A Multicenter, Randomized, Controlled Trial for Assessing the Usefulness of Suppressing Thyroid Stimulating Hormone Target Levels after Thyroid Lobectomy in Low to Intermediate Risk Thyroid Cancer Patients (MASTER): A Study Protocol

Background@#Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. @*Methods@#This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. @*Conclusion@#The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

A Multicenter, Randomized, Controlled Trial for Assessing the Usefulness of Suppressing Thyroid Stimulating Hormone Target Levels after Thyroid Lobectomy in Low to Intermediate Risk Thyroid Cancer Patients (MASTER): A Study Protocol

Background@#Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. @*Methods@#This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. @*Conclusion@#The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Serum Transferrin Predicts New-Onset Type 2 Diabetes in Koreans: A 4-Year Retrospective Longitudinal Study

Background@#It is well known that high serum ferritin, a marker of iron storage, predicts incident type 2 diabetes. Limited information is available on the association between transferrin, another marker of iron metabolism, and type 2 diabetes. Thus, we investigated the association between transferrin and incident type 2 diabetes. @*Methods@#Total 31,717 participants (mean age, 40.4±7.2 years) in a health screening program in 2005 were assessed via cross-sectional analysis. We included 30,699 subjects who underwent medical check-up in 2005 and 2009 and did not have type 2 diabetes at baseline in this retrospective longitudinal analysis. @*Results@#The serum transferrin level was higher in the type 2 diabetes group than in the non-type 2 diabetes group (58.32±7.74 μmol/L vs. 56.17±7.96 μmol/L, P<0.001). Transferrin correlated with fasting serum glucose and glycosylated hemoglobin in the correlational analysis (r=0.062, P<0.001 and r=0.077, P<0.001, respectively) after full adjustment for covariates. Transferrin was more closely related to homeostasis model assessment of insulin resistance than to homeostasis model assessment of β cell function (r=0.042, P<0.001 and r=–0.019, P=0.004, respectively) after full adjustment. Transferrin predicted incident type 2 diabetes in non-type 2 diabetic subjects in a multivariate linear regression analysis; the odds ratio (95% confidence interval [CI]) of the 3rd tertile compared to that in the 1st tertile of transferrin for incident diabetes was 1.319 (95% CI, 1.082 to 1.607) after full adjustment (P=0.006). @*Conclusion@#Transferrin is positively associated with incident type 2 diabetes in Koreans.

Comparison of outcomes according to urine chemistry testing time for the causes of acute kidney injury patients admitted to the emergency room

Objective@#The rapid identification and treatment of an acute kidney injury (AKI) can help to restore the kidney function. To differentiate between pre-renal AKI and intrinsic AKI, a urine chemistry test was performed to determine the function of the renal tubules. On the other hand, there is no report showing that it is helpful to arrive at the hospital as early as possible and to perform these urine chemistry tests as soon as possible. @*Methods@#This study analyzed the timing of urinary chemistry tests in AKI patients who were admitted to the author’s hospital through the emergency departments (ED) in the last three years and divided into two groups. The early group was defined as patients who performed the test within three hours of arrival in the ED. The late group was defined as patients who were late or not. The prognostic factors were the change in 30-day estimated glomerular filtration rate (eGFR) and duration of hospital stay. @*Results@#The changes of eGFR after 30 days in each group were 41.6±27.57 mL/min/1.73 m2 (early group, n=92) vs. 30.39±26.37 mL/min/1.73 m2 (late group, n=180) (P=0.001). Early group patients were discharged more quickly than patients in the late group (hospital day, 11.49±10.14 vs. 13.84±10.53; P=0.041). @*Conclusion@#A urine chemistry test is a test to help determine the cause of AKI. Based on the results of urine chemistry performed within three hours after arrival at the hospital, patients with AKI who visited the emergency room had betterimproved kidney function and less hospitalization time than the patients who were late or untested at the time of treatment.

