durability to sitagliptin with ongoing metformin or metformin plus glimepiride therapy in a real practice situation. The present observational study was carried out over a 60-week period and involved Korean patients with type 2 diabetes mellitus. Materials and Methods A total of 100 mg of sitagliptin were added once daily to the two most popular therapy regimens (group 1: metformin, group 2: metformin plus glimepiride). Before adding sitagliptin, mean initial glycated hemoglobin (HbA1c) levels were 7.8% (62 mmol/mol) and mean diabetes duration was 8.3 years. Results After 60 weeks, the mean change in HbA1c from baseline was −0.9% (−10 mmol/mol) in group 1 and −1.0% (−11 mmol/mol) in group 2. Decreased HbA1c levels were significantly associated with higher initial HbA1c and lower log-transformed C-peptide levels in a multivariate regression analysis. Logistic regression analysis showed that a sustained reduction in HbA1c levels after 12 weeks was significantly associated with older age (≥60 years), higher baseline HbA1c (group 1 ≥ 7.0% [53 mmol/mol], group 2 ≥ 7.5% [58 mmol/mol]) and slower reduction of HbA1c (ΔHbA1c

Aims/Introduction To evaluate whether hemoglobin A1c (HbA1c) levels are affected by hemoglobin level and gender. Materials and Methods A cross-sectional analysis was carried out in a sample of 87,284 non-diabetic Koreans without anemia who participated in comprehensive health check-ups between January and December 2009 at the Kangbuk Samsung Hospital Total Healthcare Center in Seoul, Korea. We categorized men and women separately according to fasting plasma glucose and hemoglobin level to carry out the analysis. Results HbA1c increased steadily with increasing fasting plasma glucose level. Both men and women with lower hemoglobin had significantly higher HbA1c at a given fasting glucose level, and this result was consistent across the fasting glucose quintiles within the non-diabetic range. Women had a lower mean hemoglobin value compared with men, and women had higher HbA1c levels at a given fasting glucose level consistently across the fasting glucose deciles. There was also a gender-specific association between age and HbA1c (P

We report the case of a 36-year-old woman who presented with headache, fever, and amenorrhea. Laboratory analysis revealed hypopituitarism and autoimmune thyroiditis, while a cerebrospinal fluid study suggested concurrent aseptic meningitis. A magnetic resonance image (MRI) scan revealed a 1.0×0.9 cm cystic mass enlarging the sella turcica. Surgical resection via an endoscopic transsphenoidal route was performed. The histological finding of the excised tissue revealed foamy histiocytes with vacuolated cytoplasm, supporting the diagnosis of xanthomatous hypophysitis. Although a residual soft lesion was observed on the MRI image postoperatively, the patient's headache and fever improved. Ten months after surgery, the patient complained of visual impairment and headache, and the residual mass had enlarged into the suprasellar area. High dose (500 mg intravenous) methylprednisolone was administered for 3 days. During the methylprednisolone pulse therapy, the patient's visual acuity and headache improved. A follow-up MRI taken after methylprednisolone therapy showed a marked mass reduction. Our case supports an autoimmune pathophysiology for xanthomatous hypophysitis and suggests that high dose glucocorticoid therapy as a treatment option.

