Dong Jin Chung

Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43

Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the α1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43–/fl mice, with Cx43–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

Associations among body mass index, insulin resistance, and pancreatic β-cell function in Korean patients with new-onset type 2 diabetes.

Background/Aims We investigated the associations among body mass index (BMI), insulin resistance, and β-cell function in Korean patients newly presenting with type 2 diabetes. Methods In total, 132 patients with new-onset type 2 diabetes mellitus were investigated. A standard 75-g oral glucose tolerance test was performed, and the indices of insulin secretion and insulin resistance were calculated. Results A higher BMI was associated with higher homeostasis model assessment values for insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), and insulinogenic index as well as lower levels of insulin sensitivity index composite (ISIcomp) and disposition index (DI). In multiple regression models, BMI had independent positive associations with HOMA-IR, ISIcomp, and HOMA-β and inverse associations with the DI. Conclusions Our results showed that BMI had independent positive associations with indices of insulin resistance and an inverse association with β-cell function adjusted for insulin resistance in Korean patients newly presenting with type 2 diabetes.

Prevalence of diabetes mellitus in the elderly of Namwon County, South Korea.

Background: Ethnic and geographic differences exist in the prevalence of diabetes mellitus which has increased dramatically in South Korea. A few community-based epidemiologic studies with oral glucose tolerance test were performed in South Korea. The purpose of this study was to determine the prevalence of diabetes mellitus by the World Health Organization (WHO) and the American Diabetic Association (ADA) diagnostic criteria and to investigate their associated risk factors. Also, we compared and analyzed the characteristics of Koreans by WHO and ADA diagnostic criteria. Methods : Between March 22, 1999 and July 14, 1999, a random sampling of 1,445 residents over 40 years of age in five villages (3 myons and 2 dongs) in Namwon City, Chollabuk-do Province, South Korea was carried out. WHO and ADA diagnostic criteria were used for the prevalence of DM, IGT and IPG. The associated factors of subjects were analyzed. Results : After age adjustment for the population projection of Korea (1999), the prevalence of DM and IGT was 13.7% and 13.8%, respectively, by WHO criteria, while the prevalence of DM, IGT and IFG was 15.8%, 12.8% and 5.7%, respectively, by ADA criteria, and the previous diagnosed diabetics were 5.8% in 665 adults over 40 years of age in the Namwon area. The age-adjusted prevalence of previously diagnosed diabetics was 5.8%. When the subjects classified by both criteria were compared, the level of agreement between WHO and ADA diagnostic criteria, except IFG, was very high (κ=0.94; p<0.001). The ROC curve analysis determined FSG of 114.5 mg/dL (6.4 mmol/L) to yield optimal sensitivity and specificity corresponding to a PP2SG 200 mg/dL (11.1 mmol/L). The prevalence of DM and IGT with ADA diagnostic criteria rose with increasing age (p<0.05). The body mass index was mean 23.8±3.4 in all the subjects, 23.75±3.46 in NGT group and 23.67±3.16 in DM group, but the differences in the prevalence of DM, IGT and IFG by BMI were not significant. The prevalence of DM rose significantly with the increase in the waist-hip ratio (p<0.05). The prevalence of DM significantly increased in subjects by increases in blood pressure, and triglyceride and the relative risk in the prevalence of DM was significantly high with dyslipidemia (Odds ratio 2.29, 95% CI: 1.16–3.49). Conclusion : The prevalence of Diabetes Mellitus in the population over 40 years of age in Namwon City, South Korea remarkably increased compared with the 1970s and 1980s and was similar to that of the West. Ethnic differences in obesity of normal, DM and IGT subjects and in the effect on the prevalence of DM may exist in the Korean population, but they were not significant. As there is a limit in number, it is considered that a general population-based epidemiologic study on a large scale is required to investigate ethnic and geographic differences for the risk factors of DM in South Korea. The level of agreement, except IFG, by WHO and ADA diagnostic criteria was high, which indicates that these results may show that not only fasting serum glucose but also postprandial 2-h serum glucose are important for diagnosing diabetes in Korean.

Risedronate increases osteoblastic differentiation and function through connexin43.

Bisphosphonates are potent antiresorptive drugs which have antifracture efficacy by reducing bone turnover rate and increasing bone mineral density. In addition to inhibiting osteoclast function, bisphosphonates have been reported to also promote survival of osteocyte and osteoblast via an anti-apoptotic effect, mediated by opening of hemi-gap junction channels formed by connexin43 (Cx43). In this study, we investigated the effect of risedronate, one amino-bisphosphonate, on osteoblast differentiation and Cx43 expression using the mesenchymal cell line C2C12. Risedronate dose-dependently increased the activity of osterix (OSE)-luciferase containing Runx2 response element with highest activity at 50μM. The activity of osteocalcin (OC)- and bone sialoprotein (BSP)-luciferase reporters, markers of osteoblast differentiation, were also increased by risedronate. When risedronate and BMP2 were used in combination, alkaline phosphatase (ALP) activity increased to a larger extent than when BMP2 was used alone. Risedronate as well as the pro-osteogenic transcription factors, Runx2, Osterix or Dlx5, increased transcriptional activity of the Cx43 promoter in a dose-dependent manner. In the presence of Runx2 or Dlx5, risedronate had an additive effect on Cx43 promoter activity. Accordingly, risedronate increased protein expression of Cx43, Runx2, Osterix, and Dlx5. These results suggest that risedronate promotes osteoblastic differentiation and positively regulates Cx43 gene transcription.

