Dosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosis.

Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P < 0.05). Because an elevated concentration of PAI-1 is known to be associated with the risk of venous thromboembolism, the findings of the present study suggest that the dosing time of raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene.

Granulomatous pachymeningitis around the sella turcica (Tolosa-Hunt syndrome) involving the hypophysis--case report.

A 50-year-old female presented with right painful abducens nerve palsy persisting for 4 months and mild panhypopituitarism with diabetes insipidus for 6 months. T(1)-weighted magnetic resonance (MR) imaging of the sellar region showed a homogeneously enhanced mass lesion in the right cavernous sinus which seemed to extend from the swollen pituitary gland. T(2)-weighted MR imaging clearly showed the mass in the right cavernous sinus and the thickened dura mater of the sellar floor as hypointense, and the enlarged pituitary gland as isointense. Biopsy of the thickened dura mater and swollen pituitary gland was performed via the transsphenoidal approach. Histological examination revealed inflammation and collagen fiber formation in these regions. The diagnosis was secondary panhypophysitis resulting from granulomatous pachymeningitis involving the cavernous sinus (Tolosa-Hunt syndrome). Corticosteroid therapy was begun after the biopsy. Her periorbital pain and diplopia were relieved, but diabetes insipidus persisted. Follow-up MR imaging showed a decrease in the volumes of the pituitary gland and the mass in the cavernous sinus.

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy.

The relationship between the effect of aldose reductase inhibitors (ARIs) on the activation of the polyol pathway and on diabetic neuropathy has not been fully established. To address this issue, we investigated the effect of epalrestat (150 mg/day), an ARI, on erythrocyte sorbitol levels as an index of polyol activation and on nerve function test results in 43 patients with diabetic peripheral polyneuropathy. After 6 months of epalrestat administration, erythrocyte sorbitol levels did not decrease in patients as a whole. However, a decrease in erythrocyte sorbitol levels during epalrestat administration was significantly correlated with baseline erythrocyte sorbitol levels (rho=-.47, P<.01): The higher the level at baseline, the greater the decrease after epalrestat treatment. Moreover, the mean sorbitol level during epalrestat treatment was associated with the beneficial effect of epalrestat on vibration sensitivity as measured with a C-128 tuning fork (rho=-.66, P<.01) and/or a pallesthesiometer TM-31A (rho=.53, P<.05). On the other hand, erythrocyte sorbitol levels did not reflect the prognosis of nerve conduction velocity. These findings at least partly suggest a causal relationship between polyol activation and the development of diabetic neuropathy. Aldose reductase inhibitor treatment may be clinically useful in the control of polyol activation, especially in patients with excessive accumulation of sorbitol.

Pancreatic exocrine and endocrine events occur concomitantly but independently during the course of fulminant type 1 diabetes.

Although pancreatic exocrine enzymes are often elevated in patients with fulminant type 1 diabetes, the onset of this elevation and its significance in disease development remain unclear. We therefore investigated the significance of elevated serum enzyme concentrations and pancreatic swelling in the development of fulminant type 1 diabetes. Serum pancreatic exocrine enzymes, including amylase, elastase-I, lipase and trypsin, were measured during the course of the disease in 11 patients with fulminant type 1 diabetes (3 men and 8 women; a range of age 24-73 years, median 33 years; a range of HbA1c at onset 4.5-6.7%, median 6.0%), all of whom developed ketotic diabetes requiring intensive insulin therapy within a month. At least one pancreatic exocrine enzyme was elevated in each patient during the course of the disease. The concentration of enzymes on admission could not be correlated with urinