RESUMEN
Bone mineral density (BMD) is less useful for evaluating fracture risk in type 2 diabetes. This study showed for the first time that combined evaluation by serum insulin-like growth factor-I and BMD is useful to assess the risk of vertebral fracture in postmenopausal women and men with type 2 diabetes. INTRODUCTION: BMD is less useful for evaluating fracture risk in type 2 diabetes mellitus (T2DM). We aimed to examine the usefulness of combined evaluation by BMD and serum insulin-like growth factor-I (IGF-I) to assess the risk of vertebral fracture (VF) in T2DM. METHODS: In this cross-sectional study, 412 postmenopausal women and 582 men with T2DM, whose BMD, bone turnover markers, and serum IGF-I were measured, were enrolled. The association of BMD alone, serum IGF-I alone, and combined assessment by BMD and IGF-I with the presence of VF was examined. RESULTS: Multiple logistic regression analyses showed that IGF-I as well as BMD T-score at lumbar (L) and femoral neck (FN) were significantly associated with VF except for IGF-I in men, respectively. Receiver operating characteristic curves showed that the cutoff values of IGF-I, L T-score and FN T-score were 127 ng/mL, - 1.78, and - 2.02 in postmenopausal women and 127 ng/mL, - 1.67, and - 1.24 in men. Based on the cutoff vales, the subjects were divided into four categories. The category of lower IGF-I and lower T-scores had a significant increased risk of VF compared to higher IGF-I and higher T-scores both in postmenopausal women and in men. The sensitivity and specificity of the combined assessment to detect VF were better compared to using BMD alone or IGF-I alone. CONCLUSIONS: This is the first study to show that in addition to BMD measurement, the assessment using serum IGF-I is useful to estimate the prevalence of VF in patients with T2DM.
Asunto(s)
Densidad Ósea/fisiología , Diabetes Mellitus Tipo 2/complicaciones , Factor I del Crecimiento Similar a la Insulina/análisis , Fracturas Osteoporóticas/diagnóstico , Fracturas de la Columna Vertebral/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Remodelación Ósea/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Cuello Femoral/fisiopatología , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/fisiopatología , Masculino , Persona de Mediana Edad , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/fisiopatología , Radiografía , Fracturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/fisiopatología , Vértebras Torácicas/diagnóstico por imagenRESUMEN
Advanced glycation end-products (AGEs) play important roles in the progression of diabetic complications. Although sarcopenia is recently recognized as another complication associated with diabetes mellitus, its mechanism still remains unclear. In this study, we investigated the relationship between serum levels of pentosidine, which is one of AGEs, and insulin-like growth factor-I (IGF-I) vs. skeletal muscle mass by whole body dual-energy x-ray absorptiometry in 133 postmenopausal women with type 2 diabetes. Relative skeletal muscle mass index (RSMI) was calculated by following formula; appendicular skeletal muscle mass divided by height in meters squared. Simple correlation analyses showed that serum pentosidine levels were significantly and negatively correlated with muscle mass of legs (r=-0.21, p=0.017) and RSMI (r=-0.18, p=0.022), and that IGF-I was significantly and positively correlated with muscle mass of arms and legs (r=0.23, p=0.008 and r=0.30, p=0.001, respectively) as well as RSMI (r=0.20, p=0.022). Moreover, after adjusting for age, duration of diabetes, serum creatinine, HbA1c, and IGF-I, pentosidine was significantly and negatively associated with RSMI (ß=-0.27, p=0.018) and marginally with muscle mass of legs (ß=-0.18, p=0.071). The associations between IGF-I and indices of muscle mass such as arms, legs and RSMI were still significant after additional adjustment for pentosidine (p=0.016, 0.019 and 0.021, respectively). These findings indicate that increased serum pentosidine and decreased IGF-I are independent risk factors for loss of muscle mass in postmenopausal women with type 2 diabetes.