The Duration of Diabetes is Inversely Associated with the Physiological Serum Bilirubin Levels in Patients with Type 2 Diabetes

OBJECTIVE The aim of this study was to assess the relationship between the duration of diabetes and the physiological serum bilirubin concentration in association with antioxidant properties in patients with type 2 diabetes. METHODS A total of 1,746 patients with type 2 diabetes were investigated in this cross-sectional study. An analysis of covariance was performed after adjusting for other covariates. Simple correlation analyses and a multivariate regression model were used to assess the association between the duration of diabetes and the serum bilirubin concentration. RESULTS The mean total bilirubin value differed significantly according to the tertile of diabetes duration (<5 years, 12.38 μmol/L, 95% confidence interval (CI) 12.02-12.76; 5-11.9 years, 12.33 μmol/L, 95% CI 11.97-12.69; ≥12 years, 11.73 μmol/L, 95% CI 11.35-12.11; p for trend =0.033), after adjustment for other covariates. In addition, an inverse correlation was found between the serum bilirubin concentration and diabetes duration (ρ=-0.211, p<0.001). According to a multivariate model, the association between the diabetes duration and serum bilirubin concentration remained significant, even after adjustment for confounding factors (β=-0.074, p=0.008). CONCLUSION The duration of diabetes is inversely associated with a serum bilirubin concentration within the physiologic range in patients with type 2 diabetes.

Inhibition of osteoblastic differentiation by warfarin and 18-α-glycyrrhetinic acid

Anticoagulation therapy with vitamin K antagonists such as warfarin is widely used to prevent and treat stroke in patients with chronic atrial fibrillation or mechanical heart valves. Because vitamin K is an essential factor for ggg-carboxylation of osteocalcin, vitamin K antagonists might cause bone loss. Although the association between warfarin use and bone metabolism is still controversial, several studies show that bone mineral density is decreased and fracture risk is increased with warfarin therapy. Meanwhile, attenuation of gap junctional communication (GJC) by warfarin is reported in rat liver epithelial cells. However, the effect of warfarin on osteoblasts, in which GJC is important for osteoblastic differentiation, remains unknown. Here we investigated whether warfarin has an inhibitory effect on osteoblastic differentiation using an osteoblastic cell line (C2C12). Warfarin and 18-α-glycyrrhetinic acid (AGA), which is known as a nontoxic reversible GJC inhibitor, had the same effect on osteoblastic differentiation. Warfarin and AGA inhibited the bone morphogenetic protein (BMP)2-induced mRNA levels of alkaline phosphatase (ALP), collagen I α1, osteocalcin (OC) and osterix, which are specific markers for osteoblastic differentiation, in a dose-dependent manner. Moreover, the activities of OC- and ALP-luciferase reporters, which are induced by BMP2, and the transcriptional activity of Runx2 on OC and ALP promoters were inhibited by warfarin and AGA. The amount and activity of ALP induced by BMP2 were also decreased by warfarin and AGA. These results suggest that warfarin and AGA, a GJC inhibitor, have an inhibitory effect on osteoblastic differentiation.

Association between Diabetic Polyneuropathy and Cardiovascular Complications in Type 2 Diabetic Patients

Background Diabetes mellitus is a major independent risk factor for cardiovascular disease (CVD), but high cardiovascular risk in diabetes mellitus patients is not completely explained by clustering traditional risk factors. Recently, associations between diabetic polyneuropathy (DPN) and macrovasculopathy have been suggested. We aimed to assess associations between DPN and cardiovascular complications in type 2 diabetic patients. Methods Microvascular and cardiovascular complications were evaluated in 1,041 type 2 diabetic patients. Results In patients with DPN, the age, prevalence of hypertension, diabetes duration, systolic blood pressure, pulse pressure, and hemoglobin glycation (HbA1c) levels were significantly higher, while the high density lipoprotein cholesterol (HDL-C) levels were lower than in those without DPN. The prevalence of CVD was higher in patients with DPN. In multivariate analysis, DPN was independently associated with CVD (odds ratio, 1.801; 95% confidence interval, 1.009 to 3.214). Conclusion Our results showed that DPN was associated with a high prevalence of cardiovascular disease in type 2 diabetic patients, but further studies are needed to investigate the causative nature of associations between DPN and CVD.

