Hye Soon Kim

Clusterin Attenuates the Development of Renal Fibrosis

Upregulation of clusterin occurs in several renal diseases and models of nephrotoxicity, but whether this promotes injury or is a protective reaction to injury is unknown. Here, in the mouse unilateral ureteral obstruction model, obstruction markedly increased the expression of clusterin, plasminogen activator inhibitor-1 (PAI-1), type I collagen, and fibronectin. Compared with wild-type mice, clusterin-deficient mice exhibited higher levels of PAI-1, type I collagen, and fibronectin and accelerated renal fibrosis in response to obstruction. In cultured rat tubular epithelium-like cells, adenovirus-mediated overexpression of clusterin inhibited the expression of TGF-β-stimulated PAI-1, type I collagen, and fibronectin. Clusterin inhibited TGF-β-stimulated Smad3 activity via inhibition of Smad3 phosphorylation and its nuclear translocation. Moreover, intrarenal delivery of adenovirus-expressing clusterin upregulated expression of clusterin in tubular epithelium-like cells and attenuated obstruction-induced renal fibrosis. In conclusion, clusterin attenuates renal fibrosis in obstructive nephropathy. These results suggest that upregulation of clusterin during renal injury is a protective response against the development of renal fibrosis.

Comparison of the Efficacy of Glimepiride, Metformin, and Rosiglitazone Monotherapy in Korean Drug-Naïve Type 2 Diabetic Patients: The Practical Evidence of Antidiabetic Monotherapy Study

Background Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated. Methods We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels. Results HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group. Conclusion The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information.

Comorbidity Study on Type 2 Diabetes Mellitus Using Data Mining

Background/Aims The aim of this study was to analyze comorbidity in patients with type 2 diabetes mellitus (T2DM) by using association rule mining (ARM). Methods We used data from patients who visited Keimyung University Dongsan Medical Center from 1996 to 2007. Of 411,414 total patients, T2DM was present in 20,314. The Dx Analyze Tool was developed for data cleansing and data mart construction, and to reveal associations of comorbidity. Results Eighteen associations reached threshold (support, ≥ 3%; confidence, ≥ 5%). The highest association was found between T2DM and essential hypertension (support, 17.43%; confidence, 34.86%). Six association rules were found among three comorbid diseases. Among them, essential hypertension was an important node between T2DM and stroke (support, 4.06%; confidence, 8.12%) as well as between T2DM and dyslipidemia (support, 3.44%; confidence, 6.88%). Conclusions Essential hypertension plays an important role in the association between T2DM and its comorbid diseases. The Dx Analyze Tool is practical for comorbidity studies that have an enormous clinical database.

Prevalence and clinical characteristics of restless legs syndrome in diabetic peripheral neuropathy: comparison with chronic osteoarthritis.

