High glucose promotes mineralization via bone morphogenetic protein 4-Smad signals in early stage of osteoblast differentiation.

Diabetes mellitus is associated with bone fragility. Although osteoblast maturation is disturbed in patients with diabetes mellitus, the involvement of high glucose (HG) in different stages of osteoblast maturation is unclear. We used MC3T3-E1 cells, a murine osteoblastic cell line. The cells were incubated in high glucose medium (16.5 and 27.5 mM) with three different time courses: throughout 21 days, only first 7 days (early stage) and only last 7 days (late stage). Mineralization assay showed that HG throughout 21 days increased mineralization compared with control (5.5 mM). In the time course experiment, HG increased mRNA expression of Alp, osteocalcin (Ocn), runt-related transcription factor 2 and osterix on days 3 and 5. By contrast, long-term treatment with HG (14 and 21 days) decreased expression of these osteoblastic markers. HG only during early stage enhanced mineralization, while HG only during late stage had no effects. HG increased the expression of bone morphogenetic protein (BMP) 4 and enhanced phosphorylation of Smad1/5/8. Treatment with a BMP receptor antagonist LDN193189 prevented the HG-induced mineralization during early stage of osteoblast differentiation, indicating that HG in the early stage promotes mineralization by BMP4. In conclusion, the study demonstrates that continuous HG treatment might enhance early osteoblast differentiation but disturbs osteoblast maturation, and that BMP-4-Smad signal might be involved in the HG-induced differentiation and mineralization of osteoblasts.

Higher Serum Uric Acid is a Risk Factor of Reduced Muscle Mass in Men with Type 2 Diabetes Mellitus.

OBJECTIVE: Sarcopenia has been recognized as a diabetic complication, and hyperuricemia is often accompanied by type 2 diabetes mellitus (T2DM). However, it is unknown whether serum uric acid (UA) levels are associated with reduced muscle mass in T2DM. METHODS: We conducted a cross-sectional study to investigate the association of serum UA with muscle mass in 401 subjects with T2DM (209 men and 192 postmenopausal women). The relative skeletal muscle mass index (RSMI) was evaluated using whole-body dual-energy x-ray absorptiometry. RESULTS: Multiple regression analyses adjusted for body weight, age, serum creatinine, hemoglobin A1c (HbA1c), and duration of T2DM showed that serum UA was negatively associated with RSMI in all subjects and men with T2DM (ß=-0.13, p=0.001 and ß=-0.17, p=0.003, respectively). Moreover, logistic regression analyses adjusted for these confounding factors showed that a higher serum UA level was significantly associated with low RSMI in men with T2DM [odds ratio (OR)=1.94, 95% confidence interval (CI)=1.10-3.45 per SD increase, p=0.023]. In addition, higher serum UA levels were significantly associated with low RSMI after additional adjustment for age, duration of T2DM, HbA1c level, serum creatinine level, and sex in all subjects with T2DM [OR=1.80, 95% CI=1.20-2.72 per SD increase, p=0.005]. CONCLUSIONS: The present study showed for the first time that higher serum UA is an independent risk factor of reduced muscle mass in men with T2DM.

Which Is a Better Skeletal Muscle Mass Index for the Evaluation of Physical Abilities: The Present Height or Maximum Height?

Objective Sarcopenia and osteoporosis often coexist in older adults. Sarcopenia is diagnosed using the skeletal muscle mass index (SMI), which is calculated as the appendicular skeletal muscle mass (ASM)/(present height)2, although patients with osteoporosis frequently have a loss of body height. We therefore investigated whether the present height or maximum height is more useful for calculating the SMI in the evaluation of physical abilities. Methods We conducted a cross-sectional study to investigate the association of the SMI with physical abilities, such as the grip strength and gait speed, in 587 postmenopausal women. The SMI was evaluated using whole-body dual-energy X-ray absorptiometry (DXA). The SMI [(ASM)/(present height)2], modified SMI (mSMI) [(ASM)/(maximum height)2], and SMI difference (ΔSMI) (mSMI-SMI) were calculated. Results Age and body mass index (BMI)-adjusted regression analyses showed that the SMI (ß=0.30, p<0.001 and ß=0.14, p=0.034) and mSMI (ß=0.40, p<0.001 and ß=0.29, p<0.001) were positively associated while the ΔSMI was negatively associated with the grip strength and gait speed (ß=-0.15, p<0.001 and ß=-0.24, p<0.001, respectively). Furthermore, the age, BMI, and presence of osteoporotic fractures-adjusted logistic regression analyses showed that a low mSMI (<5.4 kg/m2) was significantly associated with a low grip strength (<18 kg) and slow gait speed (1.0 m/s) [odds ratio (OR) =2.45, 95% confidence interval (CI) =1.52-3.95 per SD increase, p<0.001; and OR=1.73, 95% CI=1.01-2.96, p=0.042, respectively], although a low SMI showed no such relationship (p=0.052 and p=0.813, respectively). Conclusion The mSMI using the maximum height is more useful for evaluating physical abilities than conventional SMI estimation in postmenopausal women.

Executive summary of clinical practice guide on fracture risk in lifestyle diseases.

Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.

Modulators of Fam210a and Roles of Fam210a in the Function of Myoblasts.

Fam210a is a novel protein regulating muscle mass and strength in mice in vivo. However, detailed effects of Fam210a on the function of myoblasts as well as modulators of Fam210a are still unknown. We, thus, investigated (1) the roles of Fam210a in myoblast differentiation, proliferation, apoptosis and degradation, and (2) the factors that regulate Fam210a expression in murine C2C12 cells. We found that the level of Fam210a mRNA was reduced during myoblast differentiation. Reduction in endogenous Fam210a levels by siRNA suppressed mRNA levels of myogenic factors (Pax7, Myf5, Myogenin, and Mhc) and a muscle degradation factor (Murf1). On the other hand, Fam210a siRNA did not affect mRNA encoding the apoptotic factors Bcl-2 and Bax and the extent of apoptosis as measured by ELISA in C2C12 cells. In contrast, Fam210a siRNA increased the mRNA level of Mmp-12, which induces osteoclastogenesis. Interestingly, insulin and 1,25(OH)2D, which are known to affect cell metabolism and muscle function, significantly increased the level of Fam210a mRNA in a dose-dependent manner. In addition, a PI3-kinase inhibitor and reduction in endogenous levels of the vitamin D receptor (VDR) by siRNA suppressed insulin- and 1,25(OH)2D-induced expression of Fam210a, respectively. In conclusion, Fam210a might enhance myoblast differentiation and proteolysis. Moreover, insulin and 1,25(OH)2D may induce myoblast differentiation and degradation by enhancing the expression of Fam210a.

Higher Serum Uric Acid is a Risk Factor of Vertebral Fractures in Postmenopausal Women with Type 2 Diabetes Mellitus.

PURPOSE: Serum uric acid (UA) level may affect bone metabolism because it has an anti-oxidative effect. However, whether serum UA level is associated with a fracture risk in type 2 diabetes mellitus (T2DM) is unclear. We thus aimed to clarify the association between serum UA and bone parameters in T2DM. METHODS: We conducted a cross-sectional study to investigate the association of serum UA with bone mineral density (BMD) at lumbar spine (LS) and femoral neck (FN), bone turnover markers such as osteocalcin and urine type I collagen cross-linked N-telopeptide (uNTX), and the prevalence of vertebral fractures (VF) in 356 postmenopausal women and 512 men with T2DM. RESULTS: Multiple regression analyses adjusted for age, duration of diabetes, hemoglobin A1c, body mass index and log (serum creatinine) showed that serum UA level was significantly and negatively associated with uNTX in postmenopausal women with T2DM, whereas it was not associated with osteocalcin or BMD at each site. In men, serum UA was not associated with BMD or bone turnover markers. Because postmenopausal women with VF were significantly older and had longer duration of diabetes, higher serum creatinine level and lower BMD than those without it, logistic regression analyses adjusted for these confounding factors were performed. Higher serum UA level was significantly associated with the presence of VF. CONCLUSIONS: The present study showed that higher serum UA is a risk factor for VF independently of BMD in postmenopausal women with T2DM.

Bazedoxifene Ameliorates Homocysteine-Induced Apoptosis via NADPH Oxidase-Interleukin 1ß and 6 Pathway in Osteocyte-like Cells.

Homocysteine (Hcy) increases oxidation and inflammation; however, the mechanism of Hcy-induced bone fragility remains unclear. Because selective estrogen modulators (SERMs) have an anti-oxidative effect, SERMs may rescue the Hcy-induced bone fragility. We aimed to examine whether oxidative stress and pro-inflammatory cytokines such as interleukin (IL)-1ß and IL-6 are involved in the Hcy-induced apoptosis of osteocytes and whether bazedoxifene (BZA) inhibits the detrimental effects of Hcy. We used mouse osteocyte-like cell lines MLO-Y4-A2 and Ocy454. Apoptosis was examined by DNA fragmentation ELISA and TUNEL staining, and gene expression was evaluated by real-time PCR. Hcy 5 mM significantly increased expressions of NADPH oxidase (Nox)1, Nox2, IL-1ß, and IL-6 as well as apoptosis in MLO-Y4-A2 cells. Nox inhibitors, diphenyleneiodonium chloride and apocynin, significantly suppressed Hcy-induced IL-1ß and IL-6 expressions. In contrast, an IL-1ß receptor antagonist and an IL-6 receptor monoclonal antibody had no effects on Hcy-induced Nox1 and Nox2 expressions, but significantly rescued Hcy-induced apoptosis. BZA (1 nM-1 µM) and 17ß estradiol 100 nM significantly rescued Hcy-induced apoptosis, while an estrogen receptor blocker ICI 182,780 reversed the effects of BZA and 17ß estradiol. BZA also rescued Hcy-induced apoptosis of Ocy454 cell, and ICI canceled the effect of BZD. Moreover, BZA significantly ameliorated Hcy-induced expressions of Nox1, Nox2, IL-1ß, and IL-6, and ICI canceled the effects of BZA on their expressions. Hcy increases apoptosis through stimulating Nox 1 and Nox 2-IL-1ß and IL-6 expressions in osteocyte-like cells. BZA inhibits the detrimental effects of Hcy on osteocytes via estrogen receptor.

Successful reduction of ACTH secretion in a case of intractable Cushing's disease with pituitary Crooke's cell adenoma by combined modality therapy including temozolomide.

Crooke's cell adenoma (CCA) is an aggressive subtype of corticotroph adenoma; however, CCA is associated with a high incidence of low expression of methyl guanine methyl transferase (MGMT), suggesting that temozolomide (TMZ) treatment might be effective for this tumor type. The case of a 56-year-old woman with Cushing's disease caused by a pituitary CCA is presented. At the age of 38 years, the patient presented to our hospital with polyuria and a visual field defect. MRI and laboratory studies showed a 4.5-cm-diameter pituitary tumor with plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels of more than 500 pg/mL and 40 µg/dL, respectively. At 39 years of age, the patient underwent a craniotomy, and her plasma ACTH and cortisol levels decreased to less than 200 pg/mL and 10 µg/dL, respectively; however, these hormone levels increased gradually to 3,940 pg/mL and 70 µg/dL, respectively, by the time the patient was 56 years old. Histopathological re-examination of the previously resected specimen showed that the pituitary tumor was MGMT-negative CCA. TMZ treatment after the second operation decreased the plasma ACTH levels from 600-800 pg/mL to 70-300 pg/mL. No signs of recurrence were observed in the seven years following these treatments with added prophylactic radiation therapy. These clinical findings suggest that TMZ treatment to patients with CCA accompanied with elevated ACTH may be good indication to induce lowering ACTH levels and tumor shrinkage.

Phloretin Suppresses Bone Morphogenetic Protein-2-Induced Osteoblastogenesis and Mineralization via Inhibition of Phosphatidylinositol 3-kinases/Akt Pathway.

Phloretin has pleiotropic effects, including glucose transporter (GLUT) inhibition. We previously showed that phloretin promoted adipogenesis of bone marrow stromal cell (BMSC) line ST2 independently of GLUT1 inhibition. This study investigated the effect of phloretin on osteoblastogenesis of ST2 cells and osteoblastic MC3T3-E1 cells. Treatment with 10 to 100 µM phloretin suppressed mineralization and expression of osteoblast differentiation markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), type 1 collagen, runt-related transcription factor 2 (Runx2), and osterix (Osx), while increased adipogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid-binding protein 4, and adiponectin. Phloretin also inhibited mineralization and decreased osteoblast differentiation markers of MC3T3-E1 cells. Phloretin suppressed phosphorylation of Akt in ST2 cells. In addition, treatment with a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, LY294002, suppressed the mineralization and the expression of osteoblast differentiation markers other than ALP. GLUT1 silencing by siRNA did not affect mineralization, although it decreased the expression of OCN and increased the expression of ALP, Runx2, and Osx. The effects of GLUT1 silencing on osteoblast differentiation markers and mineralization were inconsistent with those of phloretin. Taken together, these findings suggest that phloretin suppressed osteoblastogenesis of ST2 and MC3T3-E1 cells by inhibiting the PI3K/Akt pathway, suggesting that the effects of phloretin may not be associated with glucose uptake inhibition.

Low skeletal muscle mass is associated with the risk of all-cause mortality in patients with type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of muscle mass reduction. However, the association between muscle mass and mortality in T2DM remains unknown. METHODS: This was a historical cohort study with the endpoint of all-cause mortality. This study included 163 Japanese men and 141 postmenopausal women with T2DM whose body compositions were evaluated using dual-energy X-ray absorptiometry. Low muscle mass was defined as a skeletal muscle mass index (SMI) of <7.0 kg/m2 for men and <5.4 kg/m2 for women. RESULTS: During the 6-year follow-up period, 32 men and 14 women died. In a Cox regression analysis adjusted for age, T2DM duration, glycated hemoglobin, serum creatinine, fasting C-peptide, body mass index, and lean body mass were associated with the risk of mortality in men [hazard ratio (HR) = 1.81, 95% confidence interval (CI) = 1.00-3.28 per standard deviation (SD) decrease, p = 0.049] and women (HR = 4.53, 95% CI = 1.14-17.96 per SD decrease, p = 0.032). Neither fat mass nor bone mineral content was associated with mortality. Low SMI was associated with increased mortality in women (HR = 5.97, 95% CI = 1.04-34.37, p = 0.045), while the association between low SMI and mortality was marginal in men (HR = 2.38, 95% CI = 0.92-6.14, p = 0.074). CONCLUSIONS: Low muscle mass was independently associated with all-cause mortality in patients with T2DM. The preservation of skeletal muscle mass is important to protect patients with T2DM from increased mortality risk.

Late-onset isolated adrenocorticotropic hormone deficiency caused by nivolumab: a case report.

BACKGROUND: Immune checkpoint inhibitors including nivolumab, an anti-programmed cell death protein 1 antibody, are recently developed cancer immunotherapy agents. Immune checkpoint inhibitors are known to cause autoimmune-related side effects including endocrine dysfunctions. However, there are few reports on late-onset isolated adrenocorticotropic hormone (ACTH) deficiency caused by nivolumab. CASE PRESENTATION: The patient was a 72-year-old female. When she was 64 years old, she was diagnosed with malignant melanoma of the left thigh accompanied by left inguinal lymph node metastases, and she received several courses of chemotherapy for malignant melanoma followed by the resection of these lesions. At 71 years of age, multiple metastases were found and treatment with nivolumab 2 mg/kg every 3 weeks was initiated. Six months later, replacement with levothyroxine was started because of hypothyroidism following mild transient thyrotoxicosis. Eleven months after the beginning of nivolumab, the treatment was discontinued because of tumor expansion. Four months after the discontinuation of nivolumab, general malaise and appetite loss worsened, and 2 months later, hyponatremia (Na; 120-127 mEq/L) and hypoglycemia (fasting plasma glucose; 62 mg/dL) appeared. Her ACTH and cortisol levels were extremely low (ACTH; 9.6 pg/mL, cortisol; undetectable). Challenge tests for anterior pituitary hormones showed that responses of ACTH and cortisol secretion to corticotropin-releasing hormone were disappeared, although responses of other anterior pituitary hormones were preserved. Thus, she was diagnosed with isolated ACTH deficiency. Her symptoms were improved after treatment with hydrocortisone. CONCLUSIONS: The present report showed a case of late-onset isolated ACTH deficiency accompanied by hyponatremia, which was diagnosed 6 months after the discontinuation of nivolumab. The effects of nivolumab last for a long time and the side effects of nivolumab can also appear several months after discontinuation of the drug. Repeated monitoring of serum sodium levels may be a beneficial strategy to find the unexpected development of adrenal insufficiency even after discontinuation of nivolumab.

Insulin-Like Growth Factor-I Protects Against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells.

Previous studies suggested that advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-I) are involved in the mechanism of diabetes-induced sarcopenia. In this study, we examined effects of treatments with AGEs and/or IGF-I for 24 h on myogenic differentiation and apoptosis in mouse myoblastic C2C12 cells. Real-time PCR and Western blot were performed to investigate mRNA and protein expressions, and apoptosis was examined by using a DNA fragment detection ELISA kit. AGE3 significantly decreased mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and attenuated the effects of AGE3. AGEs significantly decreased endogenous IGF-I mRNA expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM) significantly increased mRNA expression of Rage, a receptor for AGEs, while IGF-I significantly decreased it. DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. In contrast, high glucose enhanced AGE3-induced apoptosis. IGF-I significantly attenuated the effects of high glucose plus AGE3 on the mRNA and protein expressions of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGEs inhibit myogenic differentiation and increase apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I attenuated the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.

A scoring assessment tool for the risk of vertebral fractures in patients with type 2 diabetes mellitus.

BACKGROUND: Development of assessment tool for fracture risk is an urgent task, because bone mineral density (BMD) is less useful for evaluating fracture risk in type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: In total, 808 T2DM patients were enrolled in this cross-sectional study. To develop a scoring assessment tool using clinical risks for vertebral fracture (VF), we evaluated which variables were associated with VF by logistic regression analysis, and categorized these variables based on cut-off values obtained by using receiver operating characteristic (ROC) curves. For calculation of the score, the relative weight of the factors was determined, and a tentative score was assigned. Then, cut-off point of the score was examined to predict VF. RESULTS: Logistic regression analyses showed that age, diabetes duration, body mass index (BMI), serum albumin, and T score at femoral neck (FN-T score) were associated with VF risk. Parameter estimates for each risk factor obtained by logistic analyses were converted to risk scores (maximum score 23). ROC analysis showed that 8.5 was the cut-off value for detecting VF. Multiple logistic regression analysis adjusted for confounding factors showed that score ≥9 was significantly associated with an increased risk of prevalent VF (odds ratio 1.99, 95% confidence interval 1.22-3.24, p = 0.006). CONCLUSIONS: This is the first study to show that a scoring assessment tool using age, duration of diabetes, BMI, serum albumin, and FN-T score is useful to estimate VF risk in patients with T2DM, being more sensitive than BMD alone in detecting bone fragility.

Osteoporosis and vertebral fracture are associated with deterioration of activities of daily living and quality of life in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fracture. However, whether diabetes-related osteoporosis independently contributes to the deterioration of activities of daily living (ADLs) and quality of life (QOL) is unclear. This cross-sectional study investigated the association between osteoporosis, ADLs, and QOL in 309 patients with T2DM. ADLs and QOL were assessed using Barthel Index (BI) and a SF-36 questionnaire. Multiple logistic regression analyses adjusted for age, gender, T2DM duration, body mass index, hemoglobin A1c, estimated GFR, diabetic neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease, and anti-diabetic treatments were conducted. The number of patients with osteoporosis or vertebral fracture was 166 (53.7%) and 118 (38.2%), respectively. Osteoporosis was significantly associated with lower general health (GH), social functioning (SF), and role emotional (RE) (OR 2.56, 1.79, and 1.92, respectively; all p values < 0.05 at least) and marginally associated with lower BI (OR 2.39, p = 0.068). Moreover, the presence of vertebral fracture grade 2 or 3 was significantly associated with lower BI, bodily pain (BP), GH, vitality, SF, and RE (OR 2.58, 2.01, 3.64, 1.99, 2.18, and 1.97, respectively; all p values < 0.05 at least). Osteoporosis and severe vertebral fracture were associated with the deterioration of ADLs and QOL independently of other diabetic complications. Therefore, the management of diabetes-related osteoporosis is an important strategy to avoid the deterioration of ADLs and QOL in T2DM.

Overweight and underweight are risk factors for vertebral fractures in patients with type 2 diabetes mellitus.

The aim of this cross-sectional study was to examine the association between body mass index (BMI) and the prevalence of vertebral fracture (VF) in Japanese patients with type 2 diabetes (T2DM). A total of 798 patients with T2DM were enrolled. VF was determined semi-quantitatively using lateral X-ray films. The association between BMI quartiles (Q1: ≤ 21.2 kg/m2, Q2: 21.3-23.4 kg/m2, Q3: 23.5-25.8 kg/m2, Q4: 25.9≤ kg/m2) and the presence of VF was examined. Multiple logistic regression analyses adjusted for age, sex, diabetes duration, hemoglobin A1c (HbA1c), estimated glomerular filtration rate, and albumin showed that Q1, Q3, and Q4 were significantly associated with an increased VF risk compared to Q2, which served as a reference [Q1; odds ratio (OR) = 1.91, 95% confidence interval (CI) 1.24-2.95, p = 0.004, Q3; OR = 1.65, 95% CI 1.07-2.55, p = 0.023, and Q4; OR = 2.18, 95% CI 1.39-3.41, p < 0.001]. Moreover, these associations remained significant after additional adjustment for femoral neck T-score, a bone resorption marker, urinary N-terminal cross-linked telopeptide of type-I collagen, and use of insulin and thiazolidinedione. Our study shows for the first time that both overweight and underweight were associated with the bone mineral density (BMD)-independent risk of VF in patients with T2DM. Therefore, body weight control should be considered as a protective measure against diabetes-related bone fragility.

Nerve conduction velocity is negatively associated with intima-media thickness and brachial-ankle pulse wave velocity in men with type 2 diabetes mellitus.

OBJECTIVE: Previous studies suggest that the presence of diabetic peripheral polyneuropathy (DPN) is associated with atherosclerotic diseases; however, little is known about the relationship between diabetic nerve conduction velocity (NCV) versus arterial stiffness and atherosclerosis parameters. METHODS: The subjects in this study were 292 men with type 2 diabetes mellitus (T2DM). All subjects underwent NCV examination at median and tibial nerves as motor nerve (MCV) as well as median and sural nerves as sensory nerve (SCV). Brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (IMT) were evaluated as arterial stiffness and atherosclerosis parameters. RESULTS: Pearson's correlation coefficient showed that NCV at all sites negatively correlated with baPWV, maximal and mean IMT (IMT-Max and IMT-Mean), and plaque score (all p values p<0.01 at least). Multiple regression analyses adjusted for confounding factors such as age, duration of diabetes, body mass index, HbA1c, fasting C-peptide, systolic blood pressure, HDL-cholesterol, LDL-cholesterol and albuminuria showed that the association of NCV with IMT-Max, ITM-Mean, and plaque score remained significant (all p values p<0.05 at least) except that between SCV at median and IMT-Max. Moreover, SCV at median (forearm) and sural were significantly associated with baPWV (p = 0.023 and p = 0.027, respectively). CONCLUSION: The present study showed that DPN estimated by quantitative NCV is linearly associated with the deterioration of arterial stiffness and atherosclerosis parameters in T2DM independently of various diabetic and atherosclerotic factors.

