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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disrupting compound and persistent organic pollutant that has been associated with diabetes in several epidemiological studies. Oleuropein, a major phenolic compound in olive fruit, is a superior antioxidant and radical scavenger. This study aimed to examine the effects of oleuropein against TCDD-induced stress response in a pancreatic beta cell line, INS-1 cells. Cells were pre-incubated with various concentrations of oleuropein and then stimulated with TCDD (10 nM) for 48 hrs. When treated with TCDD, INS-1 cells produced robust amounts of prostaglandin E

The screening rate of diabetic retinopathy (DR) is low despite the importance of early diagnosis. We investigated the predictive value of dietary glutamic acid and aspartic acid for diagnosis of DR using the Korea National Diabetes Program cohort study. The 2067 patients with type 2 diabetes without DR were included. The baseline intakes of energy, glutamic acid and aspartic acid were assessed using a 3-day food records. The risk of DR incidence based on intake of glutamic acid and aspartic acid was analyzed. The DR group was older, and had higher HbA1c, longer DM duration, lower education level and income than non-DR group (all p p = 0.010, p = 0.025 and p = 0.042, respectively). There was no difference in the risk of developing DR according to the intake of glutamic acid and ascorbic acid. But, aspartic acid intake had a negative correlation with PDR. Hence, the intake of glutamic acid and aspartic acid did not affect in DR incidence. However, lower aspartic acid intake affected the PDR incidence.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant. TCDD accumulates in the food chain, mainly in the fatty tissues of the human body where it causes various toxic effects. Biochanin A is a natural organic compound in the class of phytochemicals known as flavonoids. We investigated whether biochanin A suppresses TCDD-induced loss of adipogenic action using 3T3-L1 adipocytes as a cell culture model of wasting syndrome. In the present study, biochanin A suppressed TCDD-induced loss of lipid accumulation. Pretreating the cells with biochanin A increased the levels of the adipogenesis-associated factors peroxisome proliferator-activated receptor γ and adiponectin, which were inhibited by TCDD. TCDD decreased insulin-stimulated glucose uptake, which was effectively restored by pretreatment with biochanin A. Biochanin A also inhibited the TCDD-driven decrease in production of insulin receptor substrate-1 and glucose transporter 4. These results suggest a preventive effect of biochanin A against TCDD in the development of insulin resistance and diabetes. TCDD increased production of intracellular calcium ([Ca2+]i), prostaglandin E2, cytosolic phospholipase A2, and cyclooxygenase-1, while reducing the level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha. However, biochanin A inhibited these TCDD-induced effects. We conclude that biochanin A is an attractive compound for preventing TCDD-induced wasting syndrome.

Background and objective: The effects of age and related factors on insulin sensitivity have not been definitively evaluated in East Asian populations. We proposed a reference range for the glucose disposal rate (M-value) on hyperinsulinemic-euglycemic study and its association with other parameters. Methods: Healthy, non-diabetic young (n=10) and elderly (n=13) male subjects with normal body mass index were eligible for this study. Subjects who passed the oral glucose tolerance test (OGTT) underwent hyperinsulinemic-euglycemic clamp with high-dose (80 mU/m2·min) insulin infusion. Results: M-values were normalized to body weight (MBW) and fat-free mass (MFFM). Neither M-value was significantly different between age groups (P=0.458 and P=0.900, respectively). An inverse correlation was observed between MFFM and baseline insulin (r=-0.418; P=0.047), baseline C-peptide (r=-0.426; P=0.043) and OGTT 2-hour glucose (r=-0.452; P=0.030). Regarding correlations with other insulin sensitivity indices, M-values were positively associated with the Matsuda index but not with homeostasis model assessment of insulin resistance. Conclusion: Our results suggest that age is not a critical determinant of insulin sensitivity, while fasting insulin and C-peptide levels, OGTT 2-hour glucose level, and Matsuda index are predictable markers of insulin sensitivity in healthy Koreans.

Background/aims Due to recent increases in the disease burden of diabetes mellitus, the Health Insurance Review and Assessment Service (HIRA) of Korea implemented a quality assessment of the treatment of diabetes to improve patient care. The present study was conducted to identify any changes after the implementation of the diabetes quality assessment (DQA). Methods The present study evaluated eight quality assessment indicators that were proposed by the HIRA in all patients with diabetes who visited a university hospital in Korea between 2009 and 2014. The indicators were statistically compared according to the characteristics of the subjects. Results There were several significant differences in the indicators among the subjects according to their demographic characteristics. Female patients had a higher continuity of treatment (COT) than that of male patients, and the insulin-treated group had a higher COT than that of the non-treated group, as well as a higher rate of undergoing the diabetes complication tests (DCTs). Patients between 40 and 80 years of age had the highest COT, while patients under 40 years of age had the lowest COT but the highest rate of taking the DCTs. Patients receiving treatment from an endocrinologist exhibited higher numbers of DCTs performed but displayed lower proportions for the prescription indicators. Conclusion The present analysis of the DQA findings revealed that endocrinologists combine prevention and management of diabetes complications with measures for glycemic control. Thus, the effective management of diabetes likely entails systematic joint treatment regimens that involve an endocrinologist.

Objective: To investigate the pathophysiologic characteristics of diabetic complications, we identified differences in plasma metabolites in subjects with type 2 diabetes (T2DM) with or without diabetic macular edema (DME) and a disease duration > 15 yrs.Subjects and Methods: An elderly cohort of T2DM patients with prolonged disease duration was established, and clinical information and biospecimens were collected following the guidelines of the National Biobank of Korea. DME phenotypes were identified by ophthalmologic specialists. For metabolomics studies, propensity matched case and control samples were selected. To discover multi-biomarkers in plasma, non-targeted metabolite profiling and oxylipin profiling in the discovery cohort were validated in an extended cohort.Results: From metabolomic studies, 5 amino acids (asparagine, aspartic acid, glutamic acid, cysteine, and lysine), 2 organic compounds (citric acid and uric acid) and 4 oxylipins (12-oxoETE, 15-oxoETE, 9-oxoODE, 20-carboxy leukotriene B4) were identified as candidate multi-biomarkers which can guide DME diagnosis among non-DME subjects. Receiver operating characteristic curves revealed high diagnostic value of the combined 5 amino acids and 2 organic compounds (AUC = 0.918), and of the 4 combined oxylipins (AUC = 0.957).Conclusions: Our study suggests that multi-biomarkers may be useful for predicting DME in elderly T2DM patients.

Persistent organic pollutants(POPs) are suggested to be potential risk factors for gestational diabetes mellitus(GDM). We examined the hypothesis that the aryl hydrocarbon receptor trans-activating(AhRT) activity, a potential biomarker for the presence of POPs, could be a GDM risk factor in pregnant women. A total of 390 GDM and 100 normal pregnant(non-GDM) subjects in the Korea National Diabetes Program cohort voluntarily participated. We measured AhRT activity and concentrations of ATP and reactive oxygen in the serum collected at the screening of the participants for GDM using recombinant Hepa1c1c7 cells. Odds ratios(ORs) and 95% confidence intervals(CIs) were estimated using multivariable logistic regression models. The sensitivity and specificity of AhRT activity for GDM diagnostics were measured by receiver operating characteristic(ROC) analysis. Body mass index at pre-pregnancy and delivery and systolic blood pressure were significantly higher in the GDM group. AhRT activity was higher, and ATP concentrations were lower in the GDM group than the non-GDM group(P P 2 = 0.387) and negatively correlated with ATP production(r2 = −0.650). In the ROC curve, AhRT activity had 70.9% sensitivity and 90.0% specificity for glucose-50, a GDM screening method. In conclusion, this study suggests that serum AhRT activity is positively associated with the risk of GDM.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has various toxicological effects in adipose tissue. Evidence is accumulating that glabridin, a flavonoid extracted from licorice, has beneficial effects on the regulation of glucose homeostasis. In this study, we investigated whether glabridin suppresses TCDD-induced loss of adipogenic action using 3T3-L1 adipocytes as a cell culture model of wasting syndrome. Glabridin effectively suppressed TCDD-induced loss of lipid accumulation in this model. Pretreating cells with glabridin increased the gene expression of not only the adipogenesis-associated key transcription factors peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha, but also lipoprotein lipase in the presence of TCDD. TCDD decreased insulin-stimulated glucose uptake, which was effectively restored by pretreatment with glabridin. Glabridin also inhibited the TCDD-driven decreased production of insulin receptor substrate 1 and glucose transporter 4. TCDD increased the production of mitochondrial superoxides, prostaglandin E2 , phospholipase A2 , cyclooxygenase-1 and intracellular calcium concentrations, while reducing the production of PPARγ coactivator 1 alpha and glycolysis. However, glabridin treatment reduced these TCDD-induced effects. We conclude that glabridin suppresses the TCDD-induced loss of lipid accumulation in 3T3-L1 adipocytes by regulating the levels of PPARγ, CCAAT/enhancer binding protein alpha, lipoprotein lipase, glucose uptake, prostaglandin E2 and energy metabolism. These results also provide in vitro evidence of the effects of glabridin on adipocyte metabolism, which suggests a protective effect against dioxin exposure in the development of insulin resistance and diabetes.

AIM To evaluate the efficacy and safety of ipragliflozin vs placebo as add-on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM). METHODS This double-blind, placebo-controlled, multi-centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT). RESULTS In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add-on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were -0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference -0.83% [95% CI -1.07 to -0.59]; P < .0001). More ipragliflozin-treated patients than placebo-treated patients achieved HbA1c target levels of

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to affect bone metabolism. We evaluated the protective effects of the triterpene glycoside actein from the herb black cohosh against TCDD-induced toxicity in MC3T3-E1 osteoblastic cells. We found that TCDD significantly reduced cell viability and increased apoptosis and autophagy in MC3T3-E1 osteoblastic cells (P

Methylglyoxal (MG) is one of the major precursors of advanced glycation end products (AGEs), which are considered to be one of the causes of diabetes and its complications. The root and rhizomes of black cohosh (Cimicifuga racemosa) have long been used medicinally, and deoxyactein is one of its major constituents. In the present study, the protective effects of deoxyactein against MG-induced oxidative cell damage were investigated in insulin-producing pancreatic β-cells. We found that deoxyactein protected the pancreatic β-cells against MG-induced cell death. Pre-treatment with deoxyactein significantly reduced the levels of intracellular reactive oxygen species (ROS), interleukin-1β (IL-1β), cardiolipin peroxidation, and protein adduct accumulation induced by MG. Pre-treatment of the cells with deoxyactein restored glyoxalase I activity and insulin secretion which were reduced by MG, and increased the mRNA expression of insulin 2 (INS2) and pancreatic and duodenal homeobox protein-1 (PDX-1). It also increased the levels of endogenous antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX). Furthermore, treatment with deoxyactein increased the levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α). These findings indicate that deoxyactein may exert beneficial effects on pancreatic β-cells via the upregulation of mitochondrial biogenesis. Taken together, these results suggest that deoxyactein may be used for the prevention of pancreatic β-cell damage.

Background The primary aim of this study was to assess the utility of fasting plasma glucose (FPG) and HbA1c to identify diabetes by the 2-hour plasma glucose (PG) criterion in the Korean population at high risk for diabetes. Methods A total of 1646 participants with a body mass index of ≥23 kg/m2 without having a history of diabetes were recruited in this study. The cut-off values of FPG and HbA1c for detecting diabetes were identified using the Youden index using receiver operating characteristic (ROC) analysis. The gold standard for diabetes prediction was defined by the 2-hour PG level of ≥200 mg/dL. Results The participants comprised 54.0% women, and the mean age of all participants was 55.0 ± 8.1 years. At baseline, FPG was 104.1 ± 14.2 mg/dL, the 2-hour PG value was 162.9 ± 55.3 mg/dL, and HbA1c was 5.9% ± 0.5%. Four hundred and forty-six subjects (27.1%) were diagnosed with diabetes and 976 subjects (59.3%) were determined to be at prediabetes. The area under the ROC curve (AUC) of FPG and HbA1c for diabetes were 0.776 and 0.802, while the AUC of FPG and HbA1c for prediabetes were 0.515 and 0.477. The optimal cut-off value for diagnosing diabetes of FPG and HbA1c were 104.5 mg/dL (sensitivity 75.8%, specificity 67.5%) and 5.9% (sensitivity 80.6%, specificity 63.8%), respectively. Conclusions FPG of 104.5 mg/dL and HbA1c value of 5.9% (41 mmol/mol) can be used as an optimal screening value for diabetes by 2-hour PG criterion in the Korean population at high risk for diabetes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) accumulates in human body, probably influencing adipocyte differentiation and causing various toxic effects, including wasting syndrome. Recently, orientin, a phenolic compound abundant in natural health products, has been shown to have antioxidant properties. We investigated the protective effects of orientin against TCDD-induced adipocyte dysfunction and its underlying mechanisms. In this study, orientin suppressed TCDD-induced loss of lipid accumulation. Orientin inhibited TCDD-driven decreases in the levels of peroxisome proliferator-activated receptor γ and adiponectin. Orientin also reduced TCDD-induced prostaglandin E2, and cytosolic phospholipase A2α levels, and increased TCDD-inhibited peroxisome proliferator-activated receptor gamma coactivator 1-alpha levels in 3T3-L1 adipocytes. TCDD reduced the levels of insulin receptor substrate 1 and glucose transporter 4, and decreased insulin-stimulated glucose uptake activity; however, orientin diminished these TCDD-induced effects. These results suggest that orientin may have beneficial effects on the prevention of TCDD-induced wasting syndrome and type II diabetes mellitus accompanied by insulin resistance.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce glycosylated hemoglobin (HbA1c, 0.5% to 1.0%), and are associated with moderate weight loss and a relatively low risk of hypoglycemia. There are differences between Asian and non-Asian populations. We reviewed available data on GLP-1RAs, focusing on Korean patients, to better understand their risk/benefit profile and help inform local clinical practice. Control of postprandial hyperglycemia is important in Asians in whom the prevalence of post-challenge hyperglycemia is higher (vs. non-Asians). The weight lowering effects of GLP-1RAs are becoming more salient as the prevalence of overweight and obesity among Korean patients increases. The higher rate of gastrointestinal adverse events amongst Asian patients in clinical trials may be caused by higher drug exposure due to the lower body mass index of the participants (vs. non-Asian studies). Data on the durability of weight loss, clinically important health outcomes, safety and optimal dosing in Korean patients are lacking. Use of GLP-1RAs is appropriate in several patient groups, including patients whose HbA1c is uncontrolled, especially if this is due to postprandial glucose excursions and patients who are overweight or obese due to dietary problems (e.g., appetite control). The potential for gastrointestinal adverse events should be explained to patients at treatment initiation to facilitate the promotion of better compliance.