Comparison of outcomes according to urine chemistry testing time for the causes of acute kidney injury patients admitted to the emergency room

Objective@#The rapid identification and treatment of an acute kidney injury (AKI) can help to restore the kidney function. To differentiate between pre-renal AKI and intrinsic AKI, a urine chemistry test was performed to determine the function of the renal tubules. On the other hand, there is no report showing that it is helpful to arrive at the hospital as early as possible and to perform these urine chemistry tests as soon as possible. @*Methods@#This study analyzed the timing of urinary chemistry tests in AKI patients who were admitted to the author’s hospital through the emergency departments (ED) in the last three years and divided into two groups. The early group was defined as patients who performed the test within three hours of arrival in the ED. The late group was defined as patients who were late or not. The prognostic factors were the change in 30-day estimated glomerular filtration rate (eGFR) and duration of hospital stay. @*Results@#The changes of eGFR after 30 days in each group were 41.6±27.57 mL/min/1.73 m2 (early group, n=92) vs. 30.39±26.37 mL/min/1.73 m2 (late group, n=180) (P=0.001). Early group patients were discharged more quickly than patients in the late group (hospital day, 11.49±10.14 vs. 13.84±10.53; P=0.041). @*Conclusion@#A urine chemistry test is a test to help determine the cause of AKI. Based on the results of urine chemistry performed within three hours after arrival at the hospital, patients with AKI who visited the emergency room had betterimproved kidney function and less hospitalization time than the patients who were late or untested at the time of treatment.

Multiple Endocrine Neoplasia Type 2B Diagnosed Early by Conjunctival Neuroma: a Case Report

Multiple endocrine neoplasia type 2B (MEN 2B) is an autosomal dominant disorder characterized by medullary thyroid cancer, pheochromocytoma, neuroma and Marfanoid feature. Medullary thyroid cancer occurs in more than 95% patients of MEN 2B and increases mortality. So, the early diagnosis of multiple endocrine neoplasia is very important, because in the early diagnosed and treated medullary thyroid cancer, the prognosis is excellent. This is a case of multiple endocrine neoplasia type 2B that diagnosed early by conjunctival neuroma. A 15-year-old female patient was presented with both conjunctival masses that occurred 6 months ago. The excisional biopsy revealed conjunctival neuroma. The multiple endocrine tumor was suspected, further evaluation was performed. Medullary thyroid cancer was confirmed by thyroid ultrasound and fine needle aspiration. Finally, MEN type 2B was confirmed by a RET mutation genetic testing.

Effects of Short-Term Exenatide Treatment on Regional Fat Distribution, Glycated Hemoglobin Levels, and Aortic Pulse Wave Velocity of Obese Type 2 Diabetes Mellitus Patients

BACKGROUND: Most type 2 diabetes mellitus patients are obese and have obesity related vascular complications. Exenatide treatment is well known for both decreasing glycated hemoglobin levels and reduction in body weight. So, this study aimed to determine the effects of exenatide on body composition, glycated hemoglobin levels, and vascular stiffness in obese type 2 diabetes mellitus patients. METHODS: For 1 month, 32 obese type 2 diabetes mellitus patients were administered 5 µg of exenatide twice daily. The dosage was then increased to 10 µg. Patients' height, body weight, glycated hemoglobin levels, lipid profile, pulse wave velocity (PWV), body mass index, fat mass, and muscle mass were measured by using Inbody at baseline and after 3 months of treatment. RESULTS: After 3 months of treatment, glycated hemoglobin levels decreased significantly (P=0.007). Triglyceride, total cholesterol, and low density lipoprotein levels decreased, while aspartate aminotransferase and alanine aminotransferase levels were no change. Body weight, and fat mass decreased significantly (P=0.002 and P=0.001, respectively), while interestingly, muscle mass did not decrease (P=0.289). In addition to, Waist-to-hip ratio and aortic PWV decreased significantly (P=0.006 and P=0.001, respectively). CONCLUSION: Effects of short term exenatide use in obese type 2 diabetes mellitus with cardiometabolic high risk patients not only reduced body weight without muscle mass loss, body fat mass, and glycated hemoglobin levels but also improved aortic PWV in accordance with waist to hip ratio.

