Kwang-won Kim - Academia.edu (original) (raw)

Papers by Kwang-won Kim

Research paper thumbnail of Cardiac Autonomic Neuropathy as a Predictor of Deterioration of the Renal Function in Normoalbuminuric, Normotensive Patients with Type 2 Diabetes Mellitus

Journal of Korean Medical Science, 2009

Our study was performed to determine whether cardiac autonomic neuropathy can predict deteriorati... more Our study was performed to determine whether cardiac autonomic neuropathy can predict deterioration of the renal function in normoalbuminuric, normotensive people with type 2 diabetes mellitus (DM). One hundred and fifty-six normoalbuminuric, normotensive people with type 2 DM were included in our retrospective longitudinal study. We categorized normal patterns, early patterns, and definite or severe patterns according to the results of the cardiac autonomic function test. Of 156 patients included, 54 had normal patterns, 75 had early patterns, 25 had definite or severe patterns, and 2 had atypical patterns. During a median follow-up of nine years, glomerular filtration rates (GFR) remained stable in the normal and early pattern groups (mean changes, 4.50% and 0.77%, respectively) but declined in those with definite or severe patterns (mean change, -10.28%; p=0.047). An abnormal heart response to the deep breathing test of the cardiac autonomic function tests was an independent predictor of GFR decline. Our data suggest that cardiac autonomic neuropathy, especially with a definite or severe pattern, might be associated with a subsequent deterioration in renal function in normoalbuminuric, normotensive people with type 2 DM.

Research paper thumbnail of Role of JNK activation in pancreatic β-cell death by streptozotocin

Molecular and Cellular Endocrinology, 2010

a b s t r a c t c-Jun N-terminal kinase (JNK) is activated by cellular stress and plays critical ... more a b s t r a c t 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 ␤-cell injury is obscure. We investigated the role for JNK in streptozotocin (STZ)-induced ␤-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 ␤-cell death.

Research paper thumbnail of Antiobesity Effects and Improvement of Insulin Sensitivity by 1-Deoxynojirimycin in Animal Models

Journal of Agricultural and Food Chemistry, 2008

The alpha-glucosidase inhibitor 1-deoxynojirimycin (DNJ) is one of the simplest naturally occurri... more The alpha-glucosidase inhibitor 1-deoxynojirimycin (DNJ) is one of the simplest naturally occurring carbohydrate mimics, with promising biological activity in vivo. Although there is considerable interest in the pharmacological effects of DNJ, the antidiabetic effects of DNJ in type 2 diabetes mellitus have received little attention. In this work, DNJ was isolated from the silkworm (Bombyx mori), and its antidiabetic effects were evaluated in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes mellitus, and in control Long-Evans Tokushima Otsuka (LETO) rats. DNJ treatment showed significant antidiabetic effects in OLETF rats, with significant improvements in fasting blood glucose levels and glucose tolerance and, especially, increased insulin sensitivity. Furthermore, there was significant loss of body weight in both groups. DNJ also showed significant antihyperglycemic effects in streptozotocin- and high-fat-diet-induced hyperglycemic rats. Its efficacy and dose profiles were better than those of acarbose, a typical alpha-glucosidase inhibitor in clinical use. Furthermore, a substantial fraction of DNJ was absorbed into the bloodstream within a few minutes of oral administration. DNJ was also detected in the urine. These findings suggest that its postprandial hypoglycemic effect in the gastrointestinal tract is a possible but insufficient mechanism of action underlying the antidiabetic effects of DNJ. Its antiobesity effect and improvement of insulin sensitivity are other possible antidiabetic effects of DNJ.

Research paper thumbnail of Differences in donor CXCR4 expression levels are correlated with functional capacity and therapeutic outcome of angiogenic treatment with endothelial colony forming cells

Biochemical and Biophysical Research Communications, 2010

a b s t r a c t CXCR4 expression is important for cell migration and recruitment, suggesting that... more a b s t r a c t 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-1a-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-1a-induced migratory capacity. ECFCs with high CXCR4 expression showed enhanced ERK and Akt activation in response to SDF-1a. In addition, SDF-1a-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-CXCR4expressing 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.

Research paper thumbnail of Apoptosis of pancreatic β-cells detected in accelerated diabetes of NOD mice: no role of Fas-Fas ligand interaction in autoimmune diabetes

European Journal of Immunology, 1999

Autoreactive T lymphocytes probably cause pancreatic g -cell death by inducing apoptosis. To visu... more Autoreactive T lymphocytes probably cause pancreatic g -cell death by inducing apoptosis. To visualize apoptotic g -cells in vivo, we accelerated diabetes of NOD mice with cyclophosphamide (CY) or adoptive transfer. We also studied whether Fas-mediated apoptosis is involved in the development of diabetes by administrating anti-Fas ligand (FasL) Ab and by grafting Fas-deficient neonatal pancreas from NOD-lpr/lpr mice. Apoptotic cells were clearly shown 8 days after CY treatment. g -cell apoptosis was also observed after adoptive transfer but in a different kinetic pattern. Anti-FasL Ab administration failed to inhibit diabetes after CY treatment or adoptive transfer, while it inhibited Con A-induced hepatitis. Fas-deficient neonatal pancreata were destroyed by lymphocytic infiltration in diabetic NOD mice. Our results clearly demonstrate apoptosis of g -cells in accelerated diabetes and indicate that Fas-FasL interaction is not involved in diabetes of NOD mice, contrary to the previous reports.

