Assessment using serum insulin-like growth factor-I and bone mineral density is useful for detecting prevalent vertebral fractures in patients with type 2 diabetes mellitus.

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.

Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus.

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.

Serum osteocalcin levels are inversely associated with abdominal aortic calcification in men with type 2 diabetes mellitus.

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.

Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain.

Dentatorubral-pallidoluysian atrophy (DRPLA) is associated with the expansion of an unstable CAG repeat. Using antibodies against a synthetic peptide corresponding to the sequence of the DRPLA gene product C terminus, we have identified the DRPLA gene product in normal human brains as a approximately 190 kD protein. We also find a larger approximately 205 kD protein specifically in DRPLA brains. Immunohistochemically, the DRPLA gene product is observed mainly in the neuronal cytoplasm. Our results demonstrate the existence of the expanded CAG repeat gene product and support the possibility that the expanded CAG-encoded polyglutamine stretch may participate in the pathological process of the similar trinucleotide repeat diseases.

Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease.

A specific isoform of apolipoprotein E has been associated with the accelerated rate of disease expression of sporadic Alzheimer's disease (AD) and late-onset familial AD (FAD). An earlier age at onset has also been demonstrated in familial AD patients with mutations in the amyloid precursor protein (APP) gene (APP717 and APP670/671)13 carrying the APOE epsilon-4 allele compared to those who do not, but not in familial AD patients with APP692 or 693 mutations, or in chromosome 14-linked familial AD patients. Hypothesizing that receptors for apoE-containing lipoproteins act as a potential risk factor for AD, we performed an association study using a polymorphic triplet (CGG) repeat in the gene for the VLDL receptor (VLDL-R), a receptor for apoE-containing lipoproteins. The frequency of the 5-repeat allele was significantly higher in all of the Japanese sporadic AD patients (P < 0.02) than in the Japanese controls. Moreover, the odds ratio was significantly increased in the AD patients homozygous for the 5-repeat allele (OR = 2.1, 95% CI = [1.1-4.2]). Multiple logistic regression analysis reveals that the relative risk conferred by the presence of two copies of the 5-repeat allele and at least one copy of the APOE epsilon-4 allele is 8.7 (95% CI = [2.9-25.8]). Our results suggest that the VLDL-R gene is a susceptibility gene for AD.

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.

Huntington disease (HD) is associated with the expansion of a polyglutamine tract, greater than 35 repeats, in the HD gene product, huntingtin. Here we describe a novel huntingtin interacting protein, HIP1, which co-localizes with huntingtin and shares sequence homology and biochemical characteristics with Sla2p, a protein essential for function of the cytoskeleton in Saccharomyces cerevisiae. The huntingtin-HIP1 interaction is restricted to the brain and is inversely correlated to the polyglutamine length in huntingtin. This provides the first molecular link between huntingtin and the neuronal cytoskeleton and suggests that, in HD, loss of normal huntingtin-HIP1 interaction may contribute to a defect in membrane-cytoskeletal integrity in the brain.

Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.

At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

Effects of intensive glycemic control on serum levels of insulin-like growth factor-I and dehydroepiandrosterone sulfate in Type 2 diabetes mellitus.

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.

Serum insulin-like growth factor-I is a marker for assessing the severity of vertebral fractures in postmenopausal women with type 2 diabetes mellitus.

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.

Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus.

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.

Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus.

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.

Bcl-2 inhibits retinoic acid-induced apoptosis during the neural differentiation of embryonal stem cells.

We report here that all trans-retinoic acid (RA), a classical morphogen, induces apoptosis during the neural differentiation of the embryonic stem cell line P19. The apoptotic cells showed, in addition to DNA cleavage, typical morphological changes including chromatin condensation, nuclear fragmentation, and cytoplasmic vacuolation. These apoptotic changes became obvious by 12 h after the addition of RA. The endogenous expression of bcl-2 in surviving cells was down-regulated during this process, and the compelled expression of bcl-2 by retroviral vectors reduced the number of apoptotic cells. Apoptosis was partially inhibited by adding antisense oligonucleotides against RA receptors (RARs) simultaneously or by transfecting a plasmid vector flanked with a RA-responsive element. Antisense oligonucleotides against retinoid X receptors (RXRs), the receptors for 9 cis-RA, did not inhibit apoptosis induced by all trans-RA. Cycloheximide and actinomycin D, inhibitors of protein and RNA syntheses, respectively, suppressed apoptosis. No changes were seen in the expression of tumor necrosis factors, their receptors, Fas, FasL, p53, or c-myc, molecules which have been suggested to participate in the apoptotic process. Addition of neurotrophins to the culture medium did not affect apoptosis. These findings suggest that the signals themselves, promote expression of molecules essential for apoptosis. Furthermore, we observed that RA induced apoptosis of cerebral neurons from murine embryos in primary culture, which suggests that RA might participate in cell death which occurs during neural development.

Presenilin 1 suppresses the function of c-Jun homodimers via interaction with QM/Jif-1.

