USP37 Deubiquitinates CDC73 in HPT-JT Syndrome.

The CDC73/HRPT2 gene, a defect which causes hyperparathyroidism-jaw tumor (HPT-JT) syndrome, encodes CDC73/parafibromin. We aimed to investigate whether CDC73 would be a target for ubiquitin-proteasome degradation. We cloned full-length cDNAs encoding a family of 58 ubiquitin-specific deubiquitinating enzymes (DUBs), also known as ubiquitin-specific proteases (USPs). Use of the yeast two-hybrid system then enabled us to identify USP37 as interacting with CDC73. The biochemical interaction between the USP37 and CDC73 and their reciprocal binding domains were studied. Co-localization of CDC73 and USP37 was observed in cells. CDC73 was found to be polyubiquitinated, and polyubiquitination of CDC73 was prominent in mutants. CDC73 was deubiquitinated via K48-specific ubiquitin chains by USP37, but not by the catalytically inactive USP37C350S mutant. Observation of the binding between deletion mutants of CDC73 and USP37 revealed that the ß-catenin binding site of CDC73 and the ubiquitin-interacting motifs 2 and 3 (UIM2 and 3) of USP37 were responsible for the interaction between the two proteins. Moreover, these two enzymes co-existed within the nucleus of COS7 cells. We conclude that USP37 is a DUB for CDC73 and that the two proteins interact through specific domains, suggesting that USP37 is responsible for the stability of CDC73 in HPT-JT syndrome.

Serum gamma-glutamyltransferase is not associated with subclinical atherosclerosis in patients with type 2 diabetes.

BACKGROUND: This study investigated the association between serum gamma-glutamyltransferase (GGT) level and subclinical atherosclerosis in patients with type 2 diabetes. METHODS: This cross-sectional study involved 1024 patients with type 2 diabetes mellitus. Measurement of brachial-ankle pulse wave velocity (baPWV; as a marker of arterial stiffness) and an ultrasound assessment of carotid atherosclerosis were performed. Subclinical atherosclerosis was defined by the presence of a high baPWV (≥1720 cm/s), carotid atherosclerosis (intima-media thickness >0.8 mm or the presence of plaques), and carotid stenosis (≥50 % of luminal narrowing). The subjects were stratified into quartiles according to GGT level, and the relationship between GGT level and subclinical atherosclerosis was analysed. RESULTS: Serum GGT levels were closely associated with obesity, atherogenic dyslipidemia, and metabolic syndrome. However, serum GGT levels did not show a linear association with baPWV, carotid intima-media thickness, or plaque grade. The prevalence of high baPWV, carotid atherosclerosis, and carotid stenosis did not differ between the quartiles in men and women. Multivariate logistic regression analyses revealed no association between GGT level and high baPWV, carotid atherosclerosis, and carotid stenosis, either as continuous variables or quartiles. CONCLUSIONS: Serum GGT levels were significantly associated with obesity, atherogenic dyslipidaemia, and metabolic syndrome, but not with the early and late stages of atherosclerotic vascular changes, in patients with type 2 diabetes. Serum GGT level may not be a reliable marker of subclinical atherosclerosis in type 2 diabetes.

Identification and functional analysis of a novel CaSR mutation in a family with familial hypocalciuric hypercalcemia.

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that plays an essential role in maintaining calcium homeostasis. In the present study, we analyzed the CaSR gene in a Korean family with familial hypocalciuric hypercalcemia (FHH). Genetic studies were performed by direct sequence analysis of the CaSR gene in genomic DNA obtained from peripheral leukocytes. A novel heterozygous G to T substitution at nucleotide position 1711 in exon 6, resulting in the G571W mutation, was identified in the CaSR gene in a 26-year-old female with asymptomatic hypercalcemia, a low calcium/creatinine clearance ratio, and normal intact parathyroid hormone. To study CaSR expression, the mutation was introduced by site-directed mutagenesis into a wild-type (WT) CaSR-expressing pCR3.1 vector, and COS-7 cells were transfected with either the WT or mutant CaSR-containing vector. Transfected cells loaded with Fura-2/AM, a fluorescent indicator of Ca2+, were assessed for CaSR function by the change in intracellular calcium [as measured by the 340 nm/380 nm fluorescence intensity ratio (F340/F380)] made in response to challenge with extracellular Ca2+. Both WT and G571W cells had equivalent amounts of CaSR protein in the cell membrane. However, after challenge with extracellular Ca2+, cells transfected with G571W CaSR responded with a lower F340/F380 ratio than those transfected with WT CaSR and showed decreased sensitivity to extracellular Ca2+ concentrations. The G571W mutation had therefore impaired the CaSR function. In conclusion, we identified a novel loss-of-function mutation, G571W, in the CaSR gene in a Korean family with FHH.