The Effect of Vildagliptin on Visfatin in Korean Patients with Type 2 Diabetes: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Prospective Study / 임상당뇨병

BACKGROUND: The effects of dipeptidyl peptidase-4 inhibitors on adipokines remain obscure. The aim of this study was to evaluate the effect of the addition of vildagliptin on visfatin, an adipokine that represents inflammatory biomarkers of adipose tissue, in patients with type 2 diabetes inadequately controlled with prior metformin monotherapy. METHODS: In this 16-week, double-blind, randomized, parallel-group, placebo-controlled study, 71 patients were randomly assigned to vildagliptin 50 mg twice a day (n = 35) or placebo (n = 36) added to ongoing metformin therapy. Fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), plasma lipids, and visfatin levels were measured at baseline and 16 weeks after treatment. RESULTS: After 16 weeks, significant reduction in HbA1c and FPG was observed with vildagliptin addon treatment compared to placebo (-0.54 +/- 0.52%, P = 0.001 and -14.80 +/- 19.21 mg/dL, P = 0.004, respectively). However, no other clinically meaningful changes in lipid parameters or visfatin were observed. CONCLUSION: Vildagliptin add-on to metformin significantly improved fasting blood glucose and HbA1c. However, in this study, no significant differences in lipid parameters or visfatin level were observed between the two groups.

Omega-3 Polyunsaturated Fatty Acids May Attenuate Streptozotocin-Induced Pancreatic beta-Cell Death via Autophagy Activation in Fat1 Transgenic Mice

BACKGROUND: Inflammatory factors and beta-cell dysfunction due to high-fat diets aggravate chronic diseases and their complications. However, omega-3 dietary fats have anti-inflammatory effects, and the involvement of autophagy in the etiology of diabetes has been reported. Therefore, we examined the protective effects of autophagy on diabetes using fat-1 transgenic mice with omega-3 self-synthesis capability. METHODS: Streptozotocin (STZ) administration induced beta-cell dysfunction in mice; blood glucose levels and water consumption were subsequently measured. Using hematoxylin and eosin (H&E) and Masson's trichrome staining, we quantitatively assessed STZ-induced changes in the number, mass, and fibrosis of pancreatic islets in fat-1 and control mice. We identified the microtubule-associated protein 1A/1B light chain 3-immunoreactive puncta in beta-cells and quantified p62 levels in the pancreas of fat-1 and control mice. RESULTS: STZ-induced diabetic phenotypes, including hyperglycemia and polydipsia, were attenuated in fat-1 mice. Histological determination using H&E and Masson's trichrome staining revealed the protective effects of the fat-1 expression on cell death and the scarring of pancreatic islets after STZ injection. In the beta-cells of control mice, autophagy was abruptly activated after STZ treatment. Basal autophagy levels were elevated in fat-1 mice beta-cells, and this persisted after STZ treatment. Together with autophagosome detection, these results revealed that n-3 polyunsaturated fatty acid (PUFA) enrichment might partly prevent the STZ-related pancreatic islet damage by upregulating the basal activity of autophagy and improving autophagic flux disturbance. CONCLUSION: Fat-1 transgenic mice with a n-3 PUFA self-synthesis capability exert protective effects against STZ-induced beta-cell death by activating autophagy in beta-cells.

Adrenocortical Insufficiency due to Spontaneous Bilateral Adrenal Hemorrhage Presented as Acute Abdominal Pain / 이화의대지

Adrenocortical insufficiency is the clinical manifestation of deficient production or action of glucocorticoids. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal failure due to impairment of the hypothalamic-pituitary axis. Primary adrenocortical insufficiency can be caused by autoimmune adrenalitis, infection (especially, tuberculosis), metastatic cancer, lymphoma, adrenal hemorrhage, infarction or drugs. Among these, adrenal hemorrhage may be caused by anticoagulant drug or heparin therapy, thromboembolic disease, hypercoagulable states such as antiphospholipid syndrome, physical trauma, postoperative state, sepsis and severe stress from any cause. However, even fewer reports exist of adrenocortical insufficiency due to spontaneous bilateral adrenal hemorrhage. We report a rare case of acute adrenocortical insufficiency due to spontaneous bilateral adrenal hemorrhage presenting as acute abdominal pain.

