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Background: This study aimed to investigate the long-term effects of diabetes drug costs on cardiovascular (CV) events and death.Methods: This retrospective observational study used data from 2009 to 2018 from the National Health Insurance in Korea. Among the patients with type 2 diabetes, those taking antidiabetic drugs and who did not have CV events until 2009 were included. Patients were divided into quartiles (Q1 [lowest]–4 [highest]) according to the 2009 diabetes drug cost. In addition, the 10-year incidences of CV events (non-fatal myocardial infarction, stroke, hospitalization for heart failure, and coronary revascularization) and CV death (death due to CV events) were analyzed.Results: A total of 441,914 participants were enrolled (median age, 60 years; men, 57%). CV events and death occurred in 28.1% and 8.36% of the patients, respectively. The 10-year incidences of CV events and deaths increased from Q1 to 4. After adjusting for sex, age, income, type of diabetes drugs, comorbidities, and smoking and drinking status, the risk of CV events significantly increased according to the sequential order of the cost quartiles. In contrast, the risk of CV death showed a U-shaped pattern, which was the lowest in Q3 (hazard ratio [HR], 0.953; 95% confidence interval [CI], 0.913 to 0.995) and the highest in Q4 (HR, 1.266; 95% CI, 1.213 to 1.321).Conclusion: Diabetes drug expenditure affects 10-year CV events and mortality. Therefore, affording an appropriate diabetes drug cost at a similar risk of CV is an independent protective factor against CV death.

We investigated the long-term effect of changes in hepatic steatosis on the risk of developing T2DM.We evaluated 3510 participants from the 2001-2016 Korean Genome and Epidemiology Study. Those with significant alcohol consumption or T2DM during 2001-2004 were excluded. Steatosis was defined as non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS) of over -0.64, and baseline values were assessed between 2001 and 2002. Differences in NAFLD-LFS (ΔLFS) and changes in steatosis status (no, intermittent [resolved or incident], and persistent steatosis) were assessed between 2003 and 2004. Changes in the risk of diabetes status were observed until 2016.Over 52,650 person-years of follow-up, T2DM developed in 296 participants (8.4%). The incidence of diabetes in those with no steatosis, intermittent steatosis, and persistent steatosis during follow-up increased by 5.1%, 14.1%, and 27.1% respectively. Multivariate-adjusted analysis revealed that the risk was higher in those with persistent steatosis than those with no steatosis and intermittent steatosis. Baseline NAFLD-LFS and ΔLFS was associated with increased risk of incident T2DM.Initial severity as well as aggravation of steatosis is an independent predictor of incident T2DM. Strategies aimed at reducing liver fat may prevent future development of diabetes among patients with NAFLD.

BACKGROUND Plasma soluble cluster determinant 36 (sCD36) level is closely related with insulin resistance and atherosclerosis, but little is known whether it could be a surrogate for estimating risk of developing diabetes or not. To address this, we evaluated association between sCD36 index, the product of sCD36 and fasting plasma glucose (FPG), and the prevalence of type 2 diabetes mellitus (T2DM), and then compared with triglyceride-glucose (TyG) index which has been suggested simple index for insulin resistance. METHODS This was cross-sectional study, and participants were classified as normal glucose tolerance (NGT), prediabetes, and T2DM according to glucose tolerance. The formula of TyG index was 'ln [FPG (mg/dL)×triglyceride (mg/dL)/2],' and the sCD36 index was 'ln [sCD36 (pg/mL)×FPG (mg/dL)/2].' RESULTS One hundred and fifty-five subjects (mean age, 55.2 years) were enrolled, and patients with T2DM were 75. Both indexes were significantly increased in prediabetes and T2DM rather than NGT, and sCD36 index was positively correlated with both glycosylated hemoglobin and homeostasis model assessment of insulin resistance (r=0.767 and r=0.453, respectively; P