Association between serum calcium and phosphorus concentrations with non-alcoholic fatty liver disease in Korean population.

BACKGROUND AND AIM: Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is interrelated with renal dysfunction and disturbed bone metabolism, both of which play a key role in calcium and phosphorus homeostasis. We investigated the association between NAFLD and serum calcium and phosphorus levels in Korean subjects. METHODS: We performed a cross-sectional analysis of 16,592 subjects undergoing a general health checkup. NAFLD was assessed based on ultrasonographically detected fatty liver in the absence of excessive alcohol consumption and other causes of liver disease. RESULTS: The proportion of the population with fatty liver detected by ultrasonography was 43.2% for males and 17.6% for females. We observed that a higher serum albumin-corrected calcium (Ca(c)) level was associated with smoking, hypertension, and unfavorable metabolic parameters in both genders, but the serum phosphorus levels showed an inconsistent correlation with metabolic abnormalities. After adjusting for age, gender, waist circumference, body mass index, smoking status, exercise, diabetes, hypertension, lipid profiles, and renal function, serum Cac , phosphorus, and Cac -phosphorus products were independent risk factors for fatty liver (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.49-1.95, P < 0.001; OR: 1.34, 95% CI: 1.22-1.48, P < 0.001; and OR: 1.20, 95% CI: 1.14-1.26, P < 0.001, respectively), and the risk of fatty liver increased in a graded manner over the quartiles. CONCLUSION: Serum calcium and phosphorus levels are significantly associated with NAFLD. Further investigation is needed to verify whether calcium and phosphorus levels indicate a higher risk of NAFLD.

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2).

BACKGROUND/AIMS: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. METHODS: We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. RESULTS: The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. CONCLUSION: We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.

Analysis of aberrantly spliced HRPT2 transcripts and the resulting proteins in HPT-JT syndrome.

The risk for parathyroid carcinoma is high in those with the HPT-JT syndrome. Parafibromin is a protein derived from HRPT2 gene and its inactivation has been coupled to familial form of parathyroid malignancy. We previously identified altered transcripts resulting from splice site mutation of the HRPT2 gene in a family with this syndrome. In the present work, we investigated the stability of the altered HRPT2 transcripts and translation products produced in the HPT-JT syndrome. We quantified the differentially expressed HRPT2 mRNAs using real-time RT-PCR and developed a novel monoclonal parafibromin antibody to study the expression of parafibromin in the HPT-JT syndrome. The relative quantification ratios of the wild type HRPT2 mRNA, 23 bp deleted HRPT2 mRNA, and 70 bp deleted HRPT2 mRNA in the HPT-JT syndrome were 0.68, 0.17 and 0.15, respectively. But endogenous parafibromin expression was not detectable in the HPT-JT syndrome carcinoma. The altered HRPT2 mRNAs resulting from the splice site mutation in the HPT-JT syndrome were stable, but their parafibromin translation products from the HPT-JT syndrome carcinoma were probably degraded rapidly. Additional studies that aim to fully characterize the consequences of altered HRPT2 mRNAs in HPT-JT syndrome are required to explore these possibilities.

Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures.

It has been suggested that oxidative stress is associated with the pathogenesis of osteoporosis. The objective of this study was to explore the association between a marker of oxidative stress and either bone turnover markers or bone mineral density (BMD) in postmenopausal women. In addition, the effects of oxidative stress on the formation of osteoclasts in human bone marrow cell culture were examined. We performed a cross-sectional analysis in healthy postmenopausal women aged 60-78 years (n = 135, 68.2 +/- 4.9). Oxidative stress was evaluated in the serum by measuring 8-hydroxy-2'-deoxyguanosine (8-OH-dG) levels. The biochemical markers of bone turnover and areal BMD were measured in all participants. Multivariate linear regression analysis revealed a negative association between 8-OH-dG levels and BMD of the lumbar spine, total hip, femoral neck, and trochanter and positive association with type I collagen C-telopeptide (ICTP) levels. The odds ratio of 8-OH-dG for osteoporosis was 1.54 (1.14-2.31, P = 0.003). In cultures of primary human marrow cells, H2O2 caused concentration-dependent activation of TRAP-positive multinucleated giant cells. H2O2 also increased the area of pits per osteoclast activity assay substrate. RT-PCR showed that H2O2 stimulated the expression of M-CSF and RANKL and increased the RANKL/OPG ratio. The data support the view that oxidative stress is associated with increased bone resorption and low bone mass in otherwise healthy women. In addition, RANKL and M-CSF stimulation induced by oxidative stress may participate in osteoclastogenesis in human bone.

Short-term changes in bone and mineral metabolism following gastrectomy in gastric cancer patients.

Changes in bone and mineral metabolism that occur after gastrectomy have long been recognized. Gastrectomy has been identified as a risk factor for decreased bone mass and the increased fracture incidence. Previous investigations concerning postgastrectomy bone disease have been observational studies. No prospective studies have been reported that quantify the amount of bone loss after gastrectomy within the same patients. This study investigated 46 patients undergoing gastrectomy for gastric adenocarcinoma and analyzed 36 patients (58.1+/-10.8 years, 24 men and 12 women) who had dual energy X-ray absorptiometry (DXA) performed before and 1 year after gastrectomy. Systemic adjuvant chemotherapy was administered to 14 patients. Blood was sampled from all patients to determine serum calcium, phosphorous, and bone turnover marker levels before gastrectomy and at 1, 3, 6 and 12 months after surgery and for serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels before and 12 months after surgery. The mean bone loss in the lumbar spine, total hip, femoral neck, and trochanter, which was calculated as the percentage change from the baseline to the level measured at 12 months, was 5.7% (P<0.01), 5.4% (P<0.01), 6.6% (P<0.01) and 8.7% (P<0.01), respectively. Bone loss was generally greater in the group receiving chemotherapy. The serum calcium and phosphorous levels were not changed significantly and remained within the normal range throughout the observation period. After gastrectomy, the level of ICTP increased and reached a peak at 1 and 3 months, and progressively declined to baseline by 12 months. The osteocalcin levels were not coupled to an increase before 6 months. The level of 25-hydroxyvitamin D at 12 months postgastrectomy was not significantly changed compared to the baseline, however, the PTH levels increased by a mean of 63.6% at 12 months compared to the baseline (P<0.01). Significant correlations were found between the percent change in the BMD at the lumbar spine and total hip and the percentage change for the PTH level from their baselines to 12 months. The changes in the BMD at total hip, femoral neck, and trochanter also correlated to the change in body weight at 12 months. The data obtained by this study provides evidence that profound bone loss occurs in the setting of a bone remodeling imbalance during the early postgastrectomy period and allows the speculation that the gastrectomy related bone loss may be partially due to an overproduction of PTH.

Functional Identification of Compound Heterozygous Mutations in the CYP17A1 Gene Resulting in Combined 17α-Hydroxylase/17,20-Lyase Deficiency.

BACKGROUND: We previously reported a patient with congenital adrenal hyperplasia (CAH) with compound heterozygous mutations in the cytochrome P450 17A1 (CYP17A1) gene. One allele had a p.His373Leu and the other a new p.Glu383fsX36 mutation. The aim of this study was to investigate the functional properties of a new allele present in a compound heterozygote of CYP17A1. METHODS: To understand how p.His373Leu and p.Glu383fsX36 affect P450c17 enzymatic activity, wild type and mutant CYP17A1 cDNAs were cloned into flag-tagged pcDNA3 vector and introduced into human embryonic kidney cells 293T (HEK293T) cells. Protein expression levels of CYP17A1 were then analyzed. And the activities of 17α-hydroxylase and 17,20-lyase of CYP17A1 were evaluated by measuring the conversion of progesterone to 17α-hydroxyprogesterone and of 17α-hydroxypregnenolone to dehydroepiandrosterone, respectively. In addition a computer model was used to create the three-dimensional structure of the mutant CYP17A1 enzymes. RESULTS: Production of the p.His373Leu mutant protein was significantly lower than that of the wild type protein, and the p.Glu383fsX36 protein was hardly produced. Similarly the enzymatic activity derived from the p.His373Leu mutant vector was significantly lower than that obtained from the wild type vector, and little activity was obtained from the p.Glu383fsX36 vector. Three-dimensional modeling of the enzyme showed that p.His373 was located in region important for heme-binding and proper folding. Neither the p.His373Leu nor the p.Glu383fsX36 mutant protein formed a heme-binding structure. CONCLUSION: Enzyme activity measured in both mutants disappeared completely in both 17α-hydroxylase and 17,20-lyase. This result accounts for the clinical manifestations of the patient with the compound heterozygous CYP17A1 mutations.

Impact of weight changes on the incidence of diabetes mellitus: a Korean nationwide cohort study.

Obesity is a well-known risk factor for type 2 diabetes, but few data exist on the association between weight changes and diabetes risk in non-obese subjects. This study aimed to investigate the effect of weight changes on the incidence of type 2 diabetes in Korea, using 51,405 non-diabetic subjects. Individuals who developed type 2 diabetes were more likely to be older and male, to have high body mass index (BMI), blood pressure, fasting blood glucose, and total cholesterol, to be current smokers and frequent drinkers, to be hypertensive and hyperlipidemic, and to have a family history of diabetes, compared to those without type 2 diabetes. Compared with the consistently non-obese group, there was a higher hazard ratio for incident diabetes (95% confidence interval) in subjects becoming obese [1.49 (1.26-1.77)] and remaining obese [2.56 (2.34-2.81)] after adjustment for confounding factors. Decreased BMI was significantly associated with lower risks for incident diabetes and the trends were more evident in the non-obese group. However, overall there was no significant association of increased BMI with incident diabetes. In conclusion, weight loss was significantly associated with lower risk for diabetes both in non-obese and obese Koreans, but particularly in the non-obese.

Impact of metabolic status on the incidence of psoriasis: a Korean nationwide cohort study.

Growing evidence suggests that obesity is a risk factor for incident psoriasis. This study was aimed to evaluate the association of obesity and metabolic status with the incidence of psoriasis. A total of 418,057 adults were followed-up using a nationwide prospective cohort study in Korea. Participants were stratified based on the body mass index categories and metabolic condition. During the follow-up visit, 11054 (2.6%) cases were found to have psoriasis. Diabetes, hypertension, hyperlipidemia, and obesity were all found to be risk factors for incident psoriasis. The metabolically unhealthy non-obese (MUNO) subjects (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.22-1.37) and metabolically unhealthy obese subjects (MUO; HR, 1.33; 95% CI, 1. 26-1.41) had a significantly higher risk of psoriasis incidence as compared to metabolically healthy non-obese subjects. The risk of psoriasis development was found to be high among the MUNO and MUO subjects in both sexes and all age groups. In conclusion, the metabolic health status was significantly associated with an increased risk of psoriasis in both obese and non-obese individuals. However, further studies are needed to evaluate whether the control of metabolic parameters can lower the incidence of psoriasis.

Changes in the serum sex steroids, IL-7 and RANKL-OPG system after bone marrow transplantation: influences on bone and mineral metabolism.

This study prospectively investigated the changes of the serum levels of the sex steroids, IL-7, soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and osteoprotegerin (OPG) in bone marrow transplantation (BMT) recipients. This study also examined whether the changes of these cytokine levels and sex steroids actually influence bone turnover and post-BMT bone loss by correlation analysis. Data were analyzed from 39 patients (33.6+/-6.4 years, 19 men and 20 women) who had DXA performed before BMT and at 1 year after BMT. The bone turnover markers, sex steroids and the cytokine levels were measured before BMT and serially after BMT. The mean bone loss in the lumbar spine and the total proximal femur was 5.9% (P < 0.01) and 11.3% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas the bone resorption increased. For the female recipients, the estradiol levels declined at 1 week after BMT, and they did not recover to the basal levels. For the male recipients, the testosterone levels decreased at 1 week and then it increased to its baseline level. The IL-7 levels reached their maximum at 1 week and then declined to baseline level by 3 months. The serum sRANKL, OPG levels and the sRANKL/OPG ratio showed their peak at post-BMT 3 weeks. The mean daily dose of steroid was associated with suppressed bone formation, enhanced bone resorption and increased sRANKL levels. The IL-7 levels were also noted to be either positively correlated with the levels of ICTP or they were negatively correlated with the levels of osteocalcin at 1 and 3 weeks after BMT. Bone loss at the lumbar spine and the proximal femur was influenced by the decreased sex steroids and increased IL-7 levels. During the observation period, the IL-7 levels showed positive correlations with the sRANKL levels and the sRANKL/OPG ratio. For the female patients, the serum IL-7 levels were negatively associated with the estradiol levels at 1 and 3 weeks after BMT. All these findings suggest that IL-7 plays an important role for post-BMT bone loss, and this possibly happens via the RANKL pathway. These data also suggest that the up-regulation of IL-7 during the early post-BMT period may result from a deficiency of estrogen.

Association of serum calcium concentrations with fibrinogen and homocysteine in nondiabetic Korean subjects.

Considerable evidence shows that increased serum calcium levels are associated with metabolic disorders, cardiovascular disease, and increased mortality. This study investigated whether serum calcium, within a normal range, is significantly associated with serum fibrinogen and homocysteine, markers of increased cardiovascular disease risk in nondiabetic Korean subjects.A cross-sectional analysis was performed on 1096 subjects (mean age, 55.1 ±â€Š11.1 years; 36.1% women) undergoing a general health checkup. Serum biochemistry was analyzed including serum albumin-corrected calcium (Cac), insulin resistance (IR, using homeostasis model assessment [HOMA]), fibrinogen, and homocysteine.Compared with patients within the lowest Cac quartile, those with higher Cac levels had increased fibrinogen and homocysteine levels as well as an increased proportion of smoking, dyslipidemia, and HOMA-IR. Correlation analyses revealed linear relationships for Cac with fibrinogen and homocysteine in both genders. After adjustment for confounding factors, serum Cac was significantly associated with high fibrinogen (odds ratio [OR] for the highest vs the lowest quartile = 1.76, 95% confidence interval [CI] = 1.09-2.83, P = 0.02) and homocysteine (OR = 1.83, 95% CI = 1.07-3.11, P = 0.027). Multivariate regression models showed that Cac was linearly associated with fibrinogen (standardized ß = 0.14, P < 0.001) and homocysteine (standardized ß = 0.07, P = 0.009).High normal calcium concentrations were independently associated with increased levels of fibrinogen and homocysteine. Further investigation is needed to validate whether slightly increased calcium levels within the normal range indicate a higher risk of cardiovascular disease.

Serum bilirubin levels are inversely associated with PAI-1 and fibrinogen in Korean subjects.

OBJECTIVES: Oxidative stress may contribute to atherosclerosis and increased activation of the coagulation pathway. Bilirubin may reduce activation of the hemostatic system to inhibit oxidative stress, which would explain its cardioprotective properties shown in many epidemiological studies. This study investigated the association of serum bilirubin with fibrinogen and plasminogen activator inhibitor-1 (PAI-1), respectively. METHODS: A cross-sectional analysis was performed on 968 subjects (mean age, 56.0 ± 11.2 years; 61.1% men) undergoing a general health checkup. Serum biochemistry was analyzed including bilirubin subtypes, insulin resistance (using homeostasis model of assessment [HOMA]), C-reactive protein (CRP), fibrinogen, and PAI-1. RESULTS: Compared with subjects with a total bilirubin (TB) concentration of <10.0 µmol/L, those with a TB concentration of >17.1 µmol/L had a smaller waist circumference, a lower triglyceride level, a lower prevalence of metabolic syndrome, and decreased HOMA-IR and CRP levels. Correlation analysis revealed linear relationships of fibrinogen with TB and direct bilirubin (DB), whereas PAI-1 was correlated with DB. After adjustment for confounding factors, bilirubin levels were inversely associated with fibrinogen and PAI-1 levels, respectively. Multivariate regression models showed a negative linear relationship between all types of bilirubin and fibrinogen, whereas there was a significant linear relationship between PAI-1 and DB. CONCLUSIONS: High bilirubin concentrations were independently associated with low levels of fibrinogen and PAI-1, respectively. The association between TB and PAI-1 was confined to the highest TB concentration category whereas DB showed a linear association with PAI-1. Bilirubin may protect against the development of atherothrombosis by reducing the hemostatic response.

A Novel IVS2-1G>A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism-jaw tumor syndrome.

HRPT2, the gene associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, was previously mapped to 1q24-q32. It was recently cloned, and several germline mutations were found to predispose to HPT-JT syndrome. We sequenced the complete HRPT2 coding sequence and splice-junctional regions in a Korean family with HPT-JT syndrome and identified a novel germline mutation, IVS2-1G>A in intron 2, that caused the autosomal dominant trait of HPT-JT syndrome in this family. RT-PCR and sequencing of the transcripts revealed that this splicing mutation generated alternative splicing errors leading to the formation of two different transcripts, one with exon 3 deleted, the other lacking the first 23 bp of exon 3 due to the use of an internal splice acceptor in exon 3. Translation of both transcripts results in premature termination. In addition, we detected two novel somatic mutations of HRPT2 in malignant parathyroid tumors from the affected individuals. One, 85delG, causes premature termination; the other, an 18 bp in-frame deletion of 13_30delCTTAGCGTCCTGCGACAG, suggests that this region may be important in the development of the parathyroid carcinomas in HPT-JT syndrome. These findings provide further evidence that mutation of HRPT2 is associated with the formation of parathyroid tumors in HPT-JT syndrome.

Mean Platelet Volume Is Closely Associated With Serum Glucose Level but Not With Arterial Stiffness and Carotid Atherosclerosis in Patients With Type 2 Diabetes.

CONTEXT: Mean platelet volume (MPV) has been suggested as a predictive biomarker for cardiovascular disease. OBJECTIVE: This study investigated the association between MPV and subclinical atherosclerosis in Korean patients with type 2 diabetes. METHODS: This cross-sectional study involved 1205 patients with type 2 diabetes mellitus. Both brachial-ankle pulse wave velocity measurements and an ultrasound assessment of carotid atherosclerosis were done. Subclinical atherosclerosis was assessed by the presence of high brachial-ankle pulse wave velocity (>1743 cm/sec), carotid atherosclerosis (intima-media thickness > 0.8 mm or the presence of plaques), and carotid stenosis (≥50% of luminal narrowing). The subjects were stratified into quartiles according to MPV, and the relationship between MPV and subclinical atherosclerosis was analyzed. RESULTS: High MPV quartiles were linearly associated with fasting glucose and glycated hemoglobin but not with diabetic duration or insulin resistance. The prevalence of high pulse wave velocity, carotid atherosclerosis, and carotid stenosis did not differ between the quartiles in men and women. Multivariate logistic regression analyses revealed no association between MPV and high pulse wave velocity, carotid atherosclerosis, and carotid stenosis. CONCLUSIONS: MPV was strongly associated with the severity of glycemic control but not significantly associated with the early and late stages of atherosclerotic vascular changes in type 2 diabetes mellitus patients. Our results suggest that MPV is not a reliable marker for subclinical atherosclerosis in a diabetic population. This is possibly confounded by the close association of MPV with poor glycemic control. Further research is needed to broaden and validate the results.

Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes.

Several studies have suggested that bilirubin, a potent innate antioxidant, plays a protective role against cardiovascular and microvascular disease. This study investigated the association between serum concentrations of total bilirubin (TB) and the presence of diabetic peripheral neuropathy (DPN) in Korean diabetic patients. This cross-sectional study involved 1207 patients aged more than 30 years with type 2 diabetes. DPN was assessed according to clinical symptoms and physical examinations using Michigan Neuropathy Screening Instrument examination score, 10-g monofilament sensation, and current perception threshold. The subjects were stratified into gender-specific tertiles based on TB values, and the relationship between the TB values and DPN was analyzed. Compared with patients within the lowest TB tertile, those with higher TB levels consisted of patients with shorter duration of diabetes, lower HbA1c, better renal function, and less autonomic neuropathy, retinopathy, and albuminuria. Serum TB levels were inversely associated with DPN. In multivariate analysis for the development of DPN after adjusting for potential confounding factors including retinopathy, albuminuria, and autonomic neuropathy, the TB levels were inversely associated with the presence of DPN, both as a continuous variable [odds ratio (OR) per log standard deviation (SD) 0.79; 95% confidence interval (CI) 0.65-0.97; P = 0.022] and when categorized in tertiles (the highest vs. the lowest tertile; OR 0.63; 95% CI 0.40-0.99; P = 0.046). Low serum bilirubin levels are significantly associated with DPN, independently of classic risk factors and other microvascular complications. Further investigation is necessary to determine whether serum bilirubin has a prognostic significance on DPN.