Celiac disease is an intestinal autoimmune disorder, triggered by ingestion of a gluten-containing diet in genetically susceptible individuals. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes, especially HLA-DQ2-positive patients. The prevalence of celiac disease has been estimated to be ~1% in Europe and the USA, but it is rarer and/or underdiagnosed in Asia. We report a case of celiac disease in a predisposed patient, with a HLA-DQ2 heterodimer, and Graves' disease that was treated successfully with a gluten-free diet. A 47-year-old woman complained of persistent chronic diarrhea and weight loss over a 9 month period. Results of all serological tests and stool exams were negative. However, the patient was found to carry the HLA DQ2 heterodimer. Symptoms improved after a gluten-free diet was initiated. The patient has been followed and has suffered no recurrence of symptoms while on the gluten-free diet. An overall diagnosis of celiac disease was made in a genetically predisposed patient (HLA-DQ2 heterodimer) with Graves' disease.

To identify clinical characteristics and risk factors of retinal neurodegeneration represented by macular ganglion cell/inner plexiform layer (mGCIPL) thinning in patients with long-standing type 2 diabetes mellitus (T2DM). Patients who had T2DM for >15 years were prospectively recruited from September 2014 to July 2015. Clinical data and samples were collected according to the Common Data Element and Standards of Procedure developed by the Korean Diabetes Association research council. Baseline characteristics included age, gender, family history, medical record of comorbidity, and microvascular complications. All patients underwent optical coherence tomography with automatic segmentation of the mGCIPL in six parafoveal regions. Multivariable regression analysis identified factors associated with mGCIPL thinning. Of 220 registered patients, 162 were included after ophthalmologic examination. The mean (SD) age was 65.0 (9.3) years, the mean duration of T2DM was 20.5 (4.0) years; mGCIPL thickness was 76.2 (8.5) µm. Hypertension, diabetic retinopathy, statin medication, estimated glomerular filtration rate, conduction velocity of the posterior tibial, peroneal, and sural nerves, and cardiac autonomic neuropathy (CAN) score were significantly correlated with mGCIPL thickness. Multivariate regression analysis showed that the CAN score (coefficient = −1.78, p = 0.001) and sural nerve velocity (coefficient = 0.458, p = 0.035) yielded a significant high regression correlation with mGCIPL thickness (overall R 2 = 0.46). This study demonstrated that various clinical features were associated with retinal neurodegeneration in T2DM. In particular, peripheral nerve conduction and autonomic nerve function were confirmed to be strong risk factors for mGCIPL thinning in patients with T2DM.

Chronic hyperglycemia aggravates insulin resistance, in part due to increased formation of advanced glycation end-products (AGEs). Methylglyoxal (MG), a major precursor of AGEs, accumulates abnormally in various tissues and organs and participates in oxidative damage. We investigated the insulinotropic benefits of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, in pancreatic β-cells exposed to MG in vitro. When exposed to cytotoxic levels of MG for 48 h, RIN-m5F β-cells exhibited a significant loss of viability and impaired insulin secretion, whereas pretreatment with magnolol protected against MG-induced cell death and decreased insulin secretion. Moreover, magnolol increased the expression of genes involved in β-cell survival and function, including Ins2 and PDX1. Furthermore, magnolol increased the levels of AMPK phosphorylation, SIRT1, and PGC1α in RIN-5F β-cells. In addition, magnolol increased the activity of glyoxalase I and decreased the levels of MG-modified protein adducts, which suggests that magnolol protects against MG-induced protein glycation. Taken together, the results indicate the potential application of magnolol as an intervention against MG-induced hyperglycemia.

Patients with diabetes have many different kinds of complications involving multiple organs, but those involving the musculoskeletal system are relatively uncommon. Diabetic muscle infarction (DMI) is a rare, painful, and potentially serious condition in patients with poorly controlled diabetes mellitus. A 35-year-old man diagnosed with type 2 diabetes eight years ago, visited with severe muscle pain in the right anteromedial thigh without any event of trauma. He had been treated with metformin, but his glycemic control was very poor with a glycated hemoglobin of 14.5%. Evaluation of his painful thigh lesion did not reveal any evidence of infection or vasculitis, but the magnetic resonance imaging and bone scan showed findings of DMI at vastus medialis muscle and an insufficiency fracture at the right medial tibial condyle. He was diagnosed with retinopathy, neuropathy and microalbuminuria but not macrovascular complications. We also diagnosed his diabetes as latent autoimmune diabetes in adults (LADA) based on his low C-peptide level, positive anti-glutamic acid decarboxylase (GAD) antibody and early onset diabetes. Instead of antibiotics, bed rest, analgesics and strict blood glucose control with multiple daily insulin injections led to symptom improvement. This is an unusual case of a young man with LADA experiencing severe musculoskeletal complication of DMI and insufficiency fracture. If a poorly controlled diabetic patient appears to have unaccounted soft tissue pain, musculoskeletal complications such as DMI associated with hyperglycemia should be considered.

Background: Fine-needle aspiration (FNA) of the thyroid is a widely accepted confirmatory test for thyroid cancer with high sensitivity and specificity. FNA is a simple procedure that is learned by many clinicians to enable accurate diagnosis of thyroid cancer. However, it is assumed that because the FNA test is a relatively simple procedure, its cytologic results are reliable regardless of the operator’s experience. The aim of this study was to evaluate the differences in the diagnostic indices of FNA between operators with different levels of experience. Methods: A total of 694 thyroid FNA specimens from 469 patients were reviewed, and were separated based on the experience of the clinicians who performed the procedure. One hundred and ninety were categorized in the experienced group, and 504 in the inexperienced group. All FNA results were then compared with histological data from surgically resected specimens, and the sample adequacy and diagnostic accuracy of the groups were compared. Results: The age, gender, and nodule size and characteristics were similar in both groups. The sample adequacy rate was not significantly different between the experienced and nonexperienced groups (96.3% vs. 95.4%, P=0.682). However, the non-experienced group had a higher false-negative rate than the experienced group (6.4% vs. 17.2%, P=0.038), and the sensitivity of the FNA test also tended to be lower in the nonexperienced group (95.6% vs. 88.9%, P=0.065). Conclusion: These results suggest that FNA operators who have less experience may miss cases of thyroid cancer by performing the procedure incorrectly. As such, the experience of the FNA operator should be considered when diagnosing thyroid cancer. When clinicians are being trained in FNA, more effort should be made to increase the accuracy of the procedure; therefore, enhanced teaching programs and/or a more detailed feedback system are recommended.