Background/Aims: Overt hypothyroidism is frequently found in patients with type 2 diabetes mellitus (T2DM), but it remains unknown the relationship between subclinical hypothyroidism (SCH) and T2DM. We attempt to evaluate the difference in prevalence of SCH between patients with T2DM and general population, and the association between SCH and glycemic control status ofdiabetic patients. Methods: This was cross-sectional study. Total 8,528 subjects who visited for health check-up were recruited. SCH was defined as an elevated level of serum thyroid stimulating hormone (> 4.0 mIU/L) with a normal level of free thyroxine. T2DM group was categorized into three groups by glycosylated hemoglobin (HbA1c): < 7% (reference), ≥ 7% and < 9%, ≥ 9%. Results: Finally, 7,966 subjects were included. The prevalence of SCH was not different between healthy controls and subjects with T2DM (8.1% vs. 7.4%, p = 0.533; in men, 5.7% vs. 5.1%, p = 0.573; in women, 10.9% vs. 11.7%, p = 0.712), but it was increased with highest HbA1c group more than well controlled group, especially in women. The risk of SCH was increased by group with poorer glycemic control; the odds ratio for HbA1c ≥ 9% compared to < 7% was 2.52 (95% confidence interval [CI], 1.09 to 5.86; p = 0.031), and 4.58 (95% CI, 1.41 to 14.87; p = 0.011) in women, but not significant in men. Conclusions: The prevalence of SCH was similar between T2DM and healthy group. Poor glycemic control in T2DM was obviously associated with the risk of SCH, especially in elderly women. These results suggest SCH as comorbidity may be considered in elderly women with poor glycemic control.

Background Visceral adiposity is related to insulin resistance. Skeletal muscle plays a central role in insulin-mediated glucose disposal; however, little is known about the association between muscle mass and metabolic syndrome (MS). This study is to clarify the clinical role of skeletal muscle mass in development of MS. Methods A total of 1,042 subjects were enrolled. Subjects with prior MS and chronic diseases were excluded. After 24 months, development of MS was assessed using NCEP-ATP III criteria. Skeletal muscle mass (SMM; kg), body fat mass (BFM; kg), and visceral fat area (VFA; cm2) were obtained from bioelectrical analysis. Then, the following values were calculated as follows: percent of SMM (SMM%; %): SMM (kg)/weight (kg), skeletal muscle index (SMI; kg/m2): SMM (kg)/height (m2), skeletal muscle to body fat ratio (MFR): SMM (kg)/BFM (kg), and skeletal muscle to visceral fat ratio (SVR; kg/cm2): SMM (kg)/VFA (cm2). Results Among 838 subjects, 88 (10.5%) were newly diagnosed with MS. Development of MS increased according to increasing quintiles of BMI, SMM, VFA, and SMI, but was negatively associated with SMM%, MFR, and SVR. VFA was positively associated with high waist circumference (WC), high blood pressure (BP), dysglycemia, and high triglyceride (TG). In contrast, MFR was negatively associated with high WC, high BP, dysglycemia, and high TG. SVR was negatively associated with all components of MS. Conclusion Relative SMM ratio to body composition, rather than absolute mass, may play a critical role in development of MS and could be used as a strong predictor.

Background: Recently, several studies reported that the cancer incidence in type 2 diabetes patients is higher than in the general population. Although a number of risks are shared between cancer and diabetes patients, there have been few studies of its correlation. We evaluated the influences of several factors including low density lipoprotein cholesterol (LDL-C), albuminuria and use of metformin on the risk of cancer in patients with type 2 diabetes. Methods: We enrolled 1,320 patients with at least 5 years of follow-up and 73 patients were diagnosed with cancer during this period. The associations of the risk factors with cancer incidence were evaluated by multiple regression analysis. The subjects were placed into two subgroups based on metformin dosage (

The purpose of the present study was to determine whether exposure of pancreatic islets to glucotoxic conditions changes fatty acid translocase cluster determinant 36 (CD36) and examine the role of CD36 on the induction of glucotoxicity. We measured the changes of CD36 and insulin secretion in high glucose (30 mM) exposed INS-1 cells and CD36 suppressed INS-1 cells by transfection of CD36 siRNA. The intracellular peroxide level of INS-1 cells increased in the high glucose media compared to normal glucose (5.6mM) media. The mRNA levels of insulin and PDX-1, as well as glucose stimulated insulin secretion (GSIS) were decreased in INS-1 cells exposed to high glucose media compared to normal glucose media, while CD36 and palmitate uptake were significantly elevated with exposure to high glucose media for 12h. The inhibition of CD36 reversed the decreased GSIS and intracellular peroxide level in INS-1 cells. These results suggest that high glucose may exacerbate glucotoxicity via increasing fatty acid influx by elevation of CD36 expression, and that CD36 may be a possible target molecule for preventing glucotoxicity in pancreatic beta-cells.

Cardiovascular disease (CVD), a leading cause of death in patients with diabetes mellitus, has several pathogenic mechanisms that are well established. However, the traditional hypoglycemic agents do not have proven positive effects on macrovascular disease. Novel therapeutic agents target the incretin pathway including the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and the dipeptidyl peptidase-4 inhibitors. The glucose-regulatory actions of these agents function by increasing insulin secretion and suppressing glucagon. They also act to increase weight loss not only by inhibiting gastric emptying, but also by reducing appetite. Although GLP-1 and GLP-1R agonists have demonstrated beneficial effects on myocardium and vascular endothelium including coronary and peripheral mouse vessels, they also have anti-inflammatory and anti-atherogenic actions. These agents also have positive effects on the lipid profile and blood pressure. Although these cardioprotective actions seem to be beyond the effects of glucose control and weight loss, they are mediated through GLP-1R- or GLP-1R-independent actions of cleaved GLP-1 (9-36). Larger randomized controlled trials are necessary to elucidate the clinical promise of these beneficial CVD effects.

Insulin has anti-inflammatory effects in short-term experiments. However, the effects of chronic insulin administration on inflammation are unknown. We hypothesised that chronic insulin administration would beneficially alter adipose tissue inflammation and several circulating inflammatory markers.We administered two forms of long-acting insulin, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin), to LDL-receptor-deficient mice. After 8 weeks on a diet that causes obesity, hyperglycaemia, adipose tissue macrophage accumulation and atherosclerosis, the mice received subcutaneous glargine, detemir or NaCl (control) for 12 weeks. Serum amyloid A (SAA) and serum amyloid P (SAP), metabolic variables, adipose tissue macrophages and aortic atherosclerosis were evaluated.Weight gain was equivalent in all groups. The glycated haemoglobin level fell equivalently in both insulin-treated groups. Plasma cholesterol and triacylglycerol levels, and hepatic triacylglycerol level significantly improved in the glargine compared with the detemir or control groups. Levels of mRNA expression for monocyte chemotactic protein-1 and F4/80, a macrophage marker, in adipose tissue were decreased only in the glargine group (p 0.05). Visceral adipose tissue macrophage content decreased in both insulin groups (p 0.05), whereas atherosclerosis decreased only in the glargine group. Circulating SAA and SAP did not decrease in either insulin-treated group, but IL-6 levels fell in the glargine-treated mice.While chronic insulin administration did not decrease SAA and SAP, administration of glargine but not detemir insulin improved dyslipidaemia, IL-6 levels and atherosclerosis, and both insulins reduced macrophage accumulation in visceral adipose tissue. Thus, chronic insulin therapy has beneficial tissue effects independent of circulating inflammatory markers in this murine model of diet-induced obesity and diabetes.

Heme oxygenase-1 (HO-1) has been described as an inducible protein that is capable of cytoprotection via radical scavenging and the prevention of apoptosis. Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, and this process has been termed glucose toxicity. Yet little is known about the relation between glucose toxicity and HO-1 in the islets. The purposes of the present study were to determine whether prolonged exposure of pancreatic islets to a supraphysiologic glucose concentration disrupts the intracellular balance between reactive oxygen species (ROS) and HO-1, and so this causes defective insulin secretion; we also wanted to evaluate a protective role for HO-1 in pancreatic islets against high glucose levels. The intracellular peroxide levels of the pancreatic islets (INS-1 cell, rat islet) were increased in the high glucose media (30 mM glucose or 50 mM ribose). The HO-1 expression was induced in the INS-1 cells by the high glucose levels. Both the HO-1 expression and glucose stimulated insulin secretion (GSIS) was decreased simultaneously in the islets by treatment of the HO-1 antisense. The HO-1 was upregulated in the INS-1 cells by hemin, an inducer of HO-1. And, HO-1 upregulation induced by hemin reversed the GSIS in the islets at a high glucose condition. These results suggest HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions.

The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of β-cells compared with glimepiride when metformin alone was failed. This was an open-label and multi-center study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the endpoint. Glargine was not superior to glimepiride in other β-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining β-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy.