Combined use of basal insulin analog and acarbose reduces postprandial glucose in patients with uncontrolled type 2 diabetes.

AIMS/INTRODUCTION: Early initiation of basal insulin therapy is recommended for normalizing fasting blood glucose in type 2 diabetes mellitus. However, basal insulin treatment might not adequately control postprandial glucose levels. The present study evaluated whether the combination of the α-glucosidase inhibitor, acarbose, and basal insulin improved blood glucose control under daily-life treatment conditions in a large sample of Korean patients. MATERIALS AND METHODS: The present study was a multicenter, prospective, observational study under daily-life treatment conditions. A total of 539 patients with type 2 diabetes who were treated with basal insulin and additional acarbose were enrolled and followed up for 20 weeks. Changes in hemoglobin A1c, fasting and postprandial blood glucose were evaluated at baseline and at the end of the observation period. The physician and patient satisfaction of the combination treatment and safety were assessed. RESULTS: Hemoglobin A1c decreased by 0.55 ± 1.05% from baseline (P < 0.0001). Fasting and postprandial blood glucose levels were reduced by 0.89 ± 3.79 and 2.59 ± 4.77 mmol/L (both P < 0.0001). The most frequently reported adverse drug reactions were flatulence (0.37%) and abnormal gastrointestinal sounds (0.37%), and all were mild in intensity and transient. In the satisfaction evaluation, 79.0% of physicians and 77.3% of patients were 'very satisfied' or 'satisfied' with the combined basal insulin and acarbose therapy. CONCLUSIONS: Combination therapy of basal insulin and acarbose in patients with type 2 diabetes improved glucose control, and had no drug-specific safety concerns, suggesting that the treatment might benefit individuals who cannot control blood glucose with basal insulin alone.

Changes in the serum growth factors and osteoprotegerin after bone marrow transplantation: impact on bone and mineral metabolism.

The loss of bone mass often occurs after bone marrow transplantation (BMT), particularly during the early posttransplant period. There are few reports on the role of growth factors and osteoprotegerin (OPG) in the post-BMT bone loss. This study prospectively investigated 110 patients undergoing BMT and analyzed 36 patients who had dual-energy x-ray absorptiometry performed before BMT and 1 yr after BMT. The biochemical markers of bone formation and resorption were measured at the short-term intervals during the year-long follow-up. The serum IGF-I, IGF binding protein (IGFBP)-3, fibroblast growth factor-2, macrophage-colony stimulating factor (M-CSF), and OPG levels were measured before and 1 wk, 3 wk, and 3 months after BMT. The mean bone loss in the lumbar spine and the total proximal femur, which was calculated as the percent change from the baseline to the level at 1 yr, was 5.2% (P < 0.05) and 11.6% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas bone resorption increased, which was indicated by the biochemical markers of bone turnover. The serum IGF-I levels also decreased progressively until 3 wk and then increased to the basal values at 3 months. The serum IGFBP-3 levels decreased progressively until 3 months. The serum fibroblast growth factor-2 levels decreased to the nadir at 1 wk and gradually recovered to the basal values at 3 months. The serum M-CSF levels increased immediately after BMT, which declined to its baseline level by 3 months. The serum OPG levels increased progressively, reached a peak at 3 weeks, and declined thereafter. There were significant correlations between the IGF-I and osteocalcin levels before BMT and at 3 wk after BMT (r = 0.45, P < 0.01; r = 0.54, P < 0.01). During the observation period, the serum IGFBP-3 and M-CSF levels showed positive correlations with the osteocalcin and serum collagen I carboxyl-terminal telopeptide levels, respectively. Although statistically not significant, the OPG levels tended to be positively associated with the serum collagen I carboxyl-terminal telopeptide levels. Significant correlations were observed between the percent changes from the baseline to 1 yr in the bone mineral density at the proximal femur and the serum IGF-I levels at 3 wk and 3 months after BMT (r = 0.52, P < 0.01; r = 0.41, P < 0.05).