Presenilin 1 (PS1) is the causative gene for an autosomal dominant familial Alzheimer's disease (AD) mapped to chromosome 14. Here we show that QM/Jun-interacting factor (Jif)-1, a negative regulator of c-Jun, is a candidate to mediate the function of PS1 in the cell. We screened for proteins that bind to PS1 from a human embryonic brain cDNA library using the two-hybrid method and isolated one clone encoding the QM/Jif-1 gene. The binding of QM/Jif-1 to full-length PS1 was confirmed in vitro by pull-down assay, and in vivo by immunoprecipitation assays with human samples, including AD brains. Immunoelectronmicroscopic analysis showed that QM/Jif-1 and PS1 are colocalized at the endoplasmic reticulum, and the nuclear matrix in human brain neurons. Chloramphenicol acetyltransferase assays in F9 cells showed that PS1 suppresses transactivation by c-Jun/c-Jun but not by c-Jun/c-Fos heterodimers, consistent with the reported function of QM/Jif-1. By monitoring fluorescent recombinant protein and by gel mobility shift assays, PS1 was shown to accelerate the translocation of QM from the cytoplasm to the nucleus and to thereby suppress the binding of c-Jun homodimer to 12-O-tetradecanoylphorbol-13- acetate (TPA)-responsive element (TRE). PS1 suppressed c-jun-associated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas this suppression of apoptosis is attenuated by mutation in PS1. Collectively, the novel function of PS1 via QM/Jif-1 influences c-jun-mediated transcription and apoptosis.

Endothelin: a novel peptide in the posterior pituitary system.

Endothelin (ET), originally characterized as a 21-residue vasoconstrictor peptide from endothelial cells, is present in the porcine spinal cord and may act as a neuropeptide. Endothelin-like immunoreactivity has now been demonstrated by immunohistochemistry in the paraventricular and supraoptic nuclear neurons and their terminals in the posterior pituitary of the pig and the rat. The presence of ET in the porcine hypothalamus was confirmed by reversed-phase high-pressure liquid chromatography and radioimmunoassay. Moreover, in situ hybridization demonstrated ET messenger RNA in porcine paraventricular nuclear neurons. Endothelin-like immunoreactive products in the posterior pituitary of the rat were depleted by water deprivation, suggesting a release of ET under physiological conditions. These findings indicate that ET is synthesized in the posterior pituitary system and may be involved in neurosecretory functions.

Inhibition of the mevalonate pathway rescues the dexamethasone-induced suppression of the mineralization in osteoblasts via enhancing bone morphogenetic protein-2 signal.

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.

Parathyroid hormone upregulates BMP-2 mRNA expression through mevalonate kinase and Rho kinase inhibition in osteoblastic MC3T3-E1 cells.

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.

Elevated Serum Pentosidine and Decreased Serum IGF-I Levels are Associated with Loss of Muscle Mass in Postmenopausal Women with Type 2 Diabetes Mellitus.

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.

Gene regulation of trkB and trkC in the chick retina by light/darkness exposure.

The trk gene family members; the neurotrophic receptors for neurotrophins, are implicated in the survival and the differentiation of neurons. The roles of these protooncogenes have been argued in the pathological conditions and in the specific developmental stage when the programmed cell death occurs to neurons. Here we studied a physiological role of the trk family members in the retina through observations of their gene regulation by light/darkness exposure. Northern blot analysis and immunohistochemistry demonstrate that trkB and trkC are up-regulated by light exposure and down-regulated by darkness in the rod/cone layer, the outer nuclear layer, and the ganglion cell layer. This physiological regulation suggests that these trk family members play a protective role from the damaging effect of light exposure in the retinal neurons.

Hemispheric lateralization in the cortical motor preparation for human vocalization.

To investigate the cortical information processing during the preparation of vocalization, we performed transcranial magnetic stimulation (TMS) over the cortex while the subjects prepared to produce voice in response to a visual cue. The control reaction time (RT) of vocalization without TMS was 250-350 msec. TMS prolonged RT when it was delivered up to 150-200 msec before the expected onset of voice (EOV). The largest delay of RT was induced bilaterally over points 6 cm to the left and right of the vertex (the left and right motor areas), resulting in 10-20% prolongation of RT. During the early phase of prevocalization period (50-100 msec before EOV), the delay induced over the left motor area was slightly larger than that induced over the right motor area, whereas, during the late phase (0-50 msec before EOV), it was significantly larger over the right motor area. Bilateral and simultaneous TMS of the left and right motor areas induced delays not significantly different from that induced by unilateral TMS during the early phase, but induced a large delay well in excess of the latter during the late phase. Thus, during the cortical preparation for human vocalization, alternation of hemispheric lateralization takes place between the bilateral motor cortices near the facial motor representations, with mild left hemispheric predominance at the early phase switching over to robust right hemispheric predominance during the late phase. Our results also suggested involvement of the motor representation of respiratory muscles and also of supplementary motor cortex.