Endoscopic transsphenoidal surgery has recently been introduced in pituitary surgery. We investigated outcomes and complications of endoscopic surgery in 2 referral centers in Korea.We enrolled 134 patients with acromegaly (microadenomas, n = 15; macroadenomas, n = 119) who underwent endoscopic transsphenoidal surgery at Seoul National University Hospital (n = 74) and Samsung Medical Center (n = 60) between January 2009 and March 2016. Remission was defined as having a normal insulin-like growth factor-1 and a suppressed growth hormone (GH)1 ng/mL during an oral glucose tolerance test.Remission was achieved in 73.1% of patients, including 13 of 15 microadenoma patients (86.7%) and 86 of 119 macroadenoma patients (72.3%). A multivariate analysis to determine a predictor of biochemical remission demonstrated that absence of cavernous sinus invasion and immediate postoperative GH levels2.5 ng/dL were significant predictors of remission (adjusted odds ratio [OR], 5.14; 95% confidence interval [CI], 1.52-17.3 and OR, 9.60; 95% CI, 3.41-26.9, respectively). After surgery, normal pituitary function was maintained in 34 patients (25.4%). Sixty-four patients (47.7%) presented complete (n = 59, 44.0%) or incomplete (n = 5, 3.7%) recovery of pituitary function. Hypopituitarism persisted in 20 patients (14.9%) and worsened in 16 patients (11.9%). Postoperatively, transient diabetes insipidus was reported in 52 patients (38.8%) but only persisted in 2 patients (1.5%). Other postoperative complications were epistaxis (n = 2), cerebral fluid leakage (n = 4), infection (n = 1), and intracerebral hemorrhage (n = 1).Endoscopic transsphenoidal surgery for acromegaly presented high remission rates and a low incidence of endocrine deficits and complications. Regardless of surgical techniques, invasive pituitary tumors were associated with poor outcome.

Since the report of type 1 diabetes reversal in seven consecutive patients by the Edmonton protocol in 2000, pancreatic islet transplantation has been reappraised based on accumulated clinical evidence. Although initially expected to therapeutically target long-term insulin independence, islet transplantation is now indicated for more specific clinical benefits. With the long-awaited report of the first phase 3 clinical trial in 2016, allogeneic islet transplantation is now transitioning from an experimental to a proven therapy for type 1 diabetes with problematic hypoglycemia. Islet autotransplantation has already been therapeutically proven in chronic pancreatitis with severe abdominal pain refractory to conventional treatments, and it holds promise for preventing diabetes after partial pancreatectomy due to benign pancreatic tumors. Based on current evidence, this review focuses on islet transplantation as a realistic approach to treating diabetes.

BACKGROUND Diabetes self-management education has an important role in diabetes management. The efficacy of education has been proven in several randomized trials. However, the status of diabetes education programs in real Korean clinical practice has not yet been evaluated in terms of patient compliance with the education prescription. METHODS We retrospectively analyzed clinical and laboratory data from all patients who were ordered to undergo diabetes education during 2009 at Samsung Medical Center, Seoul, Korea (n=2,291). After excluding ineligible subjects, 588 patients were included in the analysis. RESULTS Among the 588 patients, 433 received education. The overall compliance rate was 73.6%, which was significantly higher in the subjects with a short duration or living in a rural area compared to those with a long duration (85.0% vs. 65.1%, respectively; P

Congenital adrenal hyperplasia (CAH) is characterized by decreased adrenal hormone production due to enzymatic defects and subsequent rise of adrenocorticotrophic hormone that stimulates the adrenal cortex to become hyperplastic, and sometimes tumorous. As the pathophysiology is basically a defect in the biosynthesis of cortisol, one may not consider CAH in patients with hypercortisolism. We report a case of a 41-yr-old man with a 4 cm-sized left adrenal tumorous lesion mimicking Cushing's syndrome who was diagnosed with CAH. He had central obesity and acanthosis nigricans involving the axillae together with elevated 24-hr urine cortisol level, supporting the diagnosis of Cushing's syndrome. However, the 24-hr urine cortisol was suppressed by 95% with the low dose dexamethasone suppression test. CAH was suspected based on the history of precocious puberty, short stature and a profound suppression of cortisol production by dexamethasone. CAH was confirmed by a remarkably increased level of serum 17-hydroxyprogesterone level. Gene mutation analysis revealed a compound heterozygote mutation of CYP21A2 (I173N and R357W).