Asunto(s)
Arginina/análogos & derivados , Diabetes Mellitus Tipo 2/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lisina/análogos & derivados , Músculo Esquelético/metabolismo , Posmenopausia/sangre , Sarcopenia/sangre , Anciano , Arginina/sangre , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Lisina/sangre , Persona de Mediana Edad , Músculo Esquelético/patología , Sarcopenia/patologíaRESUMEN
UNLABELLED: We found that serum osteocalcin (OC) and undercarboxylated OC (ucOC) levels were negatively associated with abdominal aortic calcification in type 2 diabetes mellitus (T2DM) men. This finding suggests that circulating OC and ucOC are not only related to glucose or fat metabolism but also to arteriosclerosis. INTRODUCTION: Recent studies revealed that serum osteocalcin levels were associated with not only bone metabolism but also glucose and fat metabolism. However, the relationship between serum OC levels and arteriosclerosis remains controversial. We examined whether or not bone metabolic markers including OC are associated with abdominal aortic calcification in patients with type 2 diabetes mellitus. METHODS: We recruited 118 men and 100 postmenopausal women with T2DM. We evaluated the abdominal aortic calcification score (ACS) on a lateral lumbar radiograph and examined the association between serum OC or undercarboxylated OC levels and ACS. RESULTS: The ACS of 3 and greater, which corresponded well to the highest quartile, was significantly and negatively associated with serum OC and ucOC levels in men by logistic regression analyses after adjusting for age, BMI, serum levels of creatinine and LDL cholesterol, radial bone mineral density, smoking, duration of DM, hemoglobin A1c, and the index of insulin resistance [odds ratio (OR) 0.36, 95 % confidence interval (CI) 0.19-0.70, P < 0.005, and OR 0.28, 95 % CI 0.12-0.69, P < 0.01, per standard deviation increase in OC and ucOC, respectively]. These observations were still significant after an additional adjustment for other bone markers. In contrast, there were no significant relationships with serum OC or ucOC levels and ACS in women. CONCLUSIONS: These findings suggest that serum OC and ucOC levels are associated with not only bone metabolism but also arteriosclerosis in men, but not in women with type 2 diabetes mellitus.
Asunto(s)
Enfermedades de la Aorta/sangre , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/sangre , Osteocalcina/sangre , Calcificación Vascular/sangre , Anciano , Aorta Abdominal , Enfermedades de la Aorta/etiología , Enfermedades de la Aorta/fisiopatología , Biomarcadores/sangre , Glucemia/metabolismo , Densidad Ósea/fisiología , Huesos/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/fisiopatología , Femenino , Humanos , Metabolismo de los Lípidos/fisiología , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Calcificación Vascular/etiología , Calcificación Vascular/fisiopatologíaRESUMEN
UNLABELLED: Although a recent study showed that undercarboxylated osteocalcin (ucOC) is important for male fertility and testosterone production by testes, little is known about the relationship between ucOC and testosterone in humans. We found for the first time that ucOC is positively associated with free testosterone in men with type 2 diabetes. INTRODUCTION: The ucOC has been shown to play a key role in energy metabolism as an endocrine hormone. Although a recent animal study demonstrated that ucOC is also important for male fertility and testosterone production by the testes, association between serum osteocalcin and testosterone levels has not been understood in humans. METHODS: Sixty-nine male patients with type 2 diabetes were recruited and chemical bone markers [total osteocalcin (TOC), ucOC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type I collagen (uNTX)], gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], and free testosterone (FT) were measured. RESULTS: Multiple regression analysis showed that ucOC and ucOC/TOC ratio were associated positively with FT and negatively with LH (for ucOC, ß = 0.30, p = 0.042 and ß = -0.52, p = 0.048; for ucOC/TOC ratio, ß = 0.31, p = 0.031 and ß = -0.54, p = 0.036, respectively) independently of age, duration of diabetes, body mass index, and hemoglobin A1c. ucOC and ucOC/TOC ratio were significantly associated with FT even after adjusting for LH and FSH (ß = 0.24, p = 0.042 and ß = 0.25, p = 0.031, respectively). However, neither TOC, BAP, nor uNTX was associated with the gonadotropic hormones or FT levels. CONCLUSIONS: The present study indicates for the first time that ucOC is associated positively with FT and negatively with LH in type 2 diabetes. These findings support the recent evidence that ucOC is involved in testosterone production in male subjects.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Osteocalcina/sangre , Testosterona/sangre , Anciano , Biomarcadores/sangre , Estudios Transversales , Hemoglobina Glucada/análisis , Humanos , Hormona Luteinizante/sangre , Masculino , Persona de Mediana EdadRESUMEN
Adiponectin has attracted widespread attention because of its pivotal role in glucose metabolism and energy homeostasis. Adiponectin and its receptor are shown to be expressed in osteoblasts, suggesting that adiponectin might affect bone metabolism. A number of clinical studies have shown that serum adiponectin is negatively associated with bone mineral density (BMD) and positively with biochemical markers of bone turnover, suggesting that adiponectin may be a negative regulator of bone mass. However, most in vitro studies demonstrate that adiponectin stimulates the differentiation and mineralization of osteoblasts as well as the expression of osteocalcin. Adiponectin indirectly stimulates osteoclast differentiation via receptor activator for nuclear factor κB ligand and osteoprotegerin expression in osteoblasts, while adiponectin directly inhibits osteoclast activity and bone resorption. These in vitro findings suggest that adiponectin stimulates bone formation and remodeling as well as inhibits bone resorption. In contrast, previous in vivo studies using overexpression and knockout mice of adiponectin have produced controversial results. On the other hand, recent studies have shown that osteocalcin derived form osteoblasts acts as a hormone regulating glucose metabolism and fat mass. Osteocalcin could decrease fat pads and stimulate the expression of adiponectin in adipocytes, suggesting that bone metabolism is associated with fat metabolism through adiponectin and osteocalcin. In this review, I summarize the effect of adiponectin on osteoblasts and osteoclasts in vitro and in vivo, the association of adiponectin with BMD and bone markers in humans, and the role of adiponectin in the endocrine loop between bone and fat metabolism.