Hypothalamic Hypopituitarism Caused by Pituitary Stalk Dysgenesis / 대한내과학회지

Functional defects of the pituitary gland are a rare cause of pubertal delay. The pituitary stalk is an important structure that connects the hypothalamus and pituitary gland. A defect in fusion of the pituitary stalk and anterior pituitary gland will block the function of the anterior pituitary gland. A 28-year-old man was referred to our clinic with poorly developed secondary sexual characteristics. He had undeveloped facial, axillary, and pubic hair and was Tanner stage I. Laboratory tests gave random serum testosterone < 0.025 ng/mL, luteinizing hormone (LH) < 0.1 mIU/mL, follicle-stimulating hormone (FSH) 0.626 mIU/mL, thyroid-stimulating hormone (TSH) 6.85 microIU/mL, and fT4 6.96 pmol/L. Sella magnetic resonance imaging (MRI) showed no pituitary stalk enhancement. The response in the combined pituitary function test revealed multiple hormonal defects, while the TSH response to thyrotropin-releasing hormone (TRH) was exaggerated and delayed. Therefore, we concluded that pituitary stalk dysgenesis had led to hypothalamic-type panhypopituitarism.

Serum Vitamin D Status and Its Relationship to Metabolic Parameters in Patients with Type 2 Diabetes Mellitus / 전남의대학술지

The potential relationship between vitamin D (VitD) status and metabolic control in patients with type 2 diabetes mellitus (T2DM) warrants further study. We aimed to evaluate the relationship between the serum 25-hydroxyvitamin D [25(OH)D] level and various parameters in patients with T2DM. We analyzed retrospectively data from 276 Korean patients with T2DM whose serum 25(OH)D level was measured in our hospital. Nondiabetic healthy subjects who visited the hospital for health screening were selected as the control group (Non-DM, n=160). Compared with control subjects, patients with T2DM had a lower serum 25(OH)D level (15.4+/-0.5 vs. 12.9+/-0.4 ng/ml, p<0.01). Eleven percent of T2DM patients were VitD "insufficient" (20-29 ng/ml) and 87% of the patients were VitD "deficient" (<20 ng/ml). The serum 25(OH)D level was significantly related to serum fibrinogen, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), ferritin, the urine albumin creatinine ratio, and hemoglobin A1C (HbA1C). In a multivariate logistic regression analysis, high levels of HbA1C, TG, and LDL-C were independently associated with VitD deficiency in T2DM patients. The results of the present study show that the majority of Koreans with T2DM are VitD deficient, and the serum 25(OH)D level in patients with T2DM is related to lipid and glucose parameters. Further studies are required of the relationship of VitD with fibrinogen and other related parameters.

Serum Vitamin D Status and Its Relationship to Metabolic Parameters in Patients with Type 2 Diabetes Mellitus / 전남의대학술지

The potential relationship between vitamin D (VitD) status and metabolic control in patients with type 2 diabetes mellitus (T2DM) warrants further study. We aimed to evaluate the relationship between the serum 25-hydroxyvitamin D [25(OH)D] level and various parameters in patients with T2DM. We analyzed retrospectively data from 276 Korean patients with T2DM whose serum 25(OH)D level was measured in our hospital. Nondiabetic healthy subjects who visited the hospital for health screening were selected as the control group (Non-DM, n=160). Compared with control subjects, patients with T2DM had a lower serum 25(OH)D level (15.4+/-0.5 vs. 12.9+/-0.4 ng/ml, p<0.01). Eleven percent of T2DM patients were VitD "insufficient" (20-29 ng/ml) and 87% of the patients were VitD "deficient" (<20 ng/ml). The serum 25(OH)D level was significantly related to serum fibrinogen, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), ferritin, the urine albumin creatinine ratio, and hemoglobin A1C (HbA1C). In a multivariate logistic regression analysis, high levels of HbA1C, TG, and LDL-C were independently associated with VitD deficiency in T2DM patients. The results of the present study show that the majority of Koreans with T2DM are VitD deficient, and the serum 25(OH)D level in patients with T2DM is related to lipid and glucose parameters. Further studies are required of the relationship of VitD with fibrinogen and other related parameters.