The aim of this study was to assess the prevalence of diabetes and to study the effects of excess growth hormone (GH) on insulin sensitivity and β-cell function in Korean acromegalic patients. One hundred and eighty-four acromegalic patients were analyzed to assess the prevalence of diabetes, and 52 naive acromegalic patients were enrolled in order to analyze insulin sensitivity and insulin secretion. Patients underwent a 75 g oral glucose tolerance test with measurements of GH, glucose, insulin, and C-peptide levels. The insulin sensitivity index and β-cell function index were calculated and compared according to glucose status. Changes in the insulin sensitivity index and β-cell function index were evaluated one to two months after surgery. Of the 184 patients, 17.4% were in the normal glucose tolerance (NGT) group, 45.1% were in the pre-diabetic group and 37.5% were in the diabetic group. The insulin sensitivity index (ISI(0,120)) was significantly higher and the HOMA-IR was lower in the NGT compared to the diabetic group (P = 0.001 and P = 0.037, respectively). The ISI(0,120) and disposition index were significantly improved after tumor resection. Our findings suggest that both insulin sensitivity and β-cell function are improved by tumor resection in acromegalic patients.

The diagnosis of pheochromocytoma depends on the documentation of catecholamine overproduction. The use of urinary fractionated metanephrines has recently become common for the diagnosis of pheochromocytoma. In order to avoid false positive and false negative results, optimal cut-off levels are necessary; however, there have been few published reports on whether different cut-off levels are needed to diagnose pheochromocytoma according to sex. We reviewed the medical records of 815 subjects (including 103 pheochromocytoma patients) whose of 24-h urinary fractionated metanephrine was measured using high-performance liquid chromatography methods and adrenal imaging at Samsung Medical Center. Receiver operating characteristic (ROC) curves were used to determine cut-off values according to sex. The upper limit values of fractionated metanephrine in healthy volunteers and the control group were significantly higher in male subjects compared with females. When we applied cut-off values according to sex, the diagnostic efficacies (defining a positive test as either metanephrine or normetanephrine levels above the cut-off value) were a sensitivity of 96% in male subjects and 98.1% in female subjects and a specificity of 88.6% in male subjects and 94.1% in female subjects. However, when we applied cut-off values without considering sex, the specificity decreased from 88.6% to 77.8% in male subjects. In this study, urinary fractionated metanephrines had a high level of sensitivity and specificity for the diagnosis of pheochromocytoma. However, diagnostic cut-off values were higher in male subjects than in female subjects. Therefore, different cut-off values may be needed according to sex to diagnose pheochromocytoma in Koreans.

In this study, performance analyses have been conducted for a 5MW class wind turbine blade model. Advanced computational analysis system based on computational fluid dynamics(CFD) and computational structural dynamics(CSD) has been developed in order to investigate detailed dynamic responsed of wind turbine blade. Reynolds-averaged Navier-Stokes (RANS) equations with K-  turbulence model are solved for unsteady flow problems of the rotating turbine blade model. A fully implicit time marching scheme based on the Newmark direct integration method is used for computing the coupled aeroelastic governing equations of the 3D turbine blade for fluid-structure interaction (FSI) problems. Predicted aerodynamic performance considering structural deformation effect of the blade show different results compared to the case of rigid blade model. †† 1. 서 론 풍력발전기에서 발생되는 출력은 로터의 직경과 연관되기 때문에 최근에 풍력터빈 시스템은 발전효율을 높이기 위하여 그 크기가 점차 대형화되고 있다. 게다가, 풍력발전기의 고 효율화를 위하여 블레이드의 대형화, 경량화가 이루어지고 있는 추세이다. 하지만 터빈의 대형화로 인해 커진 공기력에 비하여 터빈 블레이드의 구조적 강도가 약해졌으며 이로 인해 단순히 대형 풍력 터빈 블레이드의 구조안정성 뿐만 아니라 플러터 안정성의 중요도도 높아지고 있다. 풍력발전기에서 회전날개(Rotor Blade)는 바람의 힘을 기계적인 힘으로 변형시키는 부분으로서, 풍력발전 시스템 성능의 핵심 요소이며, 블레이드의 설계에 따라 풍력발전기의 용량과 효* 국립경상대학교 기계항공공학부** 효성 (주) ***한국기계연구원 재료연구소 풍력핵심기술연구센터† 교신저자, E-mail : dhk@gnu.ac.kr율이 결정된다. 때문에 대형화된 풍력터빈 시스템의 안정성 검토를 위해 플러터 해석이 국내외적으로 연구되었다