Research paper thumbnail of Search for Materials that Influence Human Medullary Thyroid Carcinoma Cell Proliferation

Journal of Korean Endocrine Society, 2009

Background: Surgical excision is the only effective treatment of medullary thyroid carcinoma (MTC... more Background: Surgical excision is the only effective treatment of medullary thyroid carcinoma (MTC) and

Research paper thumbnail of Decreased health-related quality of life in disease-free survivors of differentiated thyroid cancer in Korea

Health and Quality of Life Outcomes, 2010

Background: Concern regarding the health-related quality of life (HRQOL) of long-term survivors o... more Background: Concern regarding the health-related quality of life (HRQOL) of long-term survivors of thyroid cancer has risen due to the rapid increase in the incidence of thyroid cancer, which generally has an excellent prognosis. The aim of this study was to evaluate the status of HRQOL in disease-free survivors of differentiated thyroid carcinoma (DTC) and to evaluate the important determinants of HRQOL. Methods: This was a cross-sectional study in which we interviewed consecutive disease-free survivors of DTC. Three different validated questionnaires ("EORTC QLQ-C30" for various functional domains, the "brief fatigue inventory (BFI)" and the "hospital anxiety and depression scale" (HADS)) were used. Data from a large, population based survey of 1,000 people were used as a control.

Research paper thumbnail of Insulin secretory dysfunction and insulin resistance in the pathogenesis of Korean type 2 diabetes mellitus

Metabolism-clinical and Experimental, 2001

Although insulin resistance has been shown to be a primary defect causing type 2 (non insulin-dep... more Although insulin resistance has been shown to be a primary defect causing type 2 (non insulin-dependent) diabetes mellitus in Pima Indians and Caucasians, insulin secretory defect has also been known to be an important factor in the development of type 2 diabetes. We undertook a study to investigate the initial abnormality of glucose intolerance in Koreans. A total of 370 Korean subjects were classified into 5 groups according to their degree of glucose intolerance (normal fasting glucose [NFG]/normal glucose tolerance [NGT], n = 95; impaired fasting glucose [IFG]/NGT, n = 29; NFG/impaired glucose tolerance [IGT], n = 60; IFG/IGT, n = 68; diabetes, n = 118). Insulinogenic index was used as an index of early-phase insulin secretion. Insulin resistance was assessed by the R value of the homeostasis model assessment [HOMA(R)]. Insulinogenic index significantly decreased in subjects with IFG/NGT and NFG/IGT compared with those with NFG/NGT. However, there was no significant difference in HOMA(R) between subjects with NFG/NGT and those with IFG/NGT or NFG/IGT. Insulinogenic index decreased significantly with the increase of plasma glucose 120-minute value at the earlier stage of glucose intolerance compared with HOMA(R). These results suggest that early-phase insulin secretory defect may be the initial abnormality in the development of type 2 diabetes in Korean subjects.

Research paper thumbnail of Influence of Pancreatic Islets on Spheroid Formation and Functions of Hepatocytes in HepatocytePancreatic Islet Spheroid Culture

Tissue Engineering, 2004

Hepatotrophic stimulation of hepatocytes is necessary to preserve long-term function of hepatocyt... more Hepatotrophic stimulation of hepatocytes is necessary to preserve long-term function of hepatocytes in hepatocyte transplantation and bioartificial liver system. The main source of hepatotrophic factors in portal venous blood seems to be the pancreatic islets. It was also reported that hepatocyte spheroids, tightly packed multicellular aggregates, showed enhanced liver-specific activities and a prolonged differentiated state compared with cells that were maintained as a monolayer. On the basis of these two facts, the authors tried to form hepatocyte-pancreatic islet spheroids and to evaluate the influence of pancreatic islets on spheroid formation and functions of hepatocytes in spheroid culture. Hepatocytes and pancreatic islet cells were harvested from adult male Sprague-Dawley rats weighing 200-250 g. Hepatocytes were cultured in spinner flasks with either basic nonstimulated medium (hepatocytes only [group BH] and cocultures with islet cells [group BI]) or hormone-stimulated medium (hepatocytes only [group HH] and cocultures with islet cells [group HI]). The size and morphology of spheroids, as determined by phase-contrast microscopy, and liver-specific functions, such as albumin secretion, urea synthesis, and ammonia removal, were compared among groups. The results were as follows: the size of spheroids, 66 +/- 53.4 microm, in group BH on day 2 was smaller than in group BI (179 +/- 66.2 microm on day 2, p < 0.05). In group BI, group HH, and group HI, smooth spheroids were observed on culture day 2. However, in group BH rugged incomplete aggregates were observed on the same day. In groups with basal medium, group BI showed better results in terms of hepatocyte-specific function such as albumin secretion, urea synthesis, and ammonia removal compared with group BH on days 2 and 3 (p < 0.05). In groups with hormone-defined medium, cocultures had no impact on albumin secretion rate, urea synthetic rate, and ammonia removal rate. In conclusion, we made a new type of hepatocyte-pancreatic islet spheroid, using a rotational culture method. Pancreatic islets in a spheroid culture system stimulated hepatocyte spheroid formation and some hepatocyte-specific functions in vitro.

Research paper thumbnail of RET ProtoOncogene Mutations Are Restricted to Codon 634 and 618 in Korean Families with Multiple Endocrine Neoplasia 2A

Thyroid, 2004

Background: RET germline mutations predispose to the development of inherited cancer syndrome mul... more Background: RET germline mutations predispose to the development of inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Several variants of the RET proto-oncogene including G691S and S904S have been suggested to act as genetic modifiers at the age of onset of MEN2. Aim: The aim of this study is to characterize clinically and molecularly 7 Cypriot patients with familial medullary thyroid carcinoma (FMTC) and 1 with MEN2A and also to determine the allelic frequencies of the RET variants G691S and S904S. Subjects and methods: Seven probands from FMTC families and 1 from MEN2A were screened for the presence of RET mutations and the G691S and S904S variants. Additionally, 226 healthy Cypriots, who served as controls were analysed in an attempt to compare the frequencies of G691S and S904S RET variants to those observed in the 8 patients. Results: The clinical diagnosis of the probands was based on clinical presentation and supported with biochemical findings. The germline C618R mutation of exon 10 was identified in all 8 probands and in 15 relatives from 7 different families. No significant difference in the G691S/S904S variants allele frequencies between patients (4/16 or 25%) and controls (124/452 or 27.4%) was found. Conclusions: Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) unrelated Cypriot patients which may be explained by a founder effect. Additionally, no association of the G691S/S904S variants was linked with the disease. (J. Endocrinol. Invest. 34: 764-769, 2011) © 2011, Editrice Kurtis Key-words: Familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia 2A, RET proto-oncogene. © 2 0 1 1 , E d i t r i c e K u r t i s F O R P E R S O N A L U S E O N L Y 2. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988, 318: 478-84.