Correlations between Glucagon Stimulated C-peptide Levels and Microvascular Complications in Type 2 Diabetes Patients

BACKGROUND: This study aimed to investigate whether stimulated C-peptide is associated with microvascular complications in type 2 diabetes mellitus (DM). METHODS: A cross-sectional study was conducted in 192 type 2 diabetic patients. Plasma basal C-peptide and stimulated C-peptide were measured before and 6 minutes after intravenous injection of 1 mg glucagon. The relationship between C-peptide and microvascular complications was statistically analyzed. RESULTS: In patients with retinopathy, basal C-peptide was 1.9+/-1.2 ng/mL, and stimulated C-peptide was 2.7+/-1.6 ng/mL; values were significantly lower compared with patients without retinopathy (P=0.031 and P=0.002, respectively). In patients with nephropathy, basal C-peptide was 1.6+/-0.9 ng/mL, and stimulated C-peptide was 2.8+/-1.6 ng/mL; values were significantly lower than those recorded in patients without nephropathy (P=0.020 and P=0.026, respectively). Stimulated C-peptide level was associated with increased prevalence of microvascular complications. Age-, DM duration-, and hemoglobin A1c-adjusted odds ratios for retinopathy in stimulated C-peptide value were 4.18 (95% confidence interval [CI], 1.40 to 12.51) and 3.35 (95% CI, 1.09 to 10.25), respectively. The multiple regression analysis between nephropathy and C-peptide showed that stimulated C-peptide was statistically correlated with nephropathy (P=0.03). CONCLUSION: In patients with type 2 diabetes, the glucagon stimulation test was a relatively simple method of short duration for stimulating C-peptide response. Stimulated C-peptide values were associated with microvascular complications to a greater extent than basal C-peptides.

Response: Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients (Diabetes Metab J 2011;35:41-9)

No abstract available.

A Case of Thyroid Storm with Delayed Diagnosis in Old Aged Person with Parkinson's Disease

A thyroid storm is a potentially fatal complication of hyperthyroidism. Early diagnosis and treatment is essential for reducing morbidity and mortality. Older patients with hyperthyroidism tend to have fewer hypermetabolic signs and increased signs of weight loss, depression, lethargy, cardiac arrhythmia, and apathetic mood. Additionally, comorbid diseases and drug history can affect thyroid function and symptoms. Here, we report an older patient with a thyroid storm and accompanied features of Parkinson's disease. She presented with generalized weakness, delirium, and anxiety. Laboratory findings were consistent with hyperthyroidism. She became drowsy with no precipitating factors. High fever, meningism, and atrial fibrilation occurred with no obvious sources. Suspecting a diagnosis of a thyroid storm, she was treated with an antithyroid drug, Lugol's solution, hydrocortisone, and supportive management. After these treatments, her clinical condition recovered and the neurological signs resolved.

Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients

BACKGROUND: Recent studies have revealed that C-peptide induces smooth muscle cell proliferation and causes human atherosclerotic lesions in diabetic patients. The present study was designed to examine whether the basal C-peptide levels correlate with cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. METHODS: Data was obtained from 467 patients with T2DM from two institutions who were followed for four years. The medical findings of all patients were reviewed, and patients with creatinine >1.4 mg/dL, any inflammation or infection, hepatitis, or type 1 DM were excluded. The relationships between basal C-peptide and other clinical values were statistically analyzed. RESULTS: A simple correlation was found between basal C-peptide and components of metabolic syndrome (MS). Statistically basal C-peptide levels were significantly higher than the three different MS criteria used in the present study, the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program's (NCEP's), World Health Organization (WHO), and the International Diabetes Federation (IDF) criteria (NCEP-ATP III, P=0.001; IDF, P<0.001; WHO, P=0.029). The multiple regression analysis between intima-media thickness (IMT) and clinical values showed that basal C-peptide significantly correlated with IMT (P=0.043), while the analysis between the 10-year coronary heart disease risk by the United Kingdom Prospective Diabetes Study risk engine and clinical values showed that basal C-peptide did not correlate with IMT (P=0.226). CONCLUSION: Basal C-peptide is related to cardiovascular predictors (IMT) of T2DM, suggesting that basal C-peptide does provide a further indication of cardiovascular disease.