Asunto(s)
Adiponectina/metabolismo , Enfermedades Óseas Metabólicas/metabolismo , Tejido Adiposo/metabolismo , Animales , Huesos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fracturas Óseas/metabolismo , Humanos , Osteoblastos/citología , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Receptores de Adiponectina/metabolismoRESUMEN
BACKGROUND: Although accumulating evidence shows that aging hormones are involved in glucose metabolism, effects of glycemic control on serum IGF-I and DHEAS levels are still unclear. OBJECTIVE AND METHODS: To investigate the effects of glycemic control on these hormone levels, we conducted a 1-month longitudinal study of 49 Japanese patients with Type 2 diabetes mellitus. We measured serum levels of IGF-I and DHEA-S before and after 1-month glycemic control and analyzed the association of changes in IGF-I and DHEA-S with glycated hemoglobin (HbA1c). RESULTS: HbA1c was decreased at 1 month with mean changes of -1.2% (p<0.001). Serum IGF-I was increased with mean changes of 11 ng/ml (p<0.05), while serum DHEA-S was decreased with mean changes of -19 µg/dl (p<0.05). Multiple regression analysis showed that changes in DHEA-S were inversely associated with changes in fasting plasma glucose (ß=-0.36, p=0.027) and HbA1c (ß=-0.33, p=0.028), while changes in IGF-I were not. CONCLUSION: The present longitudinal study showed that intensive glycemic control for 1 month increased serum IGF-I level and decreased serum DHEA-S level in Japanese patients with poorly controlled Type 2 diabetes. Further studies are needed to clarify the hormonal changes in IGF-I and DHEA-S after intensive glycemic control would affect diabetic complications.
Asunto(s)
Glucemia/metabolismo , Sulfato de Deshidroepiandrosterona/sangre , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Anciano , Envejecimiento/fisiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ayuno , Femenino , Estudios de Seguimiento , Hormonas/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
OBJECTIVE: Accumulation of advanced glycation end products (AGEs) is associated with age- and diabetes-related disease. The aim of the present study is to investigate the effects of metformin or pioglitazone on serum pentosidine levels, a well-defined AGE, in type 2 diabetes. RESEARCH DESIGN AND METHODS: 66 Japanese patients were enrolled in this 6 months open-label study. In the metformin (n=22), the pioglitazone (n=22), and the control (optimal diet therapy, sulfonylurea and/or insulin) groups (n=22), serum levels of HbA (1c) and pentosidine were measured at baseline and 6 months after each treatment. RESULTS: HbA (1c) and pentosidine levels were not different at baseline among 3 groups, and HbA(1c) was significantly decreased at 6 months in each group. In the metformin and the pioglitazone groups, serum pentosidine levels were significantly decreased at 6 months after treatments (p=0.039 and p=0.031, respectively). Percent changes in pentosidine levels in the metformin and the pioglitazone groups were significantly lower than that in the control group (p=0.012 and p=0.019, respectively). CONCLUSION: 6 months treatments with metformin or pioglitazone in clinical doses decreased serum pentosidine levels which resulted in greater %change of serum pentosidine levels than the control group, suggesting that these agents may prevent the diabetic complications associated with AGEs accumulation.