Research paper thumbnail of Severe coronary artery spasm can be associated with hyperthyroidism

Coronary Artery Disease, 2005

Coronary artery spasm is not infrequently seen in Korea. Most of the patients with coronary spasm... more Coronary artery spasm is not infrequently seen in Korea. Most of the patients with coronary spasm show a focal spasm in coronary angiography. However, the cause of the disease is not well known. There have been a few anecdotal case reports of coronary artery spasm associated with hyperthyroidism, but there has not been a report concerning a large series of such patients. Over a period of 5 years and 8 months, we experienced eight patients having the diffuse or severe type of coronary artery spasm in association with hyperthyroidism. We investigated the characteristics of the patients with coronary artery spasm, which was diagnosed by coronary angiography or by provocation with an intracoronary injection of acetylcholine or ergonovine. The demographic data, coronary angiographic findings, thyroid function test results, and the follow-up clinical data of the eight patients having coronary artery spasm associated with hyperthyroidism were analyzed. All eight patients had Graves' disease. In six patients, the coronary arterial vasoconstriction developed during the coronary angiography without an injection of ergonovine. In three patients, the left main stem coronary artery was involved in the spasm. Among these eight patients, five were female, and all of these female patients were < or = 51 years old. All of the patients were treated with anti-thyroid medications, calcium channel blockers, and long-acting nitroglycerines; they all remained free of chest pain during the median follow-up period of 5 years. A severe form of coronary artery spasm could be associated with hyperthyroidism. A high level of suspicion and the thyroid function study should be mandatory for patients with coronary artery spasm, especially for the young female patients.

Research paper thumbnail of A Case of Hyalinizing Trabecular Adenoma of the Thyroid Gland

Journal of Korean Endocrine Society, 2009

Abstract Hyalinizing trabecular tumor is a rare benign thyroid tumor first described by Carney et... more Abstract Hyalinizing trabecular tumor is a rare benign thyroid tumor first described by Carney et al. in 1987. The tumor is characterized by an encapsulated nodule, trabecular arrangement of polygonal, oval, elongated cells, and hyalinized stroma. It is easily ...

Research paper thumbnail of Three siblings with Cerebrotendinous Xanthomatosis: A novel mutation in the CYP27A1 gene

European Journal of Medical Genetics

Research paper thumbnail of Fasting Plasma Glucose Cutoff Value for the Prediction of Future Diabetes Development: A Study of Middle-Aged Koreans in a Health Promotion Center

Journal of Korean Medical Science, 2005

We determined optimal fasting plasma glucose (FPG) cutoff values predictive of future diabetes de... more We determined optimal fasting plasma glucose (FPG) cutoff values predictive of future diabetes development in a group of middle-aged Koreans who visited a health promotion center. The medical records of 2,964 subjects, who attended the Health Promotion Center in 1998 and 2003, were examined. Subjects were classified into four groups according to their baseline FPG values (Group 1:FPG <5.0 mM/L; Group 2: 5.0< or =FPG <5.6 mM/L; Group 3: 5.6< or =FPG <6.1 mM/L; Group 4: 6.1< or =FPG <7.0 mM/L). No significant difference was observed between Group 1 and Group 2 in terms of diabetes incidence. However, incidence in Group 3 was significantly higher than that in Group 1 [hazards ratio 4.88 (1.65-14.41), p=0.004] and the hazards ratio in Group 4 for diabetes was 36.91 (13.11-103.61), p<0.001, versus Group 1. Receiver operator characteristics curve analysis showed that an FPG of 5.97 mM/L represents the lower limit and gives the best combination of sensitivity and specificity. Our data shows that the risk of future diabetes development started to increase below an FPG of 6.1 mM/L and suggests the importance of efforts to modify diabetes development risk factors at lower impaired fasting glucose levels.

Research paper thumbnail of Pathologic Changes and Glucose Homeostasis According to Expression of Human Islet Amyloid Polypeptide in Type 2 Diabetic Patients

Journal of Histochemistry & Cytochemistry, 2010

S U M M A R Y The amount of amyloid detectable in islets varies, and is not always correlated wit... more S U M M A R Y The amount of amyloid detectable in islets varies, and is not always correlated with degree of b-cell loss. It has been hypothesized that islet amyloid polypeptide (IAPP) aggregation causes b-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 b-cell volume similar to that of the NGT group, as well as a significantly higher relative b-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 b-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)

Research paper thumbnail of Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia

Cell Metabolism, 2008

Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organell... more Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic b cells and glucose homeostasis has not been described. We produced mice with b cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. b cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of b cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca 2+ transients in autophagy-deficient b cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in b cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic b cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles.

Research paper thumbnail of Delayed improvement of insulin secretion after autologous islet transplantation in partially pancreatectomized patients

Metabolism-clinical and Experimental, 2009

The purpose of this study was to evaluate the effects of autologous islet transplantation (ITx) o... more The purpose of this study was to evaluate the effects of autologous islet transplantation (ITx) on glucose homeostasis and insulin secretory function after partial pancreatectomy (Px). Fourteen nondiabetic patients who underwent distal Px and autologous ITx for benign pancreatic tumors were enrolled in the study (Px + ITx group). Fourteen normal glucose-tolerant controls and 6 Px without ITx controls were recruited, and all groups were followed over a 24-month period. They performed the 75-g oral glucose tolerance test and the 1-mg glucagon stimulation test. Hemoglobin A 1c was measured, and indices of insulin secretion were calculated. In the Px + ITx group, insulin secretion increased after a nadir at 6 months. Glucose tolerance, which had been abruptly impaired immediately after Px, recovered until 6 months and stabilized thereafter. As a result, differences in glucose intolerance emerged between the subjects in the Px group and those in the Px + ITx group at 24 months after Px. Characteristic variables in the better insulin secretory subjects in the Px + ITx group included younger age, less extensive pancreas resection, and a greater number of total islets. In summary, delayed amelioration of glucose intolerance was induced by autologous ITx after partial Px, even with a small number of islets.