[Secondary osteoporosis. Bone quality deterioration in lifestyle-related disease.]

Both lifestyle-related disease and ostepoross increase with aging;thus the number of patients with these diseases will increase in future. Because diabetes mellitus, a representative lifestyle-related disease, induces bone fragility due to deterioration of bone quality, if all of the focus is given only to bone mineral density values, we might underestimate fracture risks in the patients. Previous studies have shown that accumulation of advanced glycation end products in bone matrix, abnormal bone microstructure, and dysfunction of bone remodeling with decreased bone formation are involved in the mechanism of bone quality deterioration. However, there are no specific parameters to evaluate bone quality in clinical settings so far. Therefore, it is necessary to find patients with clinical risk factor of fracture and to perform intensive treatments for osteoporosis.

Albuminuria Increases All-Cause Mortality in Japanese Patients with Type 2 Diabetes Mellitus.

Previous studies have reported that diabetic kidney disease is associated with cardiovascular events and death. Little is known about the independent association of albuminuria and estimated glomerular filtration rate (eGFR), with mortality in Asian patients with type 2 diabetes mellitus (T2DM) without renal failure. We conducted a historical cohort study to clarify this issue in Japanese patients with T2DM. In this study, we recruited 385 patients with T2DM, who never had chronic renal failure (eGFR < 30 mL/min/1.73 m² at baseline) and malignant diseases. With the end point of all-cause mortality, Cox regression analysis was performed. During the observational period of 7 years, 54 patients died. Cox regression analysis adjusted for confounding factors such as age, duration of diabetes, body mass index, and HbA1c, and showed that urinary albumin level was significantly associated with the mortality [hazard ratio (HR) = 1.32, 95% confidence interval (CI) = 1.03⁻1.70 per standard deviation (SD) increase, p = 0.031]. After additional adjustment for eGFR, the association remained significant (HR = 1.32, 95% CI = 1.02⁻1.70 per SD increase, p = 0.033). On the other hand, eGFR was not associated with the mortality. The present study showed that higher urinary albumin was associated with increased all-cause mortality in T2DM, independently of eGFR. These findings suggest that, regardless of eGFR, albuminuria is important for the increased risk of mortality in Japanese T2DM patients without chronic renal failure (eGFR < 30 mL/min/1.73 m²). However, because of several limitations, further large-scale longitudinal studies are necessary to confirm the present study.

Osteoblast AMP-activated protein kinase regulates glucose metabolism and bone mass in adult mice.

Previous studies have shown that AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, plays important roles in osteoblast differentiation and mineralization. However, little is known about in vivo roles of osteoblastic AMPK in glucose metabolism and bone mass regulation in adult mice. Here, we used the inducible Cre system to control the onset of Ampk disruption after birth by removing doxycycline supplementation. We conditionally inactivated Ampk in osterix (Osx)-expressing cells in 3-week-old Ampk-/- mice. After 6 months of Ampk inactivation, the Ampk-/- mice displayed lower serum osteocalcin levels as well as glucose intolerance and insulin resistance, as indicated by glucose tolerance and insulin tolerance tests, respectively, when compared with wild-type mice. After 18 months of Ampk inactivation, micro computed tomography showed significant reductions in trabecular bone volume and cortical bone thickness in the femur of Ampk-/- mice when compared with wild-type mice. Moreover, bone stiffness was significantly lower in Ampk-/- mice than in wild-type mice. This is the first study to show that osteoblast AMPK plays an important roles in glucose metabolism and in maintaining trabecular bone volume, cortical thickness, and bone strength in adult mice.