Background: Skeletal muscle is well established as a major target organ of insulin action, and is associated with the pathogenesis of type 2 diabetes. Therefore, we attempted to determine whether a variation in serum creatinine is related to the development of type 2 diabetes and other risk factors for diabetes. Methods: A total of 2,676 nondiabetic subjects with stable and normal renal function (estimated glomerular filtration rate >60 mL/min/1.73 m 2 ) were followed up for approximately 4.5 years. New onset diabetes was defined as fasting plasma glucose (FPG) ≥7.0 mmol/L, glycated hemoglobin (HbA1c) ≥6.5%, or subjects taking antidiabetic agents. Variation of serum creatinine (ΔCre) was defined as a difference between follow-up and baseline creatinine. In subgroup analysis, body composition was examined by bioelectric impedance analysis method. Results: A total of 106 subjects were diagnosed with new-onset diabetes during the follow-up period. Baseline serum creatinine was not different between the new-onset diabetes and no diabetes groups. Negative ΔCre (ΔCre

Background: Nonalcoholic fatty liver disease (NAFLD) is closely correlated with abnormal accumulation of visceral fat, but the role of skeletal muscle remains unclear. The aim of this study was to elucidate the role of skeletal muscle in development of NAFLD. Methods: Among 11,116 subjects (6,242 males), we examined the effects of skeletal muscle mass and visceral fat area (VFA, by bioelectric impedance analysis) on NAFLD using by the fatty liver index (FLI). Results: Of the total subjects (9,565 total, 5,293 males) included, 1,848 were classified as having NALFD (FLI ≥60). Body mass index, lipid profile, fasting plasma glucose, hemoglobin A1c, prevalence of type 2 diabetes (DM), hypertension (HTN), and met abolic syndrome were higher in males than females, but FLI showed no significant difference. The low FLI group showed the lowest VFA and highest skeletal muscle mass of all the groups. Skeletal muscle to visceral fat ratio (SVR) and skeletal muscle index had inverse correlations with FLI, when adjusted for age and gender. In multivariate regression analysis, SVR was negatively associated with FLI. Among SVR quartiles, the highest quartile showed very low risk of NAFLD when adjusted for age, gender, lipid profile, DM, HTN, and high sensitivity C-reactive protein from the lowest quartiles (odds ratio, 0.037; 95% confidence in terval, 0.029 to 0.049). Conclusion: Skeletal muscle mass was inversely associated with visceral fat area, and higher skeletal muscle mass may have a beneficial effect in preventing NAFLD. These results suggest that further studies are needed to ameliorate or slow the progression of sarcopenia.

Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36., Graphical Abstract

The metabolic syndrome (MetS) is the clustering of cardiovascular risk factors and known as a powerful predictor of diabetes and cardiovascular disease. Glycated hemoglobin (HbA1c) is used as one of the diagnostic criteria for diabetes and category of increased risk for diabetes. We examined the usefulness of HbA1c as a diagnostic tool for MetS and to determine the cut-off value of HbA1c as a criterion for MetS, in non-diabetic Korean subjects. We analyzed 7,307 participants (male: 4,181, 57%) in a medical check-up program, and applied the newly recommended guidelines of the International Diabetes Federation for diagnosis of MetS. The mean HbA1c was 5.54% in all subjects and showed no significant difference between genders. Using receiver-operating characteristic curve, HbA1c value corresponding to the fasting plasma glucose value of 100 mg/dL was 5.65% (sensitivity 52.3%, specificity 76.7%). The prevalence of MetS was 8.5% according to the IDF guideline and 10.9% according to HbA1c value of 5.7%, showing 69.5% agreement rate. The detection rate of MetS increased to 25.7% using the HbA1c criterion of 5.7% instead of fasting hyperglycemia. This study suggests that HbA1c might be used as a diagnostic criterion for MetS and the appropriate cut-off value of HbA1c may be 5.65% in this Korean population.