Asunto(s)
Arginina/análogos & derivados , Diabetes Mellitus Tipo 2/sangre , Lisina/análogos & derivados , Metformina/farmacología , Tiazolidinedionas/farmacología , Anciano , Arginina/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Hemoglobina Glucada/análisis , Productos Finales de Glicación Avanzada/sangre , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Lisina/sangre , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Pioglitazona , Tiazolidinedionas/uso terapéutico , Factores de TiempoRESUMEN
UNLABELLED: Although previous studies indicated that serum insulin-like growth factor-I (IGF-I) was inversely associated with the presence of vertebral fractures (VFs), little is known whether serum IGF-I is associated with multiple VFs. We report that serum IGF-I could be clinically useful for assessing the severity of VFs in type 2 diabetic postmenopausal women. INTRODUCTION: The number of VFs is associated with the mobility and mortality of the elderly people. Although serum IGF-I is inversely associated with the presence of VFs, little is known about the relationship between serum IGF-I and multiple VFs. METHODS: In this cross-sectional study, we recruited 479 men and 334 postmenopausal women with type 2 diabetes mellitus and measured serum IGF-I, bone mineral density, and bone turnover markers. Lateral X-ray films of the thoracic and lumbar spine were taken to diagnose the VF. RESULTS: In postmenopausal women, serum IGF-I level was decreased when the number of VFs was increased [no VFs; 138 ± 51 ng/ml (mean ± SD) vs. one VF; 119 ± 42 (p = 0.006), two VFs; 103 ± 39 (p = 0.002), and three and more VFs; 91 ± 40 (p < 0.001)]. Multiple logistic regression analysis adjusted for age, duration of diabetes, body mass index, serum creatinine, and HbA(1c) showed that serum IGF-I level was inversely associated with the presence of one VF [odds ratio (OR) = 0.67, p = 0.029], two VFs (OR = 0.40, p = 0.017), as well as three and more VFs (OR = 0.27, p = 0.005). These associations were still significant after the additional adjustment for BMD at the lumbar spine. In contrast, no significant association of serum IGF-I level with VFs was found in men. CONCLUSIONS: Serum IGF-I level was inversely associated with the number of prevalent VFs in postmenopausal women with type 2 diabetes, suggesting that serum IGF-I could be clinically useful for assessing the severity of VFs in the population.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Factor I del Crecimiento Similar a la Insulina/análisis , Fracturas Osteoporóticas/etiología , Fracturas de la Columna Vertebral/etiología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Índice de Masa Corporal , Densidad Ósea/fisiología , Creatinina/sangre , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Fracturas Osteoporóticas/sangre , Fracturas Osteoporóticas/fisiopatología , Factores Sexuales , Fracturas de la Columna Vertebral/sangre , Fracturas de la Columna Vertebral/fisiopatologíaRESUMEN
UNLABELLED: Although recent animal studies have shown that undercarboxylated osteocalcin acts as a hormone regulating glucose metabolism and fat mass, little is known about the relationships in humans. We reported here for the first time that undercarboxylated osteocalcin were associated with glucose/fat metabolism in patients with type 2 diabetes. INTRODUCTION: Recent studies have shown that undercarboxylated osteocalcin (ucOC) acts as a hormone regulating glucose metabolism and fat mass. We investigated the relationship between ucOC as well as other bone turnover markers [serum OC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type-I collagen] versus serum levels of glucose, fasting serum C-peptide, and adiponectin as well as the amount of fat mass in type 2 diabetes. METHODS: A total of 180 men and 109 postmenopausal women were consecutively recruited, and radiographic and biochemical characteristics were collected. Fat mass was measured by dual X-ray absorptiometry (DXA) and computed tomography (CT). RESULTS: In men, ucOC negatively correlated with percent trunk fat (%trunk fat; by DXA) and visceral/subcutaneous fat ratio (by CT) as well as fasting plasma glucose and HbA(1c) (at least p < 0.05). Multiple regression analysis showed that these associations were still significant independent of age, duration of diabetes, body stature, and renal function as well as glucose or fat metabolism, whereas BAP, another bone formation marker, did not correlate with any variable. On the other hand, although ucOC also negatively correlated with %fat and %trunk fat as well as HbA(1c) (at least p < 0.05) in postmenopausal women, we found no significant association in multiple regression analysis. CONCLUSIONS: These findings suggest that ucOC is associated with plasma glucose level and fat mass in men with type 2 diabetes.