Glycemic monitoring is essential for the management of diabetes mellitus. Today, glycosylated hemoglobin (HbA1c) is the most widely used parameter for glycemic monitoring and reflects average glucose levels over 2 to 3 months. However, HbA1c is limited in its ability to reflect short-term glycemic changes. Also, it cannot separately reflect postprandial hyperglycemia (PPH) and fasting hyperglycemia. In addition, HbA1c is a not a good predictor of hypoglycemic episodes as it only accounts for 8% of the probability of severe hypoglycemia [1,2]. A growing body of evidence suggests that PPH and glycemic variability (GV) may be independent risk factors for macrovascular complications in patients with diabetes [3]. The relationship between PPH and cardiovascular disease (CVD) has been consistently reported even in the context of HbA1c levels in the nondiabetic range [4]. Many experimental animal studies indicate that GV, compared with chronic hyperglycemia, promotes excess oxidative stress and worsens cellular and vascular damage [3]. Although the effect of GV on oxidative stress in clinical settings remains controversial, several studies have also confirmed these findings in human studies. Few studies have demonstrated the effect of daily GV on CVD outcomes, although visit-to-visit GV, a longer term index, may predict worse CVD outcome in patients with diabetes. Although GV usually refers to overall glycemic variation including hyper and hypoglycemia, GV is often also used to refer to postprandial glycemic excursion. Complete differentiation between GV and PPH may be impossible because they are correlated with each other, but GV is thought to be important as it is associated with hypoglycemia, especially severe hypoglycemia [5,6]. Severe hypoglycemia can not only directly cause death, but also predict higher risk of mortality, CVD or severe arrhythmia [3]. Especially, patients with type 1 diabetes mellitus (T1DM) are frequently exposed to both excessive hyperglycemia and prolonged, dangerous hypoglycemia even with the availability of insulin pumps and short and long-acting insulin analogs [7]. Thus, clinically, monitoring and minimizing GV is important for preventing hypoglycemia and CVD, in management of diabetes mellitus. There are many measures of GV, extensively reviewed by Rodbard [8]. The most simply used method to assess variability is standard deviation (SD) which is a measure of dispersion of glucose, but its meaning is insufficient in "not" normally distributed data. Mean amplitude of glycemic excursions (MAGE) by Service and colleagues [9], mean of daily differences, and several other measures are commonly used to evaluate GV. However, measurement of GV is challenging because it is still relatively new and most of these measures for GV are calculated from continuous glucose monitoring system (CGMS) [10]. In fact, CGMS is the most reliable and precise method for evaluating GV and PPH. However, it is inconvenient and not easily accessible in general practice. Recently, easily measurable glycemic biomarkers, such as 1,5-anhydroglucitol (1,5-AG), glycated albumin (GA) and fructosamine (FA) have been reported to reflect GV and PPH in T1DM and type 2 diabetes mellitus (T2DM) with various glycemic control status [11,12,]. In this issue of Diabetes & Metabolism Journal, Seok et al. [14] reported that 1,5-AG may be a useful marker for assessment of short-term change of glycemic excursion in patients with T1DM. This study showed that the changes of 1,5-AG levels for the period of 2 weeks is negatively correlated with the changes of various CGMS parameter for GV and PPH. Nonetheless, these results are significant only in moderately controlled T1DM with baseline mean CGMS glucose 8%) 1,5-AG level becomes too low to be used as a marker of glycemic excursion. Considering recent studies, 1,5-AG can reflect GV in T1DM and T2DM, but it has limited ability in well or moderately controlled patients with glycemic excursions with narrow ranges. More study is needed to find a valid biomarker for assessing GV and application to diabetes treatment in clinical practice.

To the Editor, Primary aldosteronism (PA) is associated with several cardiovascular diseases. Postulated mechanisms include inappropriate volume retention, suppression of endothelial function, and target organ inflammation and fibrosis. While heart failure in conjunction with arrhythmias is the most common cardiovascular complication in PA, few cases of coronary artery disease (CAD) in concurrence with PA have been reported [1-3]. Here, we propose a possible mechanism for CAD developing in PA based on a case of PA presenting as non-ST elevation myocardial infarction (NSTEMI) in the absence of heart failure or other comorbidities in a relatively young Korean male. To our knowledge, this is the first report of PA presenting with NSTEMI. A 43-year-old male with a 10-year history of treatment-resistant hypertension presented to the cardiology outpatient clinic with stabbing chest pain in the retrosternal area. The pain began at rest and lasted for a few seconds to a few minutes. To treat his hypertension, he was taking carvedilol 25 mg, telmisartan 80 mg, and spironolactone 25 mg. He had a 20 pack-years smoking history, but no family history of cardiovascular disease. He was admitted for further investigations. On admission, his blood pressure was 130/80 mmHg, pulse 66 per minute, body temperature 36℃, respiration rate 20 per minute, and body mass index 23.0 kg/m2. The initial laboratory testing yielded serum sodium 144 mmol/L, potassium 2.7 mmol/L, chloride 101 mmol/L, blood urea nitrogen 12 mg/dL, creatinine 0.9 mg/dL, troponin-I 0.16 ng/mL, creatine kinase 78 U/L, high-sensitivity C-reactive protein (hs-CRP) 1.81 mg/L, and creatinine kinase-MB 1.9 ng/mL. The lipid profile, liver function tests, and complete blood count with differential were all within normal limits. The chest X-ray was unremarkable and the initial electrocardiograph (ECG) showed a prominent U wave in all precordial leads and T wave inversion in V3 to 5. Echocardiography revealed a normal ejection fraction (70%) with no valvular abnormality. The right and left carotid intima-media thickness (IMT) was 0.6 and 0.5 mm, respectively, without visible plaque. The brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV), ankle-brachial index (ABI) bilaterally, and cardioankle vascular index (CAVI) bilaterally were all normal. Based on these findings, NSTEMI was diagnosed and followed by coronary angiography with successful percutaneous coronary intervention (PCI) with a drug-eluting stent at the mid-left anterior descending artery (Fig. 1). Figure 1 Coronary angiography demonstrating 75% diameter stenosis of the mid-left anterior descending artery. After PCI, his serum potassium and blood pressure remained uncorrected despite oral potassium supplementation and three antihypertensive medications. In light of his uncorrected electrolyte and blood pressure, additional endocrinological tests were performed. His thyroid-stimulating hormone level was 2.46 µU/mL, free T4 1.36 ng/dL, T3 143 ng/dL, 24-hour urine free cortisol 71 µg/day, urine vanillylmandelic acid 2.0 mg/day, urine norepinephrine 118.2 µg/day, urine epinephrine 11 ng/day, urine metanephrine 0.4 mg/day plasma norepinephrine 0.28 ng/mL, plasma epinephrine 0.04 ng/mL, plasma adrenocorticotropic hormone 65.2 pg/mL at 8:00 AM and 22.8 pg/mL at 4:00 PM, plasma cortisol 21.2 µg/dL (585.12 nmol/L) at 8:00 AM, 9.4 µg/dL (259.44 nmol/L) at 4:00 PM, and 15.6 µg/dL (430.56 nmol/L) at midnight, plasma aldosterone 1,080.3 pmol/L (cutoff value > 450 pmol/L), plasma renin activity (PRA) 0.1 ng/mL/hr, and aldosterone-renin ratio 10,803 pmol/L:ng/mL/hr (cutoff value > 750 pmol/L:ng/mL/hr). To avoid misinterpretation of the plasma cortisol level during a stressful condition (i.e., NSTEMI), we checked the serum cortisol level several times during the following 6 months and confirmed a consistently elevated level. Suspecting PA, abdominal computed tomography revealed a 1.4 × 1.2-cm mass at the right adrenal gland (Fig. 2A). After discontinuing all antihypertensive drugs, he underwent the furosemide loading test, which showed no response. Based on the high 24-hour urine free cortisol level, an overnight dexamethasone suppression test (DST) was done. After a 1-mg dose DST, the plasma cortisol level was 2.2 µg/dL. Subsequently, a low-dose DST was performed, but the result was negative. Hence, we could rule out Cushing syndrome. Figure 2 (A) Abdominal computed tomography showing an adrenal adenoma of the right adrenal gland, medial limb. (B) Histopathology confirming adrenocortical adenoma (light microscopy, H&E, × 200). The adrenal adenoma was removed laparoscopically; the specimen showed a cortical adenoma with primarily cortical hypertrophy mixed with regions of partial cortical atrophy, suggesting autonomous cortisol secretion (Fig. 2B). Postoperatively, his blood pressure, serum potassium level, and ECG normalized. The chronically elevated serum aldosterone level in patients with PA makes them susceptible to a wide spectrum of cardiovascular diseases, from arrhythmias to congestive heart failure and CAD. The relatively high incidence of heart failure in conjunction with arrhythmias in patients with PA can be explained by left ventricular hypertrophy due to hypertension, hypokalemia, and cardiac fibrosis due to aldosterone excess [1-3]. Although many have hypothesized that aldosterone plays a role in the development of CAD, the number of cases of PA occurring in concurrence with CAD remains very small, especially in Asian populations. Although Nakajima et al. [4] reported a myocardial infarction occurring in PA and Nishimura et al. [2] stable angina in PA, these patients were elderly, leaving room for discussion as to whether age along with other comorbidities associated with senility contributed to the outcome [1]. The reasons for the obvious discrepancy in the incidence of heart failure and CAD have never been explored nor has the exact mechanism underlying the development of CAD in PA been established. This case is interesting in terms of the pathophysiological role of aldosterone in the development of NSTEMI in a relatively young patient with no risk factors for CAD other than smoking. It is also notable that despite the long history of treatment-resistant hypertension, there were no signs of endothelial dysfunction or arterial stiffness, evident by the normal FMD, PWV, ABI, CAVI, hs-CRP, and carotid IMT. The atherosclerotic lesions were limited to the coronary artery. In addition, the fact that his NSTEMI was diagnosed before the diagnosis of PA makes this case unique. It appears that the lack of symptoms owing to hypokalemia, muscle weakness, and constipation delayed the detection of the PA. We would like to highlight that this NSTEMI occurred in the absence of left ventricular dysfunction, suggesting that a separate mechanism exists for the development of CAD. Although we were not able to prove it, after reviewing various studies, we suggest the autonomous secretion of cortisol in association with PA as the culprit. Recent studies support the strong correlation between the autonomous secretion of cortisol and the increase in cardiovascular events [4]. This patient had an elevated midnight cortisol, an initial 24-hour urine cortisol > 50 µg/day, and a plasma cortisol level after 1-mg DST > 2.0 µg/dL; all suggest subclinical hypercortisolism. Hypercortisolism is associated with the decreased production of vasodilators, such as nitric oxide (NO), in coronary artery endothelial cells, and this might lead to the development of CAD. Rogers et al. [5] suggested the following as the mechanism of NO synthesis downregulation: 1) decreased endothelial NO synthase (eNOS) mRNA expression, 2) increased degradation of eNOS mRNA, 3) decreased eNOS protein stability, and 4) decreased agonist-mediated intracellular calcium mobilization. Such changes inevitably lead to an increased risk of CAD developing. Although we did not demonstrate a relationship between hypercortisolism and NO production in this case, it is safe to say that this case, at least, corroborates the role of cortisol in the development of coronary events. Another possible mechanism might be that chronic aldosterone excess alters the normal immune response system by activating proinflammatory mediators such as intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin-1, plasminogen activator inhibitor-1, and matrix metalloproteinases, thereby setting a proinflammatory vascular phenotype and plaque vulnerability [3]. This inflammatory and endothelial dysfunction might be responsible for the development of CAD in PA patients. In conclusion, measuring serum cortisol level might help to predict CAD development in patients with PA. In addition, in CAD patients without typical risk factors, secondary endocrine causes should be suspected.