Ectopic thyroid is a rare entity and can occur at any location in the midline position. A role for the ectopic thyroid in the pathogenesis of hypothyroidism and nongoitrous cretinism has been emphasized.To assess the clinical characteristics of an ectopic thyroid by analyzing 49 cases reported in Korea.This study was a retrospective review of 19 cases who were diagnosed by thyroid scan at our institutions together with 30 cases reported in the Korean medical literature, found using KoreaMed.Most cases of ectopic thyroid were diagnosed in patients aged between 1 and 29 years; it was more common in females (43 patients). A lingual thyroid was found in 23 patients, a sublingual thyroid in 17 patients, combined type in 7 patients, a prelaryngeal thyroid in 1 patient, and an intratracheal thyroid in 1 patient. Only four cases had the thyroid gland in the normal position. The chief complaints at presentation were palpable mass in 20 patients, growth retardation in 10 patients, and a lump sensation in the throat in 6 patients. Twenty-six of 42 patients (61.9%) had hypothyroidism, and 16 patients (38.1%) had euthyroidism. As for the treatment modalities, 18 of 26 patients with hypothyroidism and 4 of 16 patients with normal thyroid function received thyroid hormone medication; 3 of 26 patients with hypothyroidism and 8 of 16 patients with euthyroidism underwent resection of the ectopic thyroid.Our study suggests that radionuclide thyroid scanning and function testing may be useful not only for the diagnosis of an ectopic thyroid but also before deciding on the therapeutic modality; patients should be followed up to detect changes in thyroid function and malignant transformation.

This study was performed to investigate the association between FSH receptor (FSHR) gene polymorphism at position 680 and the outcomes of controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer (IVF-ET) in Korean women. Two hundred and sixty-three patients under 40 years of age who underwent IVF-ET procedures were included in this study. Patients with polycystic ovary syndrome, endometriosis, or a previous history of ovarian surgery were excluded. Following extraction of genomic DNA, the FSHR polymorphism at position 680 was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The FSHR genotype distribution was 41.8% for Asn/Asn, 45.6% for Asn/Ser, and 12.5% for Ser/Ser FSHR genotype groups. Although there was no difference among the three genotype groups in terms of the age and infertility diagnosis of study subjects, the basal levels of FSH (day 3) were significantly different [5.7 +/- 0.3 IU/l (mean+/-SEM), 6.0 +/- 0.3 IU/l, and 8.2 +/- 0.9 IU/l for Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively. The Ser/Ser group tended to require a higher dose of gonadotropins for COH, and tended to show lower serum estradiol levels at the time of hCG administration than the other two groups, though these differences did not reach statistical significance. The numbers of oocytes retrieved tended to be different for the three groups (9.6 +/- 0.6, 10.2 +/- 0.6, and 7.9 +/- 0.8 for Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively). Clinical pregnancy rate was significantly higher in Asn/Asn, compared to the others (45.7 vs. 30.5%, P=0.013). The homozygous Ser/Ser genotype of FSHR polymorphism at position 680 may be associated with a reduced ovarian response to COH for IVF-ET, while Asn/Asn genotypes showed a higher pregnancy rate.

Received: 3 August 2011, Accepted: 30 September 2011 Corresponding author: Ji Sung Yoon Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 705-717, Korea Tel: +82-53-620-4049, Fax: +82-53-654-8386, E-mail: jsyoon9@ynu.ac.kr Ketoacidosis with Hypertriglyceridemia-Induced Pancreatitis in a Patient with Gestational Diabetes: A Case Report

Cystic parathyroid adenoma is one of rare causes of hyperparathyroidism, and tends to cause increased serum level of parathyroid hormone, alkaline phosphate and serum calcium level similar to when compared to those of solid adenoma. The possibility of a coincidental appearance of primary hyperparathyrodism and nonmedullary thyroid cancer is rare, and often neglected. A 40-year-old female presented with constipation and weight loss for 3 months. The serum calcium, phosphate and alkaline phosphate were 16.6 mg/dl, 2.2 mg/dl and 505 IU/L respectively and serum parathyroid hormone level was 1556.2 pg/mL. Neck US showed mixed nodules at both thyroid lobes, and PET-CT showed a right thyroid nodule without FDG uptake. The patient was diagnosed of primary hyperparathyroidism and underwent parathyroidectomy and a total thyroidectomy. Histopathologic results revealed parathyroid adenoma with cystic change (2 cm greater diameter) in the right lower parathyroid gland and coexistent papillary carcinoma of the right lobe of thyroid gland (infiltrating, 0.3 cm in greater diameter). She remained well and serum calcium, phosphate, parathyroid hormone level were normalized within 24 hours.

Background: The oral glucose tolerance test (OGTT) for detection of diabetes is difficult to perform in clinical settings. The aim of this study is to evaluate the performance of a more practical detection test, combined fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c), as a predictor of diabetes mellitus (DM) in a Korean sample. Methods: We examined 2,045 (M = 1,276, mean age = 47.8 ± 9.0 yrs) medical check-up program participants between January 2002 to December 2003. FPG, HbA1c and a number of other biochemical tests were performed at baseline and four after years after initial screening. Patients who originally presented with diabetes were excluded. The characteristics of newly-diagnosed DM patients and non-diabetic patients were compared. Results: The incidence of newly diagnosed diabetes was 1.6% (32/2,045) after four years of follow up. The subjects in the DM group were older, had higher levels of SBP, DBP, FPG, HbA1c, triglyceride, HDL cholesterol, GGT and LDH (P < 0.05). In multivariate logistic regression analysis, FPG (odds ratio (OR) 1.124) and HbA1c (OR 4.794) were significantly correlated with onset of diabetes (P < 0.05). The interaction parameter between FPG and HbA1c was more than 1.0, indicating that the two effects are synergistic. The predictive cut-off values of HbA1c and FPG were 5.35% (area under curve (AUC) = 0.944) and 102.5 mg/dL (AUC = 0.930), respectively. Conclusion: The combination of HbA1c above 5.35% and FPG above 102.5 mg/dL predicted the onset of diabetes in a Korean sample. These results suggest that the combination of FPG and HbA1c may be useful for predicting progression to type 2 diabetes in east Asians. (Korean Diabetes J 33:306-314, 2009)

Background: Microalbuminuria in type 2 diabetes is a predictor of development of clinical nephropathy and cardiovascular disease. But, it has been reported that reduced glomerular filtration rate (GFR) may occur in some normoalbuminuric diabetic patients. The aim of this study was to identify whether decreased GFR without microalbuminuria is to predict diabetic vascular complications. Methods: Between January 1998 and February 2001, 73 patients with type 2 diabetes who visited Yeungnam university medical center were divided into 5 groups according to initial GFR ranges: group 1 (GFR < 30 mL/min), group 2 (30 ≤ GFR < 60 mL/min), group 3 (60 ≤ GFR < 90 mL/min), group 4 (90 ≤ GFR < 125 mL/min), group 5 (125 mL/min ≤ GFR). They were examined for microvascular and macrovascular complications initially and after 4 years. Results: Decreased GFR had a negative correlation with age (r = -0.472, P = 0.001). Decreased GFR without microalbuminuria had a significant correlation with development of diabetic nephropathy (P = 0.016) after 4 years. There were no significant correlation with the prevalence of diabetic retinopathy, peripheral neuropathy, and macrovacular disease. But, our study showed that coronary artery disease had an increasing tendency with decreased GFR without statistical significance (P = 0.085). Conclusions: Our data suggest that reduced GFR, independent of albuminuria, may be an important predictor of diabetic nephropathy and coronary artery disease t o some extent. So we recommend that not only the microalbuminuria, but also the decrease in GFR should be evaluated at the follow-up of patients with type 2 diabetes. (KOREAN DIABETES J 32:252-258, 2008)

The adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations(i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species(ROS) that can impair insulin gene expression and β cell function. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause β cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. The intracellular peroxide levels of the pancreatic islets(INS-1 cells, rat islets) by flow cytometry were increased in the high glucose media compared to 5.6 mM glucose media. The insulin, MafA, PDX-1 mRNA levels and glucose stimulated insulin secretion(GSIS) were decreased in high glucose media compared to 5.6 mM glucose media. The HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions. Also, we observed decreased glutathione level, γ-GCS expression and increased oxidized LDL, malondialdehyde level at leukocytes and mesothelial cells from patients with Korean Type 2 Diabetes(esp, poorly controlled patients). In conclusion, this pathophysiologic sequence sets the scene for considering antioxidant therapy as an adjunct in the management of diabetes, especially type 2 Diabetes.(KOREAN DIABETES J 32:175-181, 2008)