Asunto(s)
Tejido Adiposo/patología , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Osteocalcina/sangre , Absorciometría de Fotón/métodos , Adiponectina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Composición Corporal/fisiología , Remodelación Ósea/fisiología , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Posmenopausia/sangre , Grasa Subcutánea/patología , Tomografía Computarizada por Rayos X/métodos , Adulto JovenRESUMEN
SUMMARY: We found that serum osteocalcin, femoral bone mineral density (F-BMD), and 1/3R-BMD were decreased during pioglitazone treatment in patients with type 2 diabetes. Moreover, baseline atherosclerosis parameter, serum insulin-like growth factor-I (IGF-I), and urinary N-terminal cross-linked telopeptide of type I collagen (uNTX) values were associated with changes in bone mineral density (BMD). Therefore, these parameters could assess the risk of BMD reduction in patients treated with pioglitazone. INTRODUCTION: The aim of this study was to investigate the effects of pioglitazone or metformin on bone mass and atherosclerosis in patients with type 2 diabetes. METHODS: A total of 55 Japanese patients were enrolled in this 1-year open-label study and randomized to either pioglitazone (n = 22, 15-30 mg/day) or metformin (n = 23, 500-750 mg/day) groups. BMD at the lumbar spine, femoral neck (F), and one third of the radius (1/3R), bone markers, and atherosclerosis parameters were measured. RESULTS: In the pioglitazone group, serum osteocalcin significantly decreased at 6 months (p < 0.05), although it almost recovered to baseline level at 12 months. F-BMD significantly decreased at 6 months (p < 0.05), and 1/3R-BMD significantly decreased at 6 and 12 months (p < 0.05), while bone markers or BMD at any site were not changed in the metformin group. Although atherosclerosis parameters were not changed in the pioglitazone group, intima-media thickness (IMT)-mean significantly increased at 6 months (p < 0.05) and plaque score significantly increased at 6 and 12 months (p < 0.01) in the metformin group. In the pioglitazone group, %changes in F-BMD were significantly and negatively correlated with baseline IMT-Max, IMT-mean, and plaque scores (r = -0.61, p < 0.01; r = -0.71, p < 0.01; and r = -0.68, p < 0.01, respectively), and %changes in 1/3R-BMD were significantly and negatively correlated with baseline uNTX and IMT-Max (r = -0.57, p < 0.01 and r = -0.48, p < 0.05, respectively) and positively with IGF-I (r = 0.45, p < 0.05). CONCLUSIONS: Baseline IMT, uNTX, and IGF-I could assess the risk of BMD reduction in diabetic patients treated with pioglitazone.
Asunto(s)
Aterosclerosis/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Osteoporosis/inducido químicamente , Tiazolidinedionas/efectos adversos , Anciano , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/metabolismo , Biomarcadores/metabolismo , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Colágeno/orina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Cuello Femoral/fisiopatología , Humanos , Hipoglucemiantes/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Vértebras Lumbares/fisiopatología , Masculino , Metformina/efectos adversos , Metformina/uso terapéutico , Persona de Mediana Edad , Osteocalcina/sangre , Osteoporosis/metabolismo , Osteoporosis/fisiopatología , Pioglitazona , Radio (Anatomía)/fisiopatología , Medición de Riesgo/métodos , Tiazolidinedionas/uso terapéutico , UltrasonografíaRESUMEN
It is well known that parathyroid hormone (PTH) possesses an anabolic effect on bone. However, the mechanisms are not fully elucidated. So far, it is unclear whether or not PTH could stimulate the expression of bone morphogenetic protein-2 (BMP-2), a strong mediator for bone formation. Growing evidence suggests that BMP-2 expression is regulated by the mevalonate pathway and Rho-associated protein kinase (ROK) activity. This study was performed to examine if PTH affects BMP-2 expression and to clarify its involvement of the mevalonate pathway. Osteoblastic MC3T3-E1 cells were treated with human PTH-(1-34) to determine BMP-2 mRNA expression levels by real-time PCR and to measure the ROK activity by the kinase assay. Incubation with 10 (-9)-10 (-8) M of hPTH-(1-34) for 6 h induced significant upregulation of BMP-2 mRNA levels in MC3T3-E1 cells. Short-term treatment of hPTH-(1-34) suppressed Rho kinase activity and mevalonate kinase mRNA levels. PTH-induced BMP-2 mRNA upregulation was selectively reversed by geranylgeranyl pyrophosphate (GGPP) pretreatment, but not by mevalonate pretreatment. These findings suggest that BMP-2 mRNA expression was upregulated by PTH in MC3T3-E1 cells mediated by mevalonate pathway suppression followed by ROK inhibition. We have now demonstrated for the first time that PTH stimulated BMP-2 mRNA expression via the mevalonate pathway and ROK in osteoblastic MC3T3-E1 cells.