Research paper thumbnail of Differences in serum thyroglobulin measurements by 3 commercial immunoradiometric assay kits and laboratory standardization using Certified Reference Material 457 (CRM457

Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2009

BackgroundSerum thyroglobulin (Tg) is essential in the follow-up of patients with differentiated ... more BackgroundSerum thyroglobulin (Tg) is essential in the follow-up of patients with differentiated thyroid carcinoma (DTC). However, interchangeability and standardization between Tg assays have not yet been achieved, even with the development of an international Tg standard (Certified Reference Material 457 [CRM-457]).Serum thyroglobulin (Tg) is essential in the follow-up of patients with differentiated thyroid carcinoma (DTC). However, interchangeability and standardization between Tg assays have not yet been achieved, even with the development of an international Tg standard (Certified Reference Material 457 [CRM-457]).MethodsSerum Tg from 30 DTC patients and serially diluted CRM-457 were measured using 3 different immunoradiometric assays (IRMA-1, IRMA-2, IRMA-3). The intraclass correlation coefficient (ICC) method was used to describe the concordance of each IRMA to CRM-457.Serum Tg from 30 DTC patients and serially diluted CRM-457 were measured using 3 different immunoradiometric assays (IRMA-1, IRMA-2, IRMA-3). The intraclass correlation coefficient (ICC) method was used to describe the concordance of each IRMA to CRM-457.ResultsThe serum Tg measured by 3 different IRMAs correlated well (r > .85, p < .0001), but clinically relevant discrepancies were found in 13.3% of patients. IRMA-3, which claims to be standardized to CRM-457, showed the best ICC (p1 = .98) for the CRM-457.The serum Tg measured by 3 different IRMAs correlated well (r > .85, p < .0001), but clinically relevant discrepancies were found in 13.3% of patients. IRMA-3, which claims to be standardized to CRM-457, showed the best ICC (p1 = .98) for the CRM-457.ConclusionsHospitals caring for patients with DTC should either set their own cutoffs for IRMAs for Tg based on their patient pools, or adopt IRMAs standardized to CRM-457 and calibrate their laboratory using CRM-457. © 2009 Wiley Periodicals, Inc. Head Neck, 2010Hospitals caring for patients with DTC should either set their own cutoffs for IRMAs for Tg based on their patient pools, or adopt IRMAs standardized to CRM-457 and calibrate their laboratory using CRM-457. © 2009 Wiley Periodicals, Inc. Head Neck, 2010

Research paper thumbnail of RET ProtoOncogene Mutations Are Restricted to Codon 634 and 618 in Korean Families with Multiple Endocrine Neoplasia 2A

Thyroid, 2004

Background: RET germline mutations predispose to the development of inherited cancer syndrome mul... more Background: RET germline mutations predispose to the development of inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Several variants of the RET proto-oncogene including G691S and S904S have been suggested to act as genetic modifiers at the age of onset of MEN2. Aim: The aim of this study is to characterize clinically and molecularly 7 Cypriot patients with familial medullary thyroid carcinoma (FMTC) and 1 with MEN2A and also to determine the allelic frequencies of the RET variants G691S and S904S. Subjects and methods: Seven probands from FMTC families and 1 from MEN2A were screened for the presence of RET mutations and the G691S and S904S variants. Additionally, 226 healthy Cypriots, who served as controls were analysed in an attempt to compare the frequencies of G691S and S904S RET variants to those observed in the 8 patients. Results: The clinical diagnosis of the probands was based on clinical presentation and supported with biochemical findings. The germline C618R mutation of exon 10 was identified in all 8 probands and in 15 relatives from 7 different families. No significant difference in the G691S/S904S variants allele frequencies between patients (4/16 or 25%) and controls (124/452 or 27.4%) was found. Conclusions: Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) unrelated Cypriot patients which may be explained by a founder effect. Additionally, no association of the G691S/S904S variants was linked with the disease. (J. Endocrinol. Invest. 34: 764-769, 2011) © 2011, Editrice Kurtis Key-words: Familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia 2A, RET proto-oncogene. © 2 0 1 1 , E d i t r i c e K u r t i s F O R P E R S O N A L U S E O N L Y 2. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988, 318: 478-84.

Research paper thumbnail of Identification of a novel human member of the DEAD box protein family

Biochimica Et Biophysica Acta-molecular Basis of Disease, 2000

The cDNA library of human pancreatic islets was screened with sera from patients with insulin-dep... more The cDNA library of human pancreatic islets was screened with sera from patients with insulin-dependent diabetes mellitus (IDDM). From the library screening, we isolated a novel cDNA, RNA helicase-like protein (RHELP), which exhibited strong sequence homology to p68 RNA helicase, a prototypic member of the DEAD (Asp-Glu-Ala-Asp) box protein family. Sequence analysis of the cDNA revealed that RHELP contained DEAD sequence motif and other conserved motifs of the DEAD box protein family, indicating that RHELP is a new member of this family. DEAD box-containing proteins are involved in the RNA processing, ribosome assembly, spermatogenesis, embryogenesis, and cell growth and division. RHELP showed 42% and 44% amino acid sequence identity to human p68 RNA helicase and yeast DBP2 RNA helicase, respectively, among the DEAD box protein family. Northern blot analysis revealed that RHELP is expressed in most tissues including the liver, lung, tonsil, thymus, and muscle in addition to the pancreatic islets. In vivo or in vitro functions of RHELP as a putative RNA helicase and its potential role as a diabetic autoantigen need to be further investigated. ß