Background: Lipid oxidation and formation of oxygen radicals have been identified to be the important factors of atherogenesis. Because bilirubin, a potent physiological antioxidant inhibits lipid oxidation, it is suggested that low serum concentrations of bilirubin is associated with atherosclerosis. The aim of this study was to evaluate the relationship between bilirubin levels and coronary atherosclerosis. Methods: The coronary calcium score (CCS) of 172 subjects (male 63, mean age 60.5 ± 1.0) with type 2 diabetes were evaluated in Yeungnam University Hospital between January 2005 and February 2007. The subjects were divided into two groups with CCS 10 as the cut off. Results: Higher CCS was significantly associated with lower bilirubin (P < 0.05), but after adjusted with age, no longer correlation were seen (P = 0.121). To determine the relationship between subclinical coronary atherosclerosis and bilirubin, the subjects with previous history of cardiovascular disease were excluded. In 138 subjects (male 54, mean age 58.4 ± 1.1), higher CCS was significantly associated with lower levels of bilirubin. After adjusted with age, duration of diabetes, and history of hypertension, CCS was also inversely related with bilirubin (P < 0.05). Conclusion: These results suggest that lower levels of bilirubin might be considered as a risk factor of coronary artery disease, especially in type 2 diabetics without cardiovascular disease. (KOREAN DIABETES J 32:338-345, 2008)

Background: Hyperglycemia is a well-recognized pathogenic factor of long term complications in diabetes mellitus and hyperglycemia also generates reactive oxygen species (ROS) in β cells when ROS accumulate in excess for prolonged periods of time, they cause chronic oxidative stress and adverse effects. Unfortunately, the islet contacts low capacity of endogenous antioxidant effects. But, γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme for glutathione synthesis, is well represented in islets. Methods: This study is to evaluate the changes in the activity of γ-GCS, glutathione in β-cells exposed to high glucose, in pancreatic tissue of OLETF (Otsuka Long Evans Tokushima Fatty) and LETO (Long-Evans Tokushima Otsuka) rats, in leukocytes from patients with Korean type 2 DM (T2DM) and to disclose the effects of high blood glucose on this impairment in patients with T2DM. We divided our patients into 3 groups by HbA1c (controls: n = 20, well controls diabetes: n=24, poorly controlled diabetes: n = 36). Results: We observed that decreased glutathione level, γ-GCS expression, glucose-stimulated (GSIS) and increased intracellular peroxide level in the INS-1 cells exposed to 30 mM glucose condition. Also decreased glutathione level at erythrocytes, γ-GCS expression at leukocytes and increased oxidized LDL, MDA (malondialdehyde) level at plasma from patients with T2DM compared to controls (esp, poorly controlled patients). Conclusion: These results suggest that insufficient antioxidant defenses by the glutathione pathway may be one of the factors responsible for development of complications in T2DM. (J Kor Diabetes Assoc 31:302~309, 2007)

Background: Secondary failure of oral hypoglycemic agents is defined as tha t blood glucose is no longer controlled with sulfonylurea after a proven period of good glycemic control. There are many causes of secondary failure, including that drug problem, acute illnesses, inappropriate drug dosages, oxidative stress & glucose toxicity of β-cell, etc. And many studies have suggested role of immunologic process such as islet cell antibody (ICA) and/or glutamic acid decarboxylase antibody (GADA) for the causes of secondary failure. So we evaluated the prevalence of ICA & GADA in type 2 diabetes with secondary failure of oral hypoglycemic agents and the pathogenesis of the secondary failure. Methods: We studied 267 patients with type 2 diabetes. We regarded 84 pa tients who could not control HbA1c less than 8% after good glycemic control for at least 1 y ear as secondary failure group (group 1) and regarded the other 183 patients as group 2. We measured GADA in both group, and measured the prevalence of GADA and ICA in secondary failure group who were especially divided into obese group and nonobese group according to BMI and were divided into insulin deficiency group and noninsulin deficiency group according to fasting C-peptide level. Results: The prevalence of GADA in all subjects was 4.1%, which was 9.5 % in group 1 and 1.6% in group 2 (P < 0.05). Among 35 patients of the group 1 who could be checked ICA, the prevalence of GADA & ICA were 33% & 25% in insulin deficiency group and 4.3% & 0% in non-insulin deficiency group, respectively (P < 0.05). The prevalence of GADA & ICA were none in obese group and 33.3% & 20% in nonobese group, respectively (P < 0.05). The prevalence of GADA & ICA were 36.4% & 27.3% in nonobese and insulin deficiency, 4.2% & 0% in obese and non-insulin deficiency. Conclusion: We suggest that autoimmune mechanism is associated with increased risk for secondary failure of oral hypoglycemic agents in type 2 diabetes, so the measurement of GADA and ICA could help to predict the potential risk and insulin treatment. (J Kor Diabetes Assoc 31:402~409, 2007)