Aims: It is necessary to evaluate glucose variability and postprandial hyperglycemia in patients with well-controlled type 2 diabetes mellitus because of the limitations associated with hemoglobin A1c (HbA1c) measurements. We evaluated parameters reflecting postprandial hyperglycemia and glycemic variability in patients with optimal HbA1c. Patients and Methods: Thirty-nine patients with HbA1c levels below 7% were recruited to the study. A continuous glucose monitoring system (CGMS) was applied for two 72-h periods. 1,5-Anhydroglucitol (1,5-AG) and fructosamine (FA) were measured as parameters for postprandial hyperglycemia and glucose variability. Using CGMS data, the following postprandial hyperglycemia parameters were calculated: mean postprandial maximum glucose (MPMG) and area under the curve for glucose above 180 mg/dL (AUC-180). To measure glycemic variability, we calculated mean amplitude of glucose excursion (MAGE) using a classical (MAGEc) and new method (MAGE group of sign [MAGEgos]). R...

Background and Aims Hypoglycemia is one of the most important adverse events in individuals with type 2 diabetes mellitus (T2DM). However, hypoglycemia-related events are usually overlooked and have been documented less in clinical practice. Materials and Methods We evaluated the incidence, clinical characteristics, and medical expenses of hypoglycemia related events in T2DM patients based on the Korea National Diabetes Program (KNDP), which is the largest multi-center, prospective cohort in Korea (n = 4,350). For accurate outcomes, the KNDP data were merged with claims data from the Health Insurance Review and Assessment Service (HIRA) of Korea. Results During a median follow-up period of 3.23 years (95% CI: 3.14, 3.19), 88 subjects (2.02%) were newly diagnosed with hypoglycemia, and the incidence of hypoglycemia was 6.44 cases per 1,000 person-years (PY). Individuals with hypoglycemia were significantly older (59.7 +/- 10.7 vs. 53.3 +/- 10.4 years, p < 0.001), had more hospital visits (121.94 +/- 126.88 days/PY, p < 0.001), had a longer hospital stays (16.13 +/- 29.21 days/PY, p < 0.001), and incurred greater medical costs ($ 2,447.56 +/- 4,056.38 vs. $ 1,336.37 +/- 3,403.39 /PY, p < 0.001) than subjects without hypoglycemia. Conclusion Hypoglycemia-related events were infrequently identified among the medical records of T2DM subjects. However, they were associated significantly with poor clinical outcomes, and thus, hypoglycemia could have a substantial burden on the Korean national healthcare system.

Diabetes mellitus (DM) patients are susceptible to foot injury or foot diseases such as diabetic foot and peripheral arterial disease. Although these conditions are considered important, few studies have investigated them in detail. Therefore, we investigated the epidemiology of diabetic foot complications (DFC) with respect to the effects on the public healthcare system.We evaluated the incidence, clinical characteristics, health service utilization frequency and medical expenses of DFC in type 2 DM patients in the Korea National Diabetes Program (KNDP), the largest multi-center, prospective cohort in Korea (n=4405). To determine precise outcomes, we used national representative databases, including claims data from the Health Insurance ReviewAssessment Service of Korea.During a median follow-up period of 3.30years, 528 patients (12.0%) were newly diagnosed with DFC at an incidence rate of 43.02 cases per 1000 person-years. The patients with DFC were significantly older than patients without DFC, but other clinical characteristics were similar between the two groups. The patients with DFC had more hospital visits (p0.001), longer duration of hospitalization (p0.001), and increased expenses (p0.001) compared to patients without DFC. After multiple adjustments, the differences in number of hospital visits and medical expenses were consistent. In a before and after comparison within the DFC group, all three variables increased significantly after the onset of DFC (p0.001).DFC were significantly associated with poor clinical outcomes and caused a substantial burden to the national healthcare system in Korea. Therefore, intervention to prevent DFC is important.