Research paper thumbnail of Cardiac Autonomic Neuropathy as a Predictor of Deterioration of the Renal Function in Normoalbuminuric, Normotensive Patients with Type 2 Diabetes Mellitus

Journal of Korean Medical Science, 2009

Our study was performed to determine whether cardiac autonomic neuropathy can predict deteriorati... more Our study was performed to determine whether cardiac autonomic neuropathy can predict deterioration of the renal function in normoalbuminuric, normotensive people with type 2 diabetes mellitus (DM). One hundred and fifty-six normoalbuminuric, normotensive people with type 2 DM were included in our retrospective longitudinal study. We categorized normal patterns, early patterns, and definite or severe patterns according to the results of the cardiac autonomic function test. Of 156 patients included, 54 had normal patterns, 75 had early patterns, 25 had definite or severe patterns, and 2 had atypical patterns. During a median follow-up of nine years, glomerular filtration rates (GFR) remained stable in the normal and early pattern groups (mean changes, 4.50% and 0.77%, respectively) but declined in those with definite or severe patterns (mean change, -10.28%; p=0.047). An abnormal heart response to the deep breathing test of the cardiac autonomic function tests was an independent predictor of GFR decline. Our data suggest that cardiac autonomic neuropathy, especially with a definite or severe pattern, might be associated with a subsequent deterioration in renal function in normoalbuminuric, normotensive people with type 2 DM.

Research paper thumbnail of Role of JNK activation in pancreatic β-cell death by streptozotocin

Molecular and Cellular Endocrinology, 2010

a b s t r a c t c-Jun N-terminal kinase (JNK) is activated by cellular stress and plays critical ... more a b s t r a c t 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 ␤-cell injury is obscure. We investigated the role for JNK in streptozotocin (STZ)-induced ␤-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 ␤-cell death.

Research paper thumbnail of Antiobesity Effects and Improvement of Insulin Sensitivity by 1-Deoxynojirimycin in Animal Models

Journal of Agricultural and Food Chemistry, 2008

The alpha-glucosidase inhibitor 1-deoxynojirimycin (DNJ) is one of the simplest naturally occurri... more The alpha-glucosidase inhibitor 1-deoxynojirimycin (DNJ) is one of the simplest naturally occurring carbohydrate mimics, with promising biological activity in vivo. Although there is considerable interest in the pharmacological effects of DNJ, the antidiabetic effects of DNJ in type 2 diabetes mellitus have received little attention. In this work, DNJ was isolated from the silkworm (Bombyx mori), and its antidiabetic effects were evaluated in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes mellitus, and in control Long-Evans Tokushima Otsuka (LETO) rats. DNJ treatment showed significant antidiabetic effects in OLETF rats, with significant improvements in fasting blood glucose levels and glucose tolerance and, especially, increased insulin sensitivity. Furthermore, there was significant loss of body weight in both groups. DNJ also showed significant antihyperglycemic effects in streptozotocin- and high-fat-diet-induced hyperglycemic rats. Its efficacy and dose profiles were better than those of acarbose, a typical alpha-glucosidase inhibitor in clinical use. Furthermore, a substantial fraction of DNJ was absorbed into the bloodstream within a few minutes of oral administration. DNJ was also detected in the urine. These findings suggest that its postprandial hypoglycemic effect in the gastrointestinal tract is a possible but insufficient mechanism of action underlying the antidiabetic effects of DNJ. Its antiobesity effect and improvement of insulin sensitivity are other possible antidiabetic effects of DNJ.

Research paper thumbnail of Differences in donor CXCR4 expression levels are correlated with functional capacity and therapeutic outcome of angiogenic treatment with endothelial colony forming cells

Biochemical and Biophysical Research Communications, 2010

a b s t r a c t CXCR4 expression is important for cell migration and recruitment, suggesting that... more a b s t r a c t 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-1a-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-1a-induced migratory capacity. ECFCs with high CXCR4 expression showed enhanced ERK and Akt activation in response to SDF-1a. In addition, SDF-1a-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-CXCR4expressing 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.

Research paper thumbnail of Apoptosis of pancreatic β-cells detected in accelerated diabetes of NOD mice: no role of Fas-Fas ligand interaction in autoimmune diabetes

European Journal of Immunology, 1999

Autoreactive T lymphocytes probably cause pancreatic g -cell death by inducing apoptosis. To visu... more Autoreactive T lymphocytes probably cause pancreatic g -cell death by inducing apoptosis. To visualize apoptotic g -cells in vivo, we accelerated diabetes of NOD mice with cyclophosphamide (CY) or adoptive transfer. We also studied whether Fas-mediated apoptosis is involved in the development of diabetes by administrating anti-Fas ligand (FasL) Ab and by grafting Fas-deficient neonatal pancreas from NOD-lpr/lpr mice. Apoptotic cells were clearly shown 8 days after CY treatment. g -cell apoptosis was also observed after adoptive transfer but in a different kinetic pattern. Anti-FasL Ab administration failed to inhibit diabetes after CY treatment or adoptive transfer, while it inhibited Con A-induced hepatitis. Fas-deficient neonatal pancreata were destroyed by lymphocytic infiltration in diabetic NOD mice. Our results clearly demonstrate apoptosis of g -cells in accelerated diabetes and indicate that Fas-FasL interaction is not involved in diabetes of NOD mice, contrary to the previous reports.