Efficacy and Safety of Weekly Alendronate Plus Vitamin D3 5600 IU versus Weekly Alendronate Alone in Korean Osteoporotic Women: 16-Week Randomized Trial

Vitamin D (vit-D) is essential for bone health, although many osteoporosis patients have low levels of 25-hydroxy-vit-D [25(OH)D]. This randomized, open-label study compared the effects of once weekly alendronate 70 mg containing 5600 IU vit-D3 (ALN/D5600) to alendronate 70 mg without additional vit-D (ALN) on the percent of patients with vit-D insufficiency [25(OH)D <15 ng/mL, primary endpoint] and serum parathyroid hormone (PTH, secondary endpoint) levels in postmenopausal, osteoporotic Korean women. Neuromuscular function was also measured. A total of 268 subjects were randomized. Overall, 35% of patients had vit-D insufficiency at baseline. After 16-weeks, there were fewer patients with vit-D insufficiency in the ALN/D5600 group (1.47%) than in the ALN group (41.67%) (p<0.001). Patients receiving ALN/D5600 compared with ALN were at a significantly decreased risk of vit-D insufficiency [odds ratio=0.02, 95% confidence interval (CI) 0.00-0.08]. In the ALN/D5600 group, significant increases in serum 25(OH)D were observed at weeks 8 (9.60 ng/mL) and 16 (11.41 ng/mL), where as a significant decrease was recorded in the ALN group at week 16 (-1.61 ng/mL). By multiple regression analysis, major determinants of increases in serum 25(OH)D were ALN/D5600 administration, seasonal variation, and baseline 25(OH)D. The least squares mean percent change from baseline in serum PTH in the ALN/D5600 group (8.17%) was lower than that in the ALN group (29.98%) (p=0.0091). There was no significant difference between treatment groups in neuromuscular function. Overall safety was similar between groups. In conclusion, the administration of 5600 IU vit-D in the ALN/D5600 group improved vit-D status and reduced the magnitude of PTH increase without significant side-effects after 16 weeks in Korean osteoporotic patients.

Clinical Characteristics, Causes and Survival in 115 Cancer Patients with Parathyroid Hormone Related Protein-mediated Hypercalcemia

Background The aim of this study is to determine the proportion of cancers presenting with parathyroid hormone (PTH) related protein (PTHrP)-mediated hypercalcemia, examine the clinical and biochemical characteristics, identify predictive factors for survival. And we also compared those characteristics between solid organ and hematologic malignancy groups. Methods Cancer patients with PTHrP-mediated hypercalcemia who were treated at Chonnam National University Hospital in Korea from January 2005 to January 2015 were retrospectively reviewed. Results Of all 115 patients, solid organ malignancies were the most common etiology (98 cases, 85.2%), with squamous cell carcinoma (50 cases, 43.4%), adenocarcinoma (27 cases, 23.4%). Interestingly, hepatocellular carcinoma (HCC; 18 cases, 15.7%) and cholangiocarcinoma (11 cases, 9.6%) were much more common causes than other previous reports. Hematologic malignancy was less common (17 cases, 14.8%), with multiple myeloma (9 cases, 7.8%) and non-Hodgkins lymphoma (5 cases, 4.3%). Overall median survival was only 37 days. There was significant difference in median survival between two groups (35 days for solid organ malignancy and 72 days for hematologic malignancy; P=0.015). Cox regression analysis identified age, the type of malignancy and the time interval of developing hypercalcemia after cancer diagnosis as independent predictive factors for survival time. Conclusions PTHrP-mediated hypercalcemia was most frequently caused by solid organ malignancy. However, HCC and cholangiocarcinoma were important causes of PTHrP-mediated hypercalcemia may be due to geographic differences in cancer incidence in Korean population. Age, the type of malignancy and the time interval of developing hypercalcemia after cancer diagnosis were independent poor predictive factors for survival time.

Relationship between serum C-peptide level and diabetic retinopathy according to estimated glomerular filtration rate in patients with type 2 diabetes

OBJECTIVE To test the hypothesis that serum C-peptide level would relate to the risk of diabetic retinopathy (DR) in type 2 diabetic patients independently of estimated glomerular filtration rate (eGFR). DESIGN A total of 2,062 patients with type 2 diabetes were investigated in this cross-sectional study. Fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) levels were measured. The patients were divided into two groups according to eGFR (ml∙min(-1)1.73m(-2)): patients without renal impairment (eGFR ≥60) and those with renal impairment (eGFR <60). RESULTS In subjects both with and without renal impairment, patients with DR showed lower levels of fasting C-peptide, postprandial C-peptide and ΔC-peptide. In multivariate analysis, serum C-peptide levels were significantly associated with DR (odds ratio [OR] of each standard deviation increase in the logarithmic value, 0.85; 95% confidence interval [CI], 0.78-0.92 for fasting C-peptide, P<0.001; OR, 0.87; 95% CI, 0.82-0.92 for postprandial C-peptide, P<0.001; OR, 0.88; 95% CI, 0.82-0.94 for ΔC-peptide, P<0.001) after adjustment for age, gender, and other confounding factors including eGFR. CONCLUSIONS Serum C-peptide levels are inversely associated with the prevalence of DR in type 2 diabetic patients independently of eGFR.