BACKGROUND The prevalence of restless legs syndrome (RLS) in patients with peripheral neuropathy has been reported to be higher than that of the general population in some studies, which suggests an association between neuropathy and RLS, but not all studies show increased RLS with neuropathy. These differences may reflect adequacy of the diagnosis, effects of chronic pain complicating the diagnosis, or population differences. Moreover, if there is increased risk for RLS with neuropathy, it may reflect consequences of the chronic pain rather than other aspects of diabetes mellitus (DM). Therefore, we investigated the effects of diagnosis rigor on the estimated prevalence of RLS in patients with diabetic peripheral neuropathy (DPN) and those with chronic leg pain from osteoarthritis (OA), and then we compared the RLS prevalence in these two populations with each other and with population prevalence for Korea. METHODS Our study is a prospective case-control study of 199 patients with DPN and 220 patients with OA. After evaluating the presence of RLS in these subjects using the diagnostic criteria of the International RLS Study Group, we confirmed the diagnosis of RLS through face-to-face interviews using the 18-item Hopkins Diagnostic Questionnaire, which removes RLS mimics; and through independent examinations by two neurologists. RESULTS Of the 199 subjects with DPN, 44 (22%) appeared to have RLS from their answers on the 4-item RLS diagnostic questionnaire compared to 8 (3.6%) of 220 subjects with OA. However, the prevalence of RLS in the DPN group dropped to 16 (8%) subjects but stayed at 8 (3.6%) OA subjects when using the Hopkins Telephone Diagnostic Interview (HTDI) adapted for clinical interview. The RLS prevalence determined by HTDI remained significantly higher (P=.042) in the DPN group compared to the OA group and was twice that reported for the general Korean population (8% vs 3.9%). Among subjects with DPN, those with RLS were older (68.06±8.43years vs 62.46±11.05years; P=.049) and had higher pain scores (visual analog scale [VAS], 4.69±2.52 vs 2.72±2.12; P=.002). The quality of sleep (MOS [Medical Outcomes Study] sleep scale) and health-related quality of life (QoL) (total score on the 36-Item Short-Form Health Survey [SF-36]) showed no significant difference between the two groups. CONCLUSIONS The prevalence of RLS in patients with DPN cannot be accurately assessed with only the four diagnostic criteria interview, but the prevalence was higher than expected for Koreans from the general population prevalence and also was higher than occurred with OA patients with chronic leg pains when accurately assessed with a structured interview. Chronic leg pain from OA does not significantly complicate RLS diagnosis, and chronic pain itself does not explain the increased RLS prevalence in diabetic neuropathy.

Effects of patient-tailored atorvastatin therapy on ameliorating the levels of atherogenic lipids and inflammation beyond lowering low-density lipoprotein cholesterol in patients with type 2 diabetes

Recently, patient‐tailored statin therapy was proven effective for achieving target low‐density lipoprotein (LDL) cholesterol levels. It is unclear, however, whether this therapeutic modality would be effective for atherogenic lipid profiles and inflammation in patients with type 2 diabetes.

The Effect of Tribbles-Related Protein 3 on ER Stress-Suppressed Insulin Gene Expression in INS-1 Cells.

Background The highly developed endoplasmic reticulum (ER) structure in pancreatic beta cells is heavily involved in insulin biosynthesis. Thus, any perturbation in ER function inevitably impacts insulin biosynthesis. Recent studies showed that the expression of tribbles-related protein 3 (TRB3), a mammalian homolog of Drosophilia tribbles, in various cell types is induced by ER stress. Here, we examined whether ER stress induces TRB3 expression in INS-1 cells and found that TRB3 mediates ER stress-induced suppression of insulin gene expression. Methods The effects of tunicamycin and thapsigargin on insulin and TRB3 expression in INS-1 cells were measured by Northern and Western blot analysis, respectively. The effects of adenovirus-mediated overexpression of TRB3 on insulin, PDX-1 and MafA gene expression in INS-1 cells were measured by Northern blot analysis. The effect of TRB3 on insulin promoter was measured by transient transfection study with constructs of human insulin promoter. Results The treatment of INS-1 cells with tunicamycin and thapsigargin decreased insulin mRNA expression, but increased TRB3 protein expression. Adenovirus-mediated overexpression of TRB3 decreased insulin gene expression in a dose-dependent manner. A transient transfection study showed that TRB3 inhibited insulin promoter activity, suggesting that TRB3 inhibited insulin gene expression at transcriptional level. Adenovirus-mediated overexpression of TRB3 also decreased PDX-1 mRNA expression, but did not influence MafA mRNA expression. Conclusions This study showed that ER stress induced TRB3 expression, but decreased both insulin and PDX-1 gene expression in INS-1 cells. Our data suggest that TRB3 plays an important role in ER stress-induced beta cell dysfunction.

Patient Understanding of Hypoglycemia in Tertiary Referral Centers

Background Hypoglycemia is an important complication in the treatment of patients with diabetes. We surveyed the insight by patients with diabetes into hypoglycemia, their hypoglycemia avoidance behavior, and their level of worry regarding hypoglycemia. Methods A survey of patients with diabetes, who had visited seven tertiary referral centers in Daegu or Gyeongsangbuk-do, Korea, between June 2014 and June 2015, was conducted. The survey contained questions about personal history, symptoms, educational experience, self-management, and attitudes about hypoglycemia. Results Of 758 participants, 471 (62.1%) had experienced hypoglycemia, and 250 (32.9%) had experienced hypoglycemia at least once in the month immediately preceding the study. Two hundred and forty-two (31.8%) of the participants had received hypoglycemia education at least once, but only 148 (19.4%) knew the exact definition of hypoglycemia. Hypoglycemic symptoms identified by the participants were dizziness (55.0%), sweating (53.8%), and tremor (40.8%). They mostly chose candy (62.1%), chocolate (37.7%), or juice (36.8%) as food for recovering hypoglycemia. Participants who had experienced hypoglycemia had longer duration of diabetes and a higher proportion of insulin usage. The mean scores for hypoglycemia avoidance behavior and worry about hypoglycemia were 21.2±10.71 and 23.38±13.19, respectively. These scores tended to be higher for participants with higher than 8% of glycosylated hemoglobin, insulin use, and experience of emergency room visits. Conclusion Many patients had experienced hypoglycemia and worried about it. We recommend identifying patients that are anxious about hypoglycemia and educating them about what to do when they develop hypoglycemic symptoms, especially those who have a high risk of hypoglycemia.

Efficacy of a Once-Monthly Pill Containing Ibandronate and Cholecalciferol on the Levels of 25-Hydroxyvitamin D and Bone Markers in Postmenopausal Women with Osteoporosis

Background The present study evaluated the efficacy of a combination of ibandronate and cholecalciferol on the restoration of the levels of 25-hydroxyvitamin D (25[OH]D) and various bone markers in postmenopausal women with osteoporosis. Methods This was a randomized, double-blind, active-controlled, prospective 16-week clinical trial conducted in 20 different hospitals. A total of 201 postmenopausal women with osteoporosis were assigned randomly to one of two groups: the IBN group, which received a once-monthly pill containing 150 mg ibandronate (n=99), or the IBN+ group, which received a once-monthly pill containing 150 mg ibandronate and 24,000 IU cholecalciferol (n=102). Serum levels of 25(OH)D, parathyroid hormone (PTH), and various bone markers were assessed at baseline and at the end of a 16-week treatment period. Results After 16 weeks of treatment, the mean serum levels of 25(OH)D significantly increased from 21.0 to 25.3 ng/mL in the IBN+ group but significantly decreased from 20.6 to 17.4 ng/mL in the IBN group. Additionally, both groups exhibited significant increases in mean serum levels of PTH but significant decreases in serum levels of bone-specific alkaline phosphatase and C-telopeptide of type 1 collagen (CTX) at 16 weeks; no significant differences were observed between the groups. However, in subjects with a vitamin D deficiency, IBN+ treatment resulted in a significant decrease in serum CTX levels compared with IBN treatment. Conclusion The present findings demonstrate that a once-monthly pill containing ibandronate and cholecalciferol may be useful for the amelioration of vitamin D deficiency in patients with postmenopausal osteoporosis. Moreover, this treatment combination effectively decreased serum levels of resorption markers, especially in subjects with a vitamin D deficiency, over the 16-week treatment period.

Blood Glucose Measurement: Is Serum Equal to Plasma?