Research paper thumbnail of Search for Materials that Influence Human Medullary Thyroid Carcinoma Cell Proliferation

Journal of Korean Endocrine Society, 2009

Background: Surgical excision is the only effective treatment of medullary thyroid carcinoma (MTC... more Background: Surgical excision is the only effective treatment of medullary thyroid carcinoma (MTC) and

Research paper thumbnail of Decreased health-related quality of life in disease-free survivors of differentiated thyroid cancer in Korea

Health and Quality of Life Outcomes, 2010

Background: Concern regarding the health-related quality of life (HRQOL) of long-term survivors o... more Background: Concern regarding the health-related quality of life (HRQOL) of long-term survivors of thyroid cancer has risen due to the rapid increase in the incidence of thyroid cancer, which generally has an excellent prognosis. The aim of this study was to evaluate the status of HRQOL in disease-free survivors of differentiated thyroid carcinoma (DTC) and to evaluate the important determinants of HRQOL. Methods: This was a cross-sectional study in which we interviewed consecutive disease-free survivors of DTC. Three different validated questionnaires ("EORTC QLQ-C30" for various functional domains, the "brief fatigue inventory (BFI)" and the "hospital anxiety and depression scale" (HADS)) were used. Data from a large, population based survey of 1,000 people were used as a control.

Research paper thumbnail of Insulin secretory dysfunction and insulin resistance in the pathogenesis of Korean type 2 diabetes mellitus

Metabolism-clinical and Experimental, 2001

Although insulin resistance has been shown to be a primary defect causing type 2 (non insulin-dep... more Although insulin resistance has been shown to be a primary defect causing type 2 (non insulin-dependent) diabetes mellitus in Pima Indians and Caucasians, insulin secretory defect has also been known to be an important factor in the development of type 2 diabetes. We undertook a study to investigate the initial abnormality of glucose intolerance in Koreans. A total of 370 Korean subjects were classified into 5 groups according to their degree of glucose intolerance (normal fasting glucose [NFG]/normal glucose tolerance [NGT], n = 95; impaired fasting glucose [IFG]/NGT, n = 29; NFG/impaired glucose tolerance [IGT], n = 60; IFG/IGT, n = 68; diabetes, n = 118). Insulinogenic index was used as an index of early-phase insulin secretion. Insulin resistance was assessed by the R value of the homeostasis model assessment [HOMA(R)]. Insulinogenic index significantly decreased in subjects with IFG/NGT and NFG/IGT compared with those with NFG/NGT. However, there was no significant difference in HOMA(R) between subjects with NFG/NGT and those with IFG/NGT or NFG/IGT. Insulinogenic index decreased significantly with the increase of plasma glucose 120-minute value at the earlier stage of glucose intolerance compared with HOMA(R). These results suggest that early-phase insulin secretory defect may be the initial abnormality in the development of type 2 diabetes in Korean subjects.

Research paper thumbnail of Influence of Pancreatic Islets on Spheroid Formation and Functions of Hepatocytes in HepatocytePancreatic Islet Spheroid Culture

Tissue Engineering, 2004

Hepatotrophic stimulation of hepatocytes is necessary to preserve long-term function of hepatocyt... more Hepatotrophic stimulation of hepatocytes is necessary to preserve long-term function of hepatocytes in hepatocyte transplantation and bioartificial liver system. The main source of hepatotrophic factors in portal venous blood seems to be the pancreatic islets. It was also reported that hepatocyte spheroids, tightly packed multicellular aggregates, showed enhanced liver-specific activities and a prolonged differentiated state compared with cells that were maintained as a monolayer. On the basis of these two facts, the authors tried to form hepatocyte-pancreatic islet spheroids and to evaluate the influence of pancreatic islets on spheroid formation and functions of hepatocytes in spheroid culture. Hepatocytes and pancreatic islet cells were harvested from adult male Sprague-Dawley rats weighing 200-250 g. Hepatocytes were cultured in spinner flasks with either basic nonstimulated medium (hepatocytes only [group BH] and cocultures with islet cells [group BI]) or hormone-stimulated medium (hepatocytes only [group HH] and cocultures with islet cells [group HI]). The size and morphology of spheroids, as determined by phase-contrast microscopy, and liver-specific functions, such as albumin secretion, urea synthesis, and ammonia removal, were compared among groups. The results were as follows: the size of spheroids, 66 +/- 53.4 microm, in group BH on day 2 was smaller than in group BI (179 +/- 66.2 microm on day 2, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In group BI, group HH, and group HI, smooth spheroids were observed on culture day 2. However, in group BH rugged incomplete aggregates were observed on the same day. In groups with basal medium, group BI showed better results in terms of hepatocyte-specific function such as albumin secretion, urea synthesis, and ammonia removal compared with group BH on days 2 and 3 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In groups with hormone-defined medium, cocultures had no impact on albumin secretion rate, urea synthetic rate, and ammonia removal rate. In conclusion, we made a new type of hepatocyte-pancreatic islet spheroid, using a rotational culture method. Pancreatic islets in a spheroid culture system stimulated hepatocyte spheroid formation and some hepatocyte-specific functions in vitro.

Research paper thumbnail of RET ProtoOncogene Mutations Are Restricted to Codon 634 and 618 in Korean Families with Multiple Endocrine Neoplasia 2A

Thyroid, 2004

Background: RET germline mutations predispose to the development of inherited cancer syndrome mul... more Background: RET germline mutations predispose to the development of inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Several variants of the RET proto-oncogene including G691S and S904S have been suggested to act as genetic modifiers at the age of onset of MEN2. Aim: The aim of this study is to characterize clinically and molecularly 7 Cypriot patients with familial medullary thyroid carcinoma (FMTC) and 1 with MEN2A and also to determine the allelic frequencies of the RET variants G691S and S904S. Subjects and methods: Seven probands from FMTC families and 1 from MEN2A were screened for the presence of RET mutations and the G691S and S904S variants. Additionally, 226 healthy Cypriots, who served as controls were analysed in an attempt to compare the frequencies of G691S and S904S RET variants to those observed in the 8 patients. Results: The clinical diagnosis of the probands was based on clinical presentation and supported with biochemical findings. The germline C618R mutation of exon 10 was identified in all 8 probands and in 15 relatives from 7 different families. No significant difference in the G691S/S904S variants allele frequencies between patients (4/16 or 25%) and controls (124/452 or 27.4%) was found. Conclusions: Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) unrelated Cypriot patients which may be explained by a founder effect. Additionally, no association of the G691S/S904S variants was linked with the disease. (J. Endocrinol. Invest. 34: 764-769, 2011) © 2011, Editrice Kurtis Key-words: Familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia 2A, RET proto-oncogene. © 2 0 1 1 , E d i t r i c e K u r t i s F O R P E R S O N A L U S E O N L Y 2. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988, 318: 478-84.