Aim Although hypoglycemia is associated with cognitive dysfunction, including dementia, in patients with type 2 diabetes mellitus (DM), the data are equivocal. The purpose of this study was to investigate the association between hypoglycemia, dementia, and other cognitive dysfunctions. Methods This was a prospective observational study based upon the Korea National Diabetes Program (KNDP). Among the 4540 participants in the KNDP cohort, individuals aged ⩾60years without any history of hypoglycemia or cognitive dysfunction ( n =1957) were included. Nationally representative data from the Health Insurance Review and Assessment Service of Korea claim database were used to obtain a more precise determination of patient outcome. Results During a mean follow-up period of 3.4±0.9years, 118 subjects experienced hypoglycemia-related events. The incidence of dementia and cognitive dysfunction was 7.5 cases per 1000 person-years (PY) and 0.61 cases per 1000 PY, respectively. In the subjects who experienced hypoglycemic events (relative to those who did not), the incidence of dementia was significantly higher ( P =0.0139), but the incidence of cognitive dysfunction was not ( P =0.1106). Hypoglycemic events were associated with dementia (HR, 2.689; 95% CI, 1.080–6.694, P =0.0335) following multiple adjustments. There was also a significant linear trend toward an increased dementia risk commensurate with an increasing number of hypoglycemic events ( P =0.0286). Conclusions Hypoglycemia is significantly associated with the risk of dementia in Korean type 2 DM patients aged ⩾60years.

Carney complex (CNC) is an autosomal dominant hereditary or sporadic multiple neoplastic syndrome that shows variable clinical symptoms. Generally, CNC appears as skin pigmentation, cardiac or cutaneous myxomas, and multiple endocrine tumours. We performed an extensive evaluation of 9 individuals within 1 family in whom CNC was suspected. Among them, 5 had CNC with various clinical manifestations. We also performed mutational analysis of suspected genes in these patients. Although all patients were members of the same family, variable CNC-related manifestations were observed in each patient. An analysis showed a novel deletion mutation (c.537delA) in exon 6 of the PRKAR1A gene in the patients. Based on our results, the patients were determined to have CNC type I. This is the first such mutational report in Korea.

Background Type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor that results in severe hyperglycemia and acanthosis nigricans. However, the mechanisms by which these autoantibodies induce hypoglycemia are largely unknown. In this paper, we report the case of patient with type B insulin resistance syndrome who presented with frequent severe fasting hypoglycemia and acanthosis nigricans. Methods To evaluate the mechanism of hypoglycemia, we measured the inhibition of insulin binding to erythrocytes and IM9 lymphocytes in a sample of the patient's dialyzed serum before and after immunosuppressive therapy. Results In the patient's pre-treatment serum IgG, the binding of 125I-insulin to erythrocytes was markedly inhibited in a dose-dependent manner until the cold insulin level reached 10-9 mol/L. We also observed dose-dependent inhibition of insulin binding to IM9 lymphocytes, which reached approximately 82% inhibition and persisted even when diluted 1:20. After treatment with glucocorticoids, insulin-erythrocyte binding activity returned to between 70% and 80% of normal, while the inhibition of insulin-lymphocyte binding was reduced by 17%. Conclusion We treated a patient with type B insulin resistance syndrome showing recurrent fasting hypoglycemia with steroids and azathioprine. We characterized the patient's insulin receptor antibodies by measuring the inhibition of insulin binding.

We analyzed the medical records of 884 type 2 DM patients who were taking different antiplatelet agents for more than 2 years. Based on the records, occurrences of cardiovascular events for 10 years were evaluated. The composite disease-free survival rate for cilostazol monotherapy group was similar to aspirin subgroup (p = 0.133).

Both IFG and IGT are prediabetic conditions that can progress to type 2 DM. However, previous studies have shown that these are not identical. This study was conducted on 307 drug naive prediabetic adults who did not meet the diagnostic criteria for diabetes based on the OGTT. According to the OGTT, the subjects were divided into isolated IFG (i-IFG), isolated IGT (i-IGT), and combined glucose intolerance (CGI) group. We also measured insulin resistance indices (HOMA-IR, WBISI), an insulin secretion indices (insulinogenic index [IGI], AUC I/G 0–120 , disposition index [DI]), and compared each of the three groups. The OGTT measurements showed that 87 subjects were diagnosed with i-IFG, 75 subjects had i-IGT, and 145 subjects had CGI. With respect to the insulin resistance indices, HOMA-IR and WBISI were not significantly different. However, insulin secretory capacity, the IGI and DI were significantly higher for the i-IFG group. Moreover, after confounders were adjusted, HOMA-IR, IGI, AUC I/G 0–120 , and the DI were significantly higher for the i-IFG group and WBISI was significantly higher for the i-IGT group. These results demonstrate that the pathogenesis of IFG is more closely associated with insulin resistance, and the pathogenesis of IGT is more closely associated with impaired insulin secretion.

A macroinvasive pituitary adenoma with plurihormonality usually causes acromegaly and hyperprolactinemia, and also accompanies with neurologic symptoms such as visual disturbances. However, its concurrent presentation with a rectal carcinoid tumor is rarely observed. This study reports the history, biochemical, colonoscopic and immunohistochemical results of a 48-year-old female with acromegaly and hyperprolactinemia. Despite the large size and invasive nature of the pituitary adenoma to adjacent anatomical structures, she did not complain of any neurologic symptoms such as visual disturbance or headache. Immunohistochemical staining of the surgical specimen from the pituitary adenoma revealed that the tumor cells were positive for growth hormone (GH), prolactin (PRL), and thyroid stimulating hormone (TSH). Staining for pituitary-specific transcription factor-1 (Pit-1) was shown to be strongly positive, which could have been possibly contributing to the plurihormonality of this adenoma. Colonoscopy found a rectal polyp that was identified to be a carcinoid tumor using immunohistochemical staining. A macroinvasive pituitary adenoma with concomitant rectal carcinoid tumor was secreting GH, PRL, and TSH, which were believed to be in association with over-expression of Pit-1. This is the first case report of double primary tumors comprising a plurihormonal pituitary macroadenoma and rectal carcinoid tumor.

The aim of this study was to investigate the relationship between somatostatinergic tone (SST) and the size of growth hormone (GH)-producing pituitary tumors. GH levels of 29 patients with newly diagnosed acromegaly were measured using a 75-gram oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), and an octreotide suppression test (OST). Differences between GH levels during the ITT and the OGTT (ΔGHIO), and between the OGTT and the OST at the same time point (ΔGHOS) were compared according to the size of the tumor and the response pattern to the OST. ΔGHIO of macroadenomas (n=22) was non-significantly higher than those of microadenomas while ΔGHOS of macroadenomas were significantly higher than those of microadenomas. According to further analyses of macroadenomas based on the response pattern to the OST, GH levels during the ITT were significantly higher in non-responders. ΔGHOS showed near-significant differences between responders and non-responders. In conclusion, as the size of the pituitary tumor increases, the effect of glucose on SST appears to be attenuated. Macroadenomas that are non-responders to the OST possess a portion of GH secretion exceeding the range of regulation by SST.

Objective. The aim of this study was to investigate how the paradoxical response of GH secretion to TRH changes according to tumor volumes. Methods. Patients with newly diagnosed acromegaly were classified as either TRH responders or nonresponders according to the results of a TRH stimulation test (TST), and their clinical characteristics were compared according to responsiveness to TRH and tumor volumes. Results. A total of 41 acromegalic patients who underwent the TST were included in this study. Between TRH responders and nonresponders, basal GH, IGF-I levels, peak GH levels, and tumor volume were not significantly different, but the between-group difference of GH levels remained near significant over the entire TST time. ΔGHmax-min during the TST were significantly different according to the responsiveness to TRH. Peak GH levels and ΔGHmax-min during the TST showed significantly positive correlations with tumor volume with higher levels in macroadenomas than in microadenomas. GH levels over the entire TST time also remained significantly higher in macroadenomas than in microadenomas. Conclusion. Our data demonstrated that the paradoxical response of GH secretion to TRH in GH-producing pituitary adenomas was not inversely correlated with tumor volumes.