Asunto(s)
Proteína Morfogenética Ósea 2/genética , Osteoblastos/efectos de los fármacos , Osteoblastos/enzimología , Hormona Paratiroidea/farmacología , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Regulación hacia Arriba/efectos de los fármacos , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Proteína Morfogenética Ósea 2/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Biológicos , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfatos de Poliisoprenilo/farmacología , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
We used dexamethasone (DEX)-treated osteoblastic MC3T3-E1 cells, and investigated the effects of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta- D-ribonucleoside (AICAR), a Rho-associated protein kinase inhibitor, fasudil hydrochrolide, as well as HMG-CoA reductase inhibitors, simvastatin and pitavastatin, all of which inhibit the mevalonate pathway. DEX (10(-8) M) significantly enhanced mRNA expression of bone morphogenetic protein (BMP)-2 antagonists, follistatin and Dan, and addition of each of 10 (-4) M AICAR, 10 (-5) M fasudil, 10(-6) M simvastatin, and 10(-6) M pitavastatin significantly reversed the enhancement in mRNA expression of follistatin and Dan and stimulated that of BMP-2 in the cells (p<0.05). DEX (10(-8) M) also significantly suppressed mineralization in the cells, and addition of each of these agents significantly reversed the suppression of mineralization (p<0.05). These findings suggest that the mevalonate pathway was involved in glucocorticoid-induced osteoblast dysfunction, and that its inhibition might promote bone formation through BMP-2 and alleviate glucocorticoid-induced osteoporosis.
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Proteína Morfogenética Ósea 2/metabolismo , Calcificación Fisiológica/efectos de los fármacos , Dexametasona/farmacología , Regulación hacia Abajo , Ácido Mevalónico/metabolismo , Osteoblastos/fisiología , Transducción de Señal/efectos de los fármacos , Animales , Proteína Morfogenética Ósea 2/genética , Línea Celular , Expresión Génica/efectos de los fármacos , Ratones , Osteoblastos/efectos de los fármacosRESUMEN
OBJECTIVE: To assess corticospinal tract involvement in patients with amyotrophic lateral sclerosis (ALS) by correlating diffusion tensor imaging (DTI) measures with intra- and extracranial central motor conduction time (CMCT) and clinical features of the patients. METHODS: We investigated 31 patients with ALS and 31 normal volunteers by DTI and measured fractional anisotropy (FA) within the corticospinal tracts and in the extramotor white matter. We measured CMCT for the first dorsal interosseous muscle and segmented it into cortical-brainstem (CTX-BS CT) and brainstem-cervical root (BS-CV CT) conduction times by magnetic brainstem stimulation at the foramen magnum level. Clinical status of each patient was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and upper motor neuron (UMN) score devised for this study. RESULTS: We found a significant decrease of mean FA in all regions of the corticospinal tracts in patients with ALS as compared with controls. We found that FA along the corticospinal tract decreased significantly with higher UMN scores. There was no significant correlation between FA and ALSFRS-R, to which both upper and lower motoneuron involvements contribute. FA showed a significant correlation with the intracranial part of the central motor conduction (CTX-BS CT) but not with the extracranial conduction time. CONCLUSIONS: Fractional anisotropy reflects functional abnormality of intracranial corticospinal tracts and can be used for objective evaluation of upper motor neuron impairment in amyotrophic lateral sclerosis.