Research paper thumbnail of Severe coronary artery spasm can be associated with hyperthyroidism

Coronary Artery Disease, 2005

Coronary artery spasm is not infrequently seen in Korea. Most of the patients with coronary spasm... more Coronary artery spasm is not infrequently seen in Korea. Most of the patients with coronary spasm show a focal spasm in coronary angiography. However, the cause of the disease is not well known. There have been a few anecdotal case reports of coronary artery spasm associated with hyperthyroidism, but there has not been a report concerning a large series of such patients. Over a period of 5 years and 8 months, we experienced eight patients having the diffuse or severe type of coronary artery spasm in association with hyperthyroidism. We investigated the characteristics of the patients with coronary artery spasm, which was diagnosed by coronary angiography or by provocation with an intracoronary injection of acetylcholine or ergonovine. The demographic data, coronary angiographic findings, thyroid function test results, and the follow-up clinical data of the eight patients having coronary artery spasm associated with hyperthyroidism were analyzed. All eight patients had Graves&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; disease. In six patients, the coronary arterial vasoconstriction developed during the coronary angiography without an injection of ergonovine. In three patients, the left main stem coronary artery was involved in the spasm. Among these eight patients, five were female, and all of these female patients were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 51 years old. All of the patients were treated with anti-thyroid medications, calcium channel blockers, and long-acting nitroglycerines; they all remained free of chest pain during the median follow-up period of 5 years. A severe form of coronary artery spasm could be associated with hyperthyroidism. A high level of suspicion and the thyroid function study should be mandatory for patients with coronary artery spasm, especially for the young female patients.

Research paper thumbnail of A Case of Hyalinizing Trabecular Adenoma of the Thyroid Gland

Journal of Korean Endocrine Society, 2009

Abstract Hyalinizing trabecular tumor is a rare benign thyroid tumor first described by Carney et... more Abstract Hyalinizing trabecular tumor is a rare benign thyroid tumor first described by Carney et al. in 1987. The tumor is characterized by an encapsulated nodule, trabecular arrangement of polygonal, oval, elongated cells, and hyalinized stroma. It is easily ...

Research paper thumbnail of Three siblings with Cerebrotendinous Xanthomatosis: A novel mutation in the CYP27A1 gene

European Journal of Medical Genetics

Research paper thumbnail of Fasting Plasma Glucose Cutoff Value for the Prediction of Future Diabetes Development: A Study of Middle-Aged Koreans in a Health Promotion Center

Journal of Korean Medical Science, 2005

We determined optimal fasting plasma glucose (FPG) cutoff values predictive of future diabetes de... more We determined optimal fasting plasma glucose (FPG) cutoff values predictive of future diabetes development in a group of middle-aged Koreans who visited a health promotion center. The medical records of 2,964 subjects, who attended the Health Promotion Center in 1998 and 2003, were examined. Subjects were classified into four groups according to their baseline FPG values (Group 1:FPG &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5.0 mM/L; Group 2: 5.0&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =FPG &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5.6 mM/L; Group 3: 5.6&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =FPG &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;6.1 mM/L; Group 4: 6.1&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =FPG &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;7.0 mM/L). No significant difference was observed between Group 1 and Group 2 in terms of diabetes incidence. However, incidence in Group 3 was significantly higher than that in Group 1 [hazards ratio 4.88 (1.65-14.41), p=0.004] and the hazards ratio in Group 4 for diabetes was 36.91 (13.11-103.61), p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001, versus Group 1. Receiver operator characteristics curve analysis showed that an FPG of 5.97 mM/L represents the lower limit and gives the best combination of sensitivity and specificity. Our data shows that the risk of future diabetes development started to increase below an FPG of 6.1 mM/L and suggests the importance of efforts to modify diabetes development risk factors at lower impaired fasting glucose levels.

Research paper thumbnail of Pathologic Changes and Glucose Homeostasis According to Expression of Human Islet Amyloid Polypeptide in Type 2 Diabetic Patients

Journal of Histochemistry & Cytochemistry, 2010

S U M M A R Y The amount of amyloid detectable in islets varies, and is not always correlated wit... more S U M M A R Y The amount of amyloid detectable in islets varies, and is not always correlated with degree of b-cell loss. It has been hypothesized that islet amyloid polypeptide (IAPP) aggregation causes b-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 b-cell volume similar to that of the NGT group, as well as a significantly higher relative b-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 b-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)

Research paper thumbnail of Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia

Cell Metabolism, 2008

Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organell... more Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic b cells and glucose homeostasis has not been described. We produced mice with b cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. b cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of b cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca 2+ transients in autophagy-deficient b cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in b cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic b cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles.

Research paper thumbnail of Delayed improvement of insulin secretion after autologous islet transplantation in partially pancreatectomized patients

Metabolism-clinical and Experimental, 2009

The purpose of this study was to evaluate the effects of autologous islet transplantation (ITx) o... more The purpose of this study was to evaluate the effects of autologous islet transplantation (ITx) on glucose homeostasis and insulin secretory function after partial pancreatectomy (Px). Fourteen nondiabetic patients who underwent distal Px and autologous ITx for benign pancreatic tumors were enrolled in the study (Px + ITx group). Fourteen normal glucose-tolerant controls and 6 Px without ITx controls were recruited, and all groups were followed over a 24-month period. They performed the 75-g oral glucose tolerance test and the 1-mg glucagon stimulation test. Hemoglobin A 1c was measured, and indices of insulin secretion were calculated. In the Px + ITx group, insulin secretion increased after a nadir at 6 months. Glucose tolerance, which had been abruptly impaired immediately after Px, recovered until 6 months and stabilized thereafter. As a result, differences in glucose intolerance emerged between the subjects in the Px group and those in the Px + ITx group at 24 months after Px. Characteristic variables in the better insulin secretory subjects in the Px + ITx group included younger age, less extensive pancreas resection, and a greater number of total islets. In summary, delayed amelioration of glucose intolerance was induced by autologous ITx after partial Px, even with a small number of islets.