Background: Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes beta cell dysfunction that is a process known as glucose toxicity. It has been reported that hyperglycemia increases the production of reactive oxygen species (ROS) in human islets and that ROS accumulation causes beta cell dysfunction associated with low capacity of intrinsic antioxidant enzymes. Also it has been postulated that this increase in ROS is prevented by an inhibitor of electron transport chain complex. The purpose of this study were to determine whether prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations disrupts the intracellular balance between ROS thereby causing defective insulin secretion and to evaluate the site of hyperglycemiainduced ROS production. Methods: INS-1 cells & rat islets were incubated in increasing concentrations of glucose and either an inhibitor of complex I & II (TTFA), an uncoupler of oxidative phosphorylation (CCCP), aCCA, etc and also incubated in increasing concentration of glyceraldehyde and N-acetylcystein. Then intracellular peroxide levels by flow cytometric analysis and glucose induced insulin secretion were detected. Results: We observed that incubation with 30 mM glucose increased intracellular peroxide levels but decreased glucose-stimulated insulin secretion (GSIS) (P

Rhabdomyolysis is the consequence of extensive muscle injury with the release of muscle cell constituents into plasma. It can arise from trauma and also from a variety of nontraumatic causes. Trauma, drugs, toxins and infection are the major causes of rhabdomyolysis, but it is rarely associated with metabolic disorders such as severe electrolyte disturbance, diabetic ketoacidosis, hyperosmolar nonketotic coma, hypothyroidism and thyrotoxicosis. There have been several reported cases of metabolic rhabdomyolysis, but panhypopituitarism as a cause has never been identified. We experienced a case of acute rhabdomyolysis associated with panhypopituitarism. Thus, So we report this case with the review of related literature. Metabolic disorder is a rare cause of rhabdomyolysis, but it should always be considered in a patient having and unexplained increased of the creatine kinase concentration (J Kor Soc Endocrinol 20:174～178, 2005).

Kallmann's syndrome is defined as the combination of hypogonadotropic hypogonadism and anosmia/hyposmia. The syndrome is a result of defect in the embryonic migratory pathway of gonadotropin-releasing hormone, which synthesizes neurons and olfactory axons. The hypogonadotropic hypogonadism results due to absence of or incomplete pubertal development and may be associated with anosmia, hyposmia, midline defect (color blindness, cleft-lip, cleft-palate, unilateral renal agenesis, sensorineural deafness), cryptorchidism and skeletal anomaly. Till date in Korea, few cases of Kallmann's syndrome have been reported but there are no available reports on cases of Kallmann's syndrome with unilateral renal aplasia and diabetes mellitus. We handled a case of Kallmann's syndrome associated with unilateral renal agenesis and diabetes mellitus. In the current work, we present a peculiar case as afore mentioned with the review of related literature (J Kor Soc Endocrinol 20:96～102, 2005).

Central diabetes insipidus (DI) is a syndrome characterized by thirst, polydipsia and polyuria. Langerhans cell histiocytosis is one of the etiologies of DI. Recently we experienced a central DI associated with Langerhans cell histiocytosis. The 44 years old female patient complained right hip pain, polydipsia and polyuria. We carried out water deprivation test. After vasopressin injection, urine osmotic pressure was increased from 109 mOsmol/kg to 327 mOsmol/kg (300%). Brain MRI showed a thickened pituitary stalk and air bubble like lesions sized with 5cm, 7cm was shown on fifth L-spine and right hip bone at hip bone CT. CT guided biopsy revealed abnormal histiocytes proliferation and abundant lymphocytes. The final diagnosis was central DI associated with systemic Langerhans cell histiocytosis invading hip bone, L-spine and pituitary stalk. Desmopressin and etoposide chemotherapy were performed to the patient.