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Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/fisiopatología , Imagen de Difusión por Resonancia Magnética/métodos , Electrodiagnóstico/métodos , Tractos Piramidales/patología , Tractos Piramidales/fisiopatología , Adulto , Anciano , Anisotropía , Tronco Encefálico/fisiopatología , Estimulación Eléctrica , Humanos , Persona de Mediana Edad , Corteza Motora/patología , Corteza Motora/fisiopatología , Neuronas Motoras/patología , Conducción Nerviosa/fisiología , Valor Predictivo de las Pruebas , Tiempo de Reacción , Factores de TiempoRESUMEN
UNLABELLED: Multivariate logistic regression analysis showed that serum IGF-I level was significantly lower in postmenopausal diabetic women with vertebral fractures than in those without fractures. Serum IGF-I level could be clinically useful for assessing the risk of vertebral fractures independent of BMD in postmenopausal women with type 2 diabetes. INTRODUCTION: We investigated the relationships among serum IGF-I and C-peptide levels, BMD, and vertebral fractures in postmenopausal women with type 2 diabetes. METHODS: A total of 131 postmenopausal women with type 2 diabetes were consecutively recruited, and radiographic and biochemical characteristics were collected. RESULTS: Either IGF-I or C-peptide was not correlated with BMD at any site or bone metabolic markers, such as osteocalcin (OC) and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX). However, serum IGF-I level was significantly lower in subjects with vertebral fractures than in those without fractures (mean +/- SD: 106.9 +/- 50.0 vs. 142.8 +/- 50.8 ng/ml, p = 0.0006). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and serum IGF-I adjusted for the parameters described above as independent variables, IGF-I was selected as an index affecting the presence of vertebral fractures [odds ratio = 0.436, 95% confidential interval 0.234-0.814 per SD increase, p = 0.0092]. This significance was almost the same after additional adjustment for lumbar BMD or C-peptide. CONCLUSIONS: Serum IGF-I level could be clinically useful for assessing the risk of vertebral fractures independent of BMD in postmenopausal women with type 2 diabetes.
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Diabetes Mellitus Tipo 2/complicaciones , Factor I del Crecimiento Similar a la Insulina/análisis , Fracturas de la Columna Vertebral/etiología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biomarcadores/orina , Densidad Ósea , Péptido C/sangre , Colágeno/orina , Diabetes Mellitus Tipo 2/sangre , Femenino , Humanos , Persona de Mediana Edad , Osteocalcina/sangre , Fracturas de la Columna Vertebral/sangreRESUMEN
Study of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE) revealed that almost all cases of distal myopathy with rimmed vacuoles were caused by GNE mutations. Seven new mutations were identified, including M712T, which is the most common mutation in Jewish hereditary inclusion body myopathy. In addition, a splice-variant characteristic of the skeletal muscle was found, whereas the difference of the expression level between GNE-mutated and -nonmutated patients was not apparent.
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Carbohidrato Epimerasas/genética , Músculo Esquelético/patología , Distrofias Musculares/genética , Distrofias Musculares/patología , Mutación , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Vacuolas/patología , Adolescente , Adulto , Edad de Inicio , Pueblo Asiatico/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Fibras Musculares Esqueléticas/patología , Enfermedades Musculares , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vacuolas/genéticaRESUMEN
Compared with 87 unventilated patients with Guillain-Barré syndrome (GBS), 44 ventilated patients with GBS more frequently had multiple cranial nerve involvement (91 vs 50%; p < 0.001) and IgG anti-GQ1b antibody (27 vs 8%; p = 0.006). In GBS patients without ophthalmoparesis, the presence of IgG anti-GQ1b antibody was associated with respiratory failure (12 [3/25] vs 0% [0/67]; p = 0.04). The presence of the antibody may be a factor predictive of respiratory failure in GBS.
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Anticuerpos Antiidiotipos/inmunología , Gangliósidos/inmunología , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/fisiopatología , Respiración Artificial , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/inmunología , Adulto , Progresión de la Enfermedad , Femenino , Síndrome de Guillain-Barré/complicaciones , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana EdadRESUMEN
The authors identified two Japanese spinocerebellar ataxia (SCA) families characterized by postural and action tremor and a very slow progression rate. A genome-wide linkage analysis revealed linkage to chromosome 3p26.1-25.3 with the highest multipoint lod score at D3S3728 (Zmax = 3.31 at theta = 0.00). The candidate region was 14.7 cM flanked by D3S1620 and D3S3691, which was partly overlapping with the locus of SCA15 characterized by pure cerebellar ataxia. Despite the difference in phenotypes, there remains a possibility that the causative gene for these Japanese SCA is allelic to SCA15.