Research paper thumbnail of Differences in serum thyroglobulin measurements by 3 commercial immunoradiometric assay kits and laboratory standardization using Certified Reference Material 457 (CRM457

Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2009

BackgroundSerum thyroglobulin (Tg) is essential in the follow-up of patients with differentiated ... more BackgroundSerum thyroglobulin (Tg) is essential in the follow-up of patients with differentiated thyroid carcinoma (DTC). However, interchangeability and standardization between Tg assays have not yet been achieved, even with the development of an international Tg standard (Certified Reference Material 457 [CRM-457]).Serum thyroglobulin (Tg) is essential in the follow-up of patients with differentiated thyroid carcinoma (DTC). However, interchangeability and standardization between Tg assays have not yet been achieved, even with the development of an international Tg standard (Certified Reference Material 457 [CRM-457]).MethodsSerum Tg from 30 DTC patients and serially diluted CRM-457 were measured using 3 different immunoradiometric assays (IRMA-1, IRMA-2, IRMA-3). The intraclass correlation coefficient (ICC) method was used to describe the concordance of each IRMA to CRM-457.Serum Tg from 30 DTC patients and serially diluted CRM-457 were measured using 3 different immunoradiometric assays (IRMA-1, IRMA-2, IRMA-3). The intraclass correlation coefficient (ICC) method was used to describe the concordance of each IRMA to CRM-457.ResultsThe serum Tg measured by 3 different IRMAs correlated well (r > .85, p < .0001), but clinically relevant discrepancies were found in 13.3% of patients. IRMA-3, which claims to be standardized to CRM-457, showed the best ICC (p1 = .98) for the CRM-457.The serum Tg measured by 3 different IRMAs correlated well (r > .85, p < .0001), but clinically relevant discrepancies were found in 13.3% of patients. IRMA-3, which claims to be standardized to CRM-457, showed the best ICC (p1 = .98) for the CRM-457.ConclusionsHospitals caring for patients with DTC should either set their own cutoffs for IRMAs for Tg based on their patient pools, or adopt IRMAs standardized to CRM-457 and calibrate their laboratory using CRM-457. © 2009 Wiley Periodicals, Inc. Head Neck, 2010Hospitals caring for patients with DTC should either set their own cutoffs for IRMAs for Tg based on their patient pools, or adopt IRMAs standardized to CRM-457 and calibrate their laboratory using CRM-457. © 2009 Wiley Periodicals, Inc. Head Neck, 2010

Research paper thumbnail of RET ProtoOncogene Mutations Are Restricted to Codon 634 and 618 in Korean Families with Multiple Endocrine Neoplasia 2A

Thyroid, 2004

Background: RET germline mutations predispose to the development of inherited cancer syndrome mul... more Background: RET germline mutations predispose to the development of inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Several variants of the RET proto-oncogene including G691S and S904S have been suggested to act as genetic modifiers at the age of onset of MEN2. Aim: The aim of this study is to characterize clinically and molecularly 7 Cypriot patients with familial medullary thyroid carcinoma (FMTC) and 1 with MEN2A and also to determine the allelic frequencies of the RET variants G691S and S904S. Subjects and methods: Seven probands from FMTC families and 1 from MEN2A were screened for the presence of RET mutations and the G691S and S904S variants. Additionally, 226 healthy Cypriots, who served as controls were analysed in an attempt to compare the frequencies of G691S and S904S RET variants to those observed in the 8 patients. Results: The clinical diagnosis of the probands was based on clinical presentation and supported with biochemical findings. The germline C618R mutation of exon 10 was identified in all 8 probands and in 15 relatives from 7 different families. No significant difference in the G691S/S904S variants allele frequencies between patients (4/16 or 25%) and controls (124/452 or 27.4%) was found. Conclusions: Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) unrelated Cypriot patients which may be explained by a founder effect. Additionally, no association of the G691S/S904S variants was linked with the disease. (J. Endocrinol. Invest. 34: 764-769, 2011) © 2011, Editrice Kurtis Key-words: Familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia 2A, RET proto-oncogene. © 2 0 1 1 , E d i t r i c e K u r t i s F O R P E R S O N A L U S E O N L Y 2. Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988, 318: 478-84.

Research paper thumbnail of Identification of a novel human member of the DEAD box protein family

Biochimica Et Biophysica Acta-molecular Basis of Disease, 2000

The cDNA library of human pancreatic islets was screened with sera from patients with insulin-dep... more The cDNA library of human pancreatic islets was screened with sera from patients with insulin-dependent diabetes mellitus (IDDM). From the library screening, we isolated a novel cDNA, RNA helicase-like protein (RHELP), which exhibited strong sequence homology to p68 RNA helicase, a prototypic member of the DEAD (Asp-Glu-Ala-Asp) box protein family. Sequence analysis of the cDNA revealed that RHELP contained DEAD sequence motif and other conserved motifs of the DEAD box protein family, indicating that RHELP is a new member of this family. DEAD box-containing proteins are involved in the RNA processing, ribosome assembly, spermatogenesis, embryogenesis, and cell growth and division. RHELP showed 42% and 44% amino acid sequence identity to human p68 RNA helicase and yeast DBP2 RNA helicase, respectively, among the DEAD box protein family. Northern blot analysis revealed that RHELP is expressed in most tissues including the liver, lung, tonsil, thymus, and muscle in addition to the pancreatic islets. In vivo or in vitro functions of RHELP as a putative RNA helicase and its potential role as a diabetic autoantigen need to be further investigated. ß