Background There have been no systematic observations regarding changes in early phase insulin secretion among Korean prediabetes and early stage type 2 diabetes mellitus (T2DM) patients. Methods We conducted 75-g oral glucose tolerance tests (OGTT) in 873 subjects with suspected abnormal glucose tolerance. All subjects were diagnosed as having normal glucose tolerance (NGT), prediabetes (preDM), or T2DM according to the OGTT results and the insulin secretory and insulin resistance indices of each subject were calculated. Additionally, we analyzed the changes in early phase insulin secretion according to changes in fasting (Glc(0)), post-prandial (Glc(120)) glucose and HbA1c (A1c) levels. Results As compared to subjects with NGT, the insulin secretory indices of the preDM and T2DM subjects progressively declined, and the insulin resistance indices were progressively aggravated. Early phase insulin secretion decreased rapidly according to the increments of Glc(0), Glc(120) and A1c, and these changes were most prominent in the NGT stage. Compared to the control group, the early phase insulin secretion levels of the preDM or T2DM subjects were less than 50% when Glc(0) was over 100 mg/dL, Glc(120) was over 145 mg/dL, and A1c was over 5.8%. Conclusion This study suggests that progressive beta cell dysfunction in Koreans may be initiated and rapidly aggravated during the period generally designated as 'normal.'

Reducing sugar, 2-deoxy-D-ribose (dRib), produces reactive oxygen species through autoxidation and protein glycosylation and causes osteoblast dysfunction. Kaempferol, a natural flavonoid, was investigated to determine whether it could influence dRib-induced cellular dysfunction and oxidative cell damage in the MC3T3-E1 mouse osteoblastic cell line. Osteoblastic cells were treated with 30 mM dRib in the presence or absence of kaempferol (10(-9)-10(-5) M) and markers of osteoblast function and lipid peroxidation were subsequently examined. Kaempferol (10(-9)-10(-5) M) significantly inhibited the dRib-induced decrease in growth of MC3T3-E1 osteoblastic cells. In addition, treatment with kaempferol resulted in a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and mineralization in the cells. Treatment with kaempferol increased osteoprotegerin (OPG) secretion and decreased malondialdehyde (MDA) contents of MC3T3-E1 osteoblastic cells in the presence of 30 mM dRib. Taken together, these results suggest that kaempferol inhibits dRib-induced osteoblastic cell damage and may be useful for the treatment of diabetes-related bone disease.

Introduction In recent studies, apolipoprotein E (apo E) genetic polymorphism in association with dyslipidemia have been proposed as the one of the risk factors for the development of diabetic nephropathy. We found that type 2 diabetic patients with microalbuminuria (MA) had higher plasma triglyceride levels than those with normoalbuminuria (NA) in our previous study. Therefore, we aimed for investigating the association among apo E genetic polymorphism, dyslipidemia and the development of diabetic nephropathy in type 2 diabetic patients. Method We included 58 subjects with normoalbuminuria and 36 subjects with microalbuminuria in analysis. They were all Korean and type 2 diabetic patients who had normal renal function, history of diabetes longer than 10 years and the data of urine albumin excretion rate at 10th year diabetes duration. Mean HbA1c, plasma total cholesterol and triglyceride levels for 10 years and several clinical characteristics were examined. Apo E genotypes were confirmed by real time PCR. Results The frequency of e3/e4 genotype (20.7% versus 5.6%, p = 0.045) and E4 carrier (22.8% versus 5.9%, p = 0.035) was significantly higher in NA group than in MA group. On logistic regression analysis, crude odds ratio of E2 carrier and E4 carrier were 0.833 (95% CI: 0.245–2.833) and 0.205 (95% CI: 0.043–0.986), respectively. However, after adjusted by HbA1c, hypertension, total cholesterol and triglyceride, odds ratio of E2 carrier and E4 carrier were 0.664 (95% CI: 0.134–3.289) and 0.365 (95% CI: 0.061–2.187) and the association became weak. There were no correlation between apo E carrier and lipid profile. HbA1c (7.6 ± 1.3% versus 7.0 ± 0.9%, p = 0.012) and mean creatinine (1.2 ± 0.7 mg/dL versus 1.0 ± 0.2 mg/dL, p = 0.004) levels were significantly higher in MA group than in NA group as expected. Conclusions These data suggest that E4 carrier might be associated with the protection for the development of diabetic nephropathy in type 2 diabetic patients without respect to dyslipidemia.

Abstract - Background: To evaluate the relationships between deterioration in insulin secretion and aggravated insulin resistance in patients with newly diagnosed prediabetes (preDM) and type 2 diabetes mellitus (T2DM) according to the presence of metabolic syndrome (MS). Methods: We performed oral glucose tolerance test (OGTT) on 322 drug naive subjects with a history of hyperglycemia of ≤ 3 months, and divided these patients into 3 groups, normal glucose tolerance (NGT), preDM (IFG and/or IGT) and T2DM. We also diagnosed these subjects with respect to MS according to ATP III criteria modified by Asia-Pacific guidelines and compared IGI and HOMA-IR in the 3 groups. Results: According to OGTT, 63 subjects were diagnosed with NGT, 81 with preDM, and 178 with T2DM. Using modified ATP III criteria, 218 (67.7%) subjects were diagnosed as MS. When compare groups stratified by the presence of MS, preDM and T2DM groups with MS showed significantly higher mean HOMA-IR and IGI than those without MS. When compare groups with respect to glucose tolerance, NGT, preDM, and T2DM subgroups in MS group showed significant higher HOMA-IR and lower IGI according to glucose tolerance. However, NGT, preDM, and T2DM subgroups in non-MS group showed a significant decrease in IGI but no significant difference in HOMA-IR as glucose tolerance worsened. Conclusion: Deterioration in IGI and aggravation of HOMA-IR are both important in the primary pathogenesis of diabetes in those with MS. However, IGI deterioration may be the only important factor in the primary pathogenesis of T2DM in the absence of MS. (J Kor Diabetes Assoc 30:198~206, 2006) ━━━━━━━━━━━━━━━━ ━━

Glucose toxicity to pancreatic β-cells is defined as irreversible β-cell damage, including apoptosis, caused by chronic exposure to high glucose levels in type 2 diabetes. Oxidative stress is an important mechanism for glucose toxicity to pancreatic β-cells. Reducing sugars produce reactive oxygen species through autoxidation and protein glycosylation. 2-Deoxy- d -ribose (dRib) is a reducing sugar with high reactivity. We investigated whether cAMP-stimulating agents could protect β-cells from dRib-induced oxidative damage. HIT-T15 cells were cultured with various concentrations of dRib for 24 h. We measured cell survival, intracellular cAMP and H 2 O 2 levels, and apoptosis. dRib decreased cell survival in a dose- and time-dependent manner and markedly increased intracellular H 2 O 2 levels and apoptosis. N -Acetyl- l -cysteine decreased dRib-induced rises in intracellular H 2 O 2 and apoptosis to control levels. Forskolin, IBMX, and dbcAMP markedly elevated intracellular cAMP levels and significantly attenuated dRib-induced cytotoxicity and apoptosis, but had no influence on the dRib-induced rise in intracellular H 2 O 2 levels. These results demonstrate that dRib produced oxidative stress and apoptosis in pancreatic β-cells and that elevated intracellular cAMP levels reduced dRib-induced damage, independent of reactive oxygen species metabolism.