Cancer incidence appears to be increased in both type 1 and type 2 diabetes mellitus (DM). DM represents a risk factor for cancer, particularly hepatocellular, hepatobiliary, pancreas, breast, ovarian, endometrial, and gastrointestinal cancers. In addition, there is evidence showing that DM is associated with increased cancer mortality. Common risk factors such as age, obesity, physical inactivity and smoking may contribute to increased cancer risk in patients with DM. Although the mechanistic process that may link diabetes to cancer is not completely understood yet, biological mechanisms linking DM and cancer are hyperglycemia, hyperinsulinemia, increased bioactivity of insulin-like growth factor 1, oxidative stress, dysregulations of sex hormones, and chronic inflammation. However, cancer screening rate is significantly lower in people with DM than that in people without diabetes. Evidence from previous studies suggests that some medications used to treat DM are associated with either increased or reduced risk of cancer. However, there is no strong evidence supporting the association between the use of anti-hyperglycemic medication and specific cancer. In conclusion, all patients with DM should be undergo recommended age- and sex appropriate cancer screenings to promote primary prevention and early detection. Furthermore, cancer should be screened in routine diabetes assessment.

Few studies have focused on the quantification of glycemic lability and hypoglycemic events in Asian patients with type 1 diabetes; therefore, we conducted a study to assess glycemic lability and the severity of hypoglycemia in type 1 diabetic patients in Korea. A total of 124 type 1 diabetic patients were enrolled. Several glycemic lability indexes and hypoglycemic indexes were calculated using four-week self-monitoring of blood glucose (SMBG) data. Due to the dependence of the lability index (LI) on the frequency of glucose measurements, we generated a modified LI by dividing by the number of SMBG measurements per day for a given patient. The numbers of patients in our study with a composite hypoglycemic score ≥ 1,047 or LI ≥ 433 mmol/L(2)/h•week(-1), which was found in a previous study to indicate high risk of severe hypoglycemia or lability, were 0 (0%) and 44 (35%), respectively. Compared to previously reported hypoglycemia indexes, the low blood glucose index was lower in our study. However, the glycemic lability indexes were similar to those in previous studies, with the exception of the LI. The modified LI and the average daily risk range (ADRR) showed higher concordance with other glycemic lability indexes than did the LI or mean amplitude of glycemic excursions (MAGE). The results showed that the hypoglycemic indexes in this study population were lower than the results from Ryan et al. Furthermore, the ADRR or modified LI were better measures for high risk of severe lability than were the LI and MAGE.

CXCR4 expression is important for cell migration and recruitment, suggesting that the expression levels of CXCR4 may be correlated with functional activity of implanted cells for therapeutic neovascularization. Here, we examined differences between umbilical cord blood (CB) donors in the CXCR4 levels of endothelial colony forming cells (ECFCs), which are a subtype of endothelial progenitor cells (EPCs). We investigated the relationships between CXCR4 expression level and SDF-1alpha-induced vascular properties in vitro, and their in vivo contributions to neovascularization. We found that ECFCs isolated from different donors showed differences in CXCR4 expression that were linearly correlated with SDF-1alpha-induced migratory capacity. ECFCs with high CXCR4 expression showed enhanced ERK and Akt activation in response to SDF-1alpha. In addition, SDF-1alpha-induced migration and ERK1/2, Akt, and eNOS activation were reduced by AMD3100, a CXCR4-specific peptide antagonist, or by siRNA-CXCR4. Administration of high-CXCR4-expressing ECFCs resulted in a significant increase in therapeutic potential for blood flow recovery, tissue healing and capillary density compared to low-CXCR4-expressing ECFCs in hindlimb ischemia. Taken together, the functional differences among ECFCs derived from different donors depended on the level of CXCR4 expression, suggesting that CXCR4 expression levels in ECFCs could be a predictive marker for success of ECFC-based angiogenic therapy.