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Cromosomas Humanos Par 3/genética , Ataxias Espinocerebelosas/genética , Adulto , Alelos , Progresión de la Enfermedad , Femenino , Genes Dominantes , Heterogeneidad Genética , Humanos , Japón/epidemiología , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Ataxias Espinocerebelosas/epidemiologíaRESUMEN
BACKGROUND: The authors previously reported that immunoglobulin G (IgG) antibody to the ganglioside N-acetylgalactosaminyl GD1a (GalNAc-GD1a) is associated with the pure motor variant of Guillain-Barré syndrome (GBS). Elucidation of the localization of GalNAc-GD1a in human peripheral nerve tissue may lead to understanding of the pathogenetic role of anti-GalNAc-GD1a antibody in GBS. METHODS: IgG anti-GalNAc-GD1a-monospecific antibody was purified from anti-GalNAc-GD1a antibody-positive rabbit sera through an affinity column. Anti-neurofilament-200 monoclonal and anti-HNK-1 monoclonal antibodies were used as the markers for axon and myelin. Immunohistochemical study using double fluorescence labeling technique was conducted in human ventral roots (VR), dorsal roots (DR), intramuscular nerves, and sural nerves. Human teased ventral fibers also were studied. RESULTS: Anti-GalNAc-GD1a antibody immunostained an inner part of compact myelin and additionally a periaxonal-axolemma-related portion in the VR, small-diameter DR fibers, and IM nerves. In sural nerves, small fibers were selectively stained. In VR, the staining was localized in the paranodal region. CONCLUSION: Anti-GalNAc-GD1a antibodies in patients' sera may bind to those regions in the VR and IM nerves where GalNAc-GD1a is localized, and may function in the pathogenesis of pure motor type GBS. Further investigation is needed to explain the discrepancy between the immunolocalization of GalNAc-GD1a in sensory nerves and the absence of sensory disturbance in patients with GBS with IgG anti-GalNAc-GD1a antibodies.
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Autoanticuerpos/inmunología , Autoantígenos/inmunología , Epítopos/inmunología , Gangliósidos/inmunología , Nervios Periféricos/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Reacciones Antígeno-Anticuerpo , Autoantígenos/análisis , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Epítopos/análisis , Femenino , Gangliósidos/análisis , Síndrome de Guillain-Barré/inmunología , Humanos , Inmunización , Inmunoglobulina G/inmunología , Microscopía Fluorescente , Músculo Esquelético/inervación , Fibras Nerviosas/química , Fibras Nerviosas/inmunología , Nervios Periféricos/química , Conejos , Raíces Nerviosas Espinales/química , Raíces Nerviosas Espinales/inmunología , Nervio Sural/química , Nervio Sural/inmunologíaRESUMEN
Organotypic slice co-culture of the ventromedial portion of the mesencephalon and striatum was used to evaluate the neurotoxicity of 1-benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous brain amine related to Parkinson's disease. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline is specifically increased in the cerebrospinal fluid of patients with Parkinson's disease and induces parkinsonian features in the monkey and mouse. Here, it decreased the dopamine content of the cultured mesencephalon in both dose- (10-100 microM) and time- (24 h to 7 days) dependent manners. This result suggests that the neurotoxicity of 1-benzyl-1,2,3,4-tetrahydroisoquinoline is correlated with the overall exposure (concentration multiplied by exposure time). Culture with 100 microM 1-benzyl-1,2,3,4-tetrahydroisoquinoline for 24 h irreversibly reduced the dopamine content. Furthermore, culture with 100 microM 1-benzyl-1,2,3,4-tetrahydroisoquinoline for 10 days caused morphological changes, including cell body shrinkage and distortion of dendritic morphology, in tyrosine hydroxylase-positive cells in the mesencephalon and reduced the number of cells by half. The increase in lactate dehydrogenase activity in the media produced by 1-benzyl-1,2,3,4-tetrahydroisoquinoline was significant in culture of the mesencephalon alone or its co-culture with striatum, but not in cultures of other brain regions. We suggest that 1-benzyl-1,2,3,4-tetrahydroisoquinoline is toxic to tyrosine hydroxylase-positive cells in the ventral mesencephalon and that it is correlated with the integral of the concentration by time of exposure. Thus a low concentration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline may first induce a decrease in the dopamine content then shrinkage of the cell body, followed by the slow death of dopaminergic neurons over a long period. This is the first report that indicates 1-benzyl-1,2,3,4-tetrahydroisoquinoline exerts neurotoxicity at the cellular level, and reveals in part the character of its neurotoxicity.