Corresponding author: Hye Soon Kim http://orcid.org/0000-0001-6298-3506 Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, 56, Dalseong-ro, Jung-gu, Daegu 41931, Korea E-mail: hsk12@dsmc.or.kr In 2002, the National Academy of Clinical Biochemistry (NACB) published “Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus” [1]. Measurement of plasma glucose was the only diagnostic criterion for diabetes. Glycemic control was monitored by measuring glucose using patients’ plasma or blood glucose with meters and laboratory analysis of glycosylated hemoglobin (HbA1c). Ten years later, these recommendations were updated by a multidisciplinary guideline team including clinical, laboratory, and evidence-based guideline methodology experts [2]. The guidelines were reviewed by the joint evidencebased Laboratory Medicine Committee of the American Association for Clinical Chemistry and the NACB, and the guidelines were accepted after revision by the Professional Practice Committee and approved by the Executive Committee of the American Diabetes Association (ADA). In addition to measurement of venous plasma glucose, HbA1c concentration in blood can also be used for the diagnosis of diabetes mellitus. When glucose is used to diagnose diabetes, the guideline recommends it to be measured in venous plasma in an accredited laboratory. Sample tube should be placed immediately in an ice-water slurry to minimize glycolysis, and the plasma should be separated from the cells within 30 minutes, otherwise a tube containing a rapidly effective glycolysis inhibitor like citrate buffer should be used. Samples for fasting plasma glucose (FPG) analysis should be drawn in the morning rather than in the daytime because of diurnal variation in FPG, which is higher in the morning than in the afternoon [3]. The concentration of glucose decreases due to glycolysis by erythrocyte, white blood cells, and platelet, which degrades glucose at a rate of 5% to 7% per hour [4]. On occasion, it needs to be transported from the site where it was sampled to a remote laboratory facility for glucose measurement, due to which the blood glucose values can appear to be lower than the actual value and lead to false diagnosis, especially for those who are near the cut-off value. The method used for blood processing can also influence blood glucose levels. Plasma glucose values are about 11% higher than those of whole blood when the hematocrit is normal. Postprandial capillary blood glucose levels are higher than venous blood glucose levels by up to 20%, probably due to glucose consumption in tissues [5]. With regards to the differences in blood glucose level between plasma and serum, some studies reported that plasma glucose is higher than serum glucose whereas other studies found no difference. Nonetheless, measurement of glucose in serum is not recommended for the diagnosis of diabetes [6,7], while plasma allows samples to be centrifuged promptly without waiting for the blood to clot. In this regards, Kang et al. [8] attempted to compare fasting serum glucose with FPG in real-life clinical situations and also examined an ordinary time delay in sample processing for a month. Serum samples were centrifuged within 1 hour and glucose was measured within 2 hours, while plasma samples were immediately centrifuged and glucose was measured within 15 minutes. Among 1,254 participants, mean glucose concentrations for plasma and serum were 119.4±9.9 and Editorial Others

Prognostic Significance of Tissue Leptin Expression in Colorectal Cancer Patients

Purpose Leptin is encoded by the ob gene and is involved in the control of food intake and energy expenditure. Recent studies have implicated leptin expression to be an indicator of tumor features and prognosis. The purpose of this study was to investigate the association of tissue expression of leptin with the clinicopathological characteristics and clinical outcomes in colorectal cancer patients. Methods Patients who had undergone a curative surgical resection for a colorectal adenocarcinoma from 2000 to 2004 were included in the study. Immunohistochemical analyses of leptin expression were performed, and clinicopathological parameters were evaluated. Results Clinical data and tumor tissues of 146 patients were evaluated. The mean age was 68.6 ± 11.3 years, and 61.0% were men. Immunohistochemically, the rates of negative, weak, moderate, and strong leptin expression were 2.7% (4 of 146), 5.5% (8 of 146), 43.2% (63 of 146), and 48.6% (71 of 146), respectively. We compared the negative, weak, and moderate expression group (group A) with the strong expression group (group B). Leptin expression was inversely associated with nodal stage (P = 0.007) between the two groups. Leptin expression was not significantly associated with differentiation (P = 0.37), T stage (P = 0.16), and American Joint Committee on Cancer stage (P = 0.49), and no significant differences in the disease-free and the overall survivals (P = 0.78 and P = 0.61) were observed. Conclusion Results demonstrated an inverse association of nodal stage with high leptin expression. Higher leptin expression level might predict better oncologic outcome. However, further studies are warranted to identify the exact role of leptin expression in colorectal cancer.