c-Jun N-terminal kinase (JNK) is activated by cellular stress and plays critical roles in diverse types of cell death. However, role of JNK in beta-cell injury is obscure. We investigated the role for JNK in streptozotocin (STZ)-induced beta-cell death. STZ induced JNK activation in insulinoma or islet cells. JNK inhibitors attenuated insulinoma or islet cell death by STZ. STZ-induced JNK activation was decreased by PARP inhibitors, suggesting that JNK activation is downstream of PARP-1. Phosphatase inhibitors induced activation of JNK and abrogated the suppression of STZ-induced JNK activation by PARP inhibitors, suggesting that the inhibition of phosphatases is involved in the activation of JNK by STZ. STZ induced production of reactive oxygen species (ROS) as potential inhibitors of phosphatases, which was suppressed by PARP inhibitors. PARP-1 siRNA attenuated insulinoma cell death and JNK activation after STZ treatment, which was reversed by MKP (MAP kinase phosphatase)-1 siRNA. These results suggest that JNK is activated by STZ downstream of PARP-1 through inactivation of phosphatases such as MKP, which plays important roles in STZ-induced beta-cell death.

The amount of amyloid detectable in islets varies, and is not always correlated with degree of β-cell loss. It has been hypothesized that islet amyloid polypeptide (IAPP) aggregation causes β-cell dysfunction. In this study, we investigated the relationship between IAPP expression and glucose homeostasis in pancreatectomized patients. Human pancreatic head tissues were collected from 46 pancreatic tumor patients. We divided the diabetic cases into two groups, patients with higher IAPP–expressing islets (DM-H) and patients with lower IAPP–expressing islets (DM-L), and compared both groups to patients with normal glucose tolerance (NGT). Interestingly, oral glucose tolerance test analyses showed that DM-L patients had significantly higher glucose levels and lower C-peptide levels than DM-H patients. Furthermore, the DM-H group showed a relative β-cell volume similar to that of the NGT group, as well as a significantly higher relative β-cell volume than the DM-L group. The DM-L group was significantly higher than the DM-H group, not only in the rates of replication and apoptosis, but also in the nuclear C/EBP homologous protein and the ratio of oligomer to IAPP. Thus, IAPP expression may not be an indicator of cell death induction. IAPP, including oligomer, may be an important determinant in the fate of islet β-cells. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 58:731–740, 2010)

Background Mesenchymal stem cells (MSCs), also known as multipotent progenitor cells, release several factors that support cell survival and enhance wound healing. We hypothesized that MSC-secreted molecules would induce a trophic effect in pancreatic islet culture conditions. Methods Pancreatic islets were co-cultured with MSCs, and ADP/ATP ratios, glucose stimulated insulin secretion (GSIS), and DNA fragmentation were evaluated to measure islet quality and viability in vitro. The induction of signal molecules related to the control of survival, function, and angiogenesis was also analyzed. Cell quality assays, DNA fragmentation assays, and islet transplantation into streptozotocin-induced diabetic mice were performed using MSC-conditioned medium (CM)-cultured islets. Furthermore, we identified soluble molecules within MSC-CM. Results Islets co-cultured with MSCs demonstrated lower ADP/ATP ratios, and higher GSIS indexes and viability. Furthermore, co-cultured islets revealed higher levels of anti-apoptotic signal molecules (X-linked inhibitor of apoptosis protein, Bcl-xL, Bcl-2, and heat shock protein-32) and demonstrated increased vascular endothelial growth factor receptor 2 and Tie-2 mRNA expression and increased levels of phosphorylated Tie-2 and focal adhesion kinase protein. Islets cultured in MSC-CM demonstrated lower ADP/ATP ratios, less apoptosis, and a higher GSIS indexes. Diabetic mice that received islet transplants (200 islet equivalent) cultured in MSC-CM for 48 hr demonstrated significantly lower blood glucose levels and enhanced blood vessel formation. In addition, interleukin-6, interleukin-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC-CM. Conclusions These results suggest that the trophic factors secreted by human MSCs enhance islet survival and function after transplantation.