Aims To compare the commonly prescribed oral anti-diabetic drug (OAD) combinations to use as an add-on therapy with insulin glargine in patients with uncontrolled type 2 diabetes despite submaximal doses of OADs. Methods People with inadequately controlled type 2 diabetes (n = 99) were randomly assigned on a 1∶1∶1 basis to receive insulin glargin, with fixed doses of glimepiride, metformin, and glimepiride plus metformin. Outcomes assessed included HbA1c, the changes in fasting glucose levels, body weight, serum lipids values, insulin dose and symptomatic hypoglycemia. Results After 24 weeks, HbA1C levels improved from (mean ± SD) 8.5±0.9% to 7.7±0.8% (69.0±10.0 mmol/mol to 60.8±8.6 mmol/mol) with insulin glargine plus metformin, from 8.4±1.0% to 7.7±1.3% (68.8±10.6 mmol/mol to 61.1±14.4 mmol/mol) with insulin glargine plus glimepiride and from 8.7±0.9% to 7.3±0.6% (71.7±9.8 mmol/mol to 56.2±6.7 mmol/mol) with insulin glargine plus glimepirde plus metformin. The decrease in HbA1c was more pronounced with insulin glargine plus glimepiride plus metformin than with insulin glargine plus metformin (0.49% [CI, 0.16% to 0.82%]; P = 0.005) (5.10 mmol/mol [CI, 1.64 to 8.61]; P = 0.005) and insulin glargine plus glimepiride (0.59% [CI, 0.13% to 1.05%]; P = 0.012) (5.87 mmol/mol [CI, 1.10 to 10.64]; P = 0.012) (overall P = 0.02). Weight gain and the risk of hypoglycemia of any type did not significantly differ among the treatment groups. Conclusion The combination therapy of metformin and glimepiride plus glargine insulin resulted in a significant improvement in overall glycemic control as compared with the other combinations. Trial registration information ClinicalTrials.gov, NCT00708578. The approval number of Kangbuk Samsung hospital's institutional review board (IRB): C0825.

It has been suggested that there is an association between environmental, low-level arsenic exposure and the risk of diabetes mellitus (DM), but little research has been conducted. Here, the glucose tolerance status and urinary creatinine adjusted total arsenic concentrations were analyzed in 3,602 subjects ≥ 20 yr of age who were registered for the Korea National Health and Nutrition Examination Survey, 2008-2009. Various demographic parameters were associated with urinary arsenic concentrations. After adjusting for these variables, urinary arsenic concentrations in subjects with DM were significantly higher than those in subjects with normal glucose tolerance and those with impaired fasting glucose (P < 0.001). Compared with the lowest quartile ( < 70.7 µg/g creatinine), the odds ratios and 95% confidence intervals for DM were 1.11 (0.73-1.68), 1.42 (0.94-2.13), and 1.56 (1.03-2.36) for urinary arsenic concentrations of 70.7 to < 117.7, 117.7 to < 193.4, and ≥ 193.4 µg/g creatinine, respectively, following multivariate adjustment. Furthermore, the urinary total arsenic concentration was inversely associated with the insulin secretion index, HOMA2 %B (β = -0.033, P = 0.032). These findings suggest that arsenic exposure, possibly involving beta cell dysfunction, is associated with an increased risk of DM in the Korean population.

Parathyroid carcinoma is very rare in patients with primary hyperparathyroidism, only accounts for 1% to 2% of all cases. It is characterized by higher incidence of renal dysfunction, metabolic bone disease and gastrointestinal symptoms. Although the clinical manifestations of hyperparathyroidism are more severe in patients with parathyroid carcinoma when compared to those with those with parathyroid adenoma, it is difficult to differentiate carcinoma from adenoma without pathologic confirmation. To our knowledge, there have only been a few cases of hyperparathyroidism due to parathyroid carcinomas reported to date. Here, we report a case of 63-year-old woman developing osteoporosis, hypercalcemia and hypophosphatemia due to a parathyroid tumor and was diagnosed with parathyroid carcinoma postoperatively. [Korean Journal of Bone Metabolism, 19(1): 59-65, 2012]

Received: 10 June 2010, Accepted: 6 January 2011 Corresponding author: In-Kyung Jeong Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea Tel: +82-2-440-6126, Fax: +82-2-440-6295, E-mail: jik1016@khu.ac.kr A Case of Primary Adrenal Insufficiency in a Patient with Acquired Immunodeficiency Syndrome Jae Ho Choi, Suk Chon, Yu Chul Hwang, Jun Seong Son, Seung Joon Oh, Kyu Jeung Ahn, Ho Yeon Chung, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, In-Kyung Jeong Department of Endocrinology and Metabolism, Infection, College of Medicine, Kyung Hee University, Seoul, Korea

SUMMARY We suspected the presence of pheochromocytoma and were able to confirm our diagnosis in a patient presenting with symp-toms of fatal cardiogenic shock due to catecholamine-induced car-diomyopathy. Furthermore, we evaluated the possibility of MEN 2A as the source of the thyroid nodules and diagnosed MTC using various tests and surgery. The patient had a younger sister who un-derwent follow-up observation for benign thyroid nodules, and as a result, the diagnosis of MTC was established during selective test-ing for MEN 2A. Genetic testing for the RET gene demonstrated that the diagnosis of MEN 2A was due to a mutation of C634R on exon 11. Using a selective test for familial genes, mutations of the same genes were confirmed, and a family of MEN 2A individuals was identified. ACKNOWLEDGEMENT The authors appreciate the efforts of Young Ji Yoon in the prepa-ration of the manuscript. REFERENCES 1. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, LoveDR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BJ: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458-460, 1993

Background : The expression of c-FLIP (cellular Fas-associated death domain-like interleukin-1 β-converting enzyme (FLICE)-inhibitory protein), which is a member of the family of inhibitors of apoptosis, has been associated with tumor development and progression. The aim of this study was to evaluate the expression of c-FLIP in gastric cancer and its correlation with tumor cell proliferation, apoptosis and the clinicopathologic features. Methods : Immunohistochemical staining with anti-c-FLIP antibody was performed in 98 tissue samples obtained from gastric cancer patients who underwent surgical treatment. The apoptotic cells were visualized by terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), and the proliferative cells were visualized by staining with Ki-67 antibody. Results : The positive expression of c-FLIP in the gastric cancer tissues was demonstrated in 57.1% of the cases. The expression of c-FLIP was increased in the gastric cancer tissues compared with the matched normal gastric mucosa. The expression of c-FLIP was significantly associated with histologic differentiation (p=0.038). However, there was no association between the c-FLIP expression and the other clinicopathological parameters, including patient survival. The Ki-67 labeling index (KI) for the 98 tumors ranged from 7.6 to 85.0 with a mean KI of 50.4±15.7. The mean KI value of the c-FLIP positive tumors was 54.1±15.3 and this was significantly higher than that of the c-FLIP negative tumors (p=0.005). The apoptotic index (AI) for the 98 tumors ranged from 0.0 to 10.0 with a mean AI of 7.4±2.3. There was no significant difference between the c-FLIP expression and the AI (p=0.347). Conclusions : These results suggest that the c-FLIP expression may be associated with tumor cell proliferation of gastric cancer.

Vitamin D is a kind of hormone that can be synthesized in the skin or it is supplied in the diet it is involved in a central role in bone and calcium homeostasis in vivo. Metabolic bone diseases such as rickets in children and osteomalacia in adults can also be caused by deficiency or metabolic defects in the vitamin D hormone related system. However, there has been a lack of generalized epidemiologic studies about the vitamin D deficiency status in Koreans. We recently experienced a case of osteomalacia caused by severe vitamin D deficiency. These kinds of case have not been reported elsewhere in Korea for the last twenty years. (J Kor Endocrinol Soc 22:55~61, 2007)