A Case of Adrenal Teratoma

Teratoma is a congenital tumor containing tissues derived from all germ layers. Teratoma in the region of the adrenal gland is a very uncommon retroperitoneal tumor. Only 7 cases of adrenal teratoma have been reported worldwide, but in Korea, no similar cases have been reported until now. This case report describes an adrenal teratoma in a 38-year-old healthy woman who was incidentally diagnosed with a left adrenal mass on abdominal ultrasonography during a medical inspection. Computed tomographic scans revealed a 9-cm heterogeneous circumscribed round mass, containing primarily fat tissue, and a solid calcification component in the left adrenal gland. Adrenal hormonal assessment results and biochemical markers for gonadal neoplasia were negative. Result of serum laboratory tests were normal. The patient underwent laparoscopic adrenalectomy. Histologic analysis confirmed the diagnosis of a mature teratoma; the obtained specimen measured 5 x 7 x 7.5 cm and weighed 267 g. The surface of the mass was smooth, and sebaceous tissue and hair with hard material were observed on the incisional surface. The patient was discharged on postoperative day 4, without complications. In this case report, we describe the incidental finding of a teratoma occurring in the adrenal gland region in a healthy woman; the teratoma was laparoscopically excised.

GLP-1 Can Protect Proinflammatory Cytokines Induced Beta Cell Apoptosis through the Ubiquitination

BACKGROUND: Proinflammatory cytokines are one of the causes of diabetes mellitus. However, the exact molecular mechanism by which proinflammatory cytokines induce beta-cell death remains to be clearly elucidated. Glucagon-like peptide-1 (GLP-1) affects the stimulation of insulin secretion and the preservation of beta-cells. Additionally, it may exert an antiapoptotic effect on beta cells; however, the mechanism underlying this effect has yet to be demonstrated. Therefore, we investigated the protective effects of GLP-1 in endoplasmic reticulum (ER)-mediated beta-cell apoptosis using proinflammatory cytokines. METHODS: To induce ER stress, hamster insulin-secreting tumor (HIT)-T15 cells were treated using a mixture of cytokines. Apoptosis was evaluated via MTT assay, Hoechst 33342 staining, and annexin/propidium iodide (PI) flow cytometry. The mRNA and protein expression levels of ER stress-related molecules were determined via PCR and Western blotting, respectively. Nitric oxide was measured with Griess reagent. The levels of inducible nitric oxide synthase (iNOS) mRNA and protein were analyzed via real-time PCR and Western blot, respectively. iNOS protein degradation was evaluated via immunoprecipitation. We pretreated HIT-T15 cells with exendin (Ex)-4 for 1 hour prior to the induction of stress. RESULTS: We determined that Ex-4 exerted a protective effect through nitric oxide and the modulation of ER stress-related molecules (glucose-regulated protein [GRP]78, GRP94, and CCAAT/enhancer-binding protein homologous protein [CHOP]) and that Ex-4 stimulates iNOS protein degradation via the ubiquitination pathway. Additionally, Ex-4 also induced the recovery of insulin2 mRNA expression in beta cells. CONCLUSION: The results of this study indicate that GLP-1 may protect beta cells against apoptosis through the ubiquitination pathway.

Exendin-4 Protects Oxidative Stress-Induced beta-Cell Apoptosis through Reduced JNK and GSK3beta Activity

Oxidative stress induced by chronic hyperglycemia in type 2 diabetes plays a crucial role in progressive loss of beta-cell mass through beta-cell apoptosis. Glucagon like peptide-1 (GLP-1) has effects on preservation of beta-cell mass and its insulin secretory function. GLP-1 possibly increases islet cell mass through stimulated proliferation from beta-cell and differentiation to beta-cell from progenitor cells. Also, it probably has an antiapoptotic effect on beta-cell, but detailed mechanisms are not proven. Therefore, we examined the protective mechanism of GLP-1 in beta-cell after induction of oxidative stress. The cell apoptosis decreased to ~50% when cells were treated with 100 microM H2O2 for up to 2 hr. After pretreatment of Ex-4, GLP-1 receptor agonist, flow cytometric analysis shows 41.7% reduction of beta-cell apoptosis. This data suggested that pretreatment of Ex-4 protect from oxidative stress-induced apoptosis. Also, Ex-4 treatment decreased GSK3beta activation, JNK phosphorylation and caspase-9, -3 activation and recovered the expression of insulin2 mRNA in beta-cell lines and secretion of insulin in human islet. These results suggest that Ex-4 may protect beta-cell apoptosis by blocking the JNK and GSK3beta mediated apoptotic pathway.