Background The purpose of this study was to investigate whether the presence of the NCEP-ATP III defined metabolic syndrome (MS) is associated with the future development of cardiovascular disease (CVD) and diabetes in Koreans. Methods The study subjects were recruited from among those who visited the Health Promotion Center at the Samsung Medical Center. 2435 subjects (1761 men and 674 women), 20 to 78 years of age, were enrolled and evaluated for the development of new onset CVD (coronary heart disease [CHD] and stroke) during a mean 8.7 years of follow-up. Results The prevalence of the MS at baseline was 21.7% (382/1761) and 11.4% (77/674) in men and women respectively, and the MS was found to be associated with the risk for CVD in both men and women (OR, 1.98; 95% CI, 1.30–3.03 in men, 4.04; 95% CI, 1.78–9.14 in women). More specifically, the MS was associated with the risk for future CHD (OR, 3.68; 95% CI, 1.93–7.01) in men and stroke (OR, 3.96; 95% CI, 1.58–9.94) in women. However, no statistical differences were found between the HOMA-IR tertiles with regard to the risk for CVD. After controlling for fasting plasma glucose (FPG) levels, the predictive power of the MS for an increased risk for diabetes was dramatically decreased (OR, from 3.69 to 1.77) in men, and it no longer was a predictor in women. Conclusions The NCEP-defined MS was found to be associated with the risk for future CVD, i.e., CHD in men and stroke in women.

Anticancer activity of silibinin, a flavonoid, has been demonstrated in various cancer cell types. However, the underlying mechanism and in vivo efficacy in glioma were not elucidated. The present study was undertaken to determine the effect of silibinin on glioma cell proliferation in vitro and to examine whether silibinin inhibits tumor growth in vivo. Silibinin resulted in inhibition of proliferation in a dose- and time-dependent manner, which was largely attributed to cell death. Silibinin induced a transient increase in intracellular Ca2+ followed by an increase in reactive oxygen species (ROS) generation. The silibinin-induced cell death was prevented by EGTA, calpain inhibitor and antioxidants (N-acetylcysteine and Trolox). Western blot analysis showed that silibinin also induced ROS-dependent activation of extracellular signal-regulated kinase, p38 kinase, and c-Jun N-terminal kinase. Inhibitors of these kinases prevented the silibinin-induced cell death. Silibinin caused caspase activation and the silibinin-induced cell death was prevented by caspase inhibitors. Glioma cell migration was also decreased by silibinin treatment. Oral administration of silibinin in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed a decrease in Ki-67 positive cells, an increase in TUNEL-positive cells, and caspase activation. These results indicate that silibinin induces a caspase-dependent cell death via Ca2+/ROS/MAPK-mediated pathway in vitro and inhibits glioma growth in vivo. These data suggest that silibinin may serve as a potential therapeutic agent for malignant human gliomas.

OBJECTIVE—Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib. RESEARCH DESIGN AND METHODS—Glucose tolerance and insulin tolerance tests were done after daily intraperitoneal injection of 25 mg/kg imatinib into db/db and C57BL/6 mice for 4 weeks. Insulin signaling and endoplasmic reticulum stress responses were studied by Western blotting. β-Cell mass and apoptotic β-cell number were determined by combined terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) staining and insulin immunohistochemistry. The in vitro effect of imatinib was studied using HepG2 cells. RESULTS—Imatinib induced remission of diabetes in db/db mice and amelioration of insulin resistance. Expression of endoplasmic reticulum stress markers in the liver and adipose tissues of db/db mice, such as phospho-PERK, phospho-eIF2α, TRB3, CHOP, and phospho–c-Jun NH2-terminal kinase, was reduced by imatinib. Insulin receptor substrate-1 tyrosine phosphorylation and Akt phosphorylation after insulin administration were improved by imatinib. Serum aminotransferase levels and hepatic triglyceride contents were decreased by imatinib. Pancreatic β-cell mass was increased by imatinib, accompanied by decreased TUNEL+ β-cell and increased BrdU+ β-cell numbers. Imatinib attenuated endoplasmic reticulum stress in hepatoma cells in vitro. CONCLUSIONS—Imatinib ameliorated endoplasmic reticulum stress and induced remission of diabetes in db/db mice. Imatinib or related compounds could be used as therapeutic agents against type 2 diabetes and metabolic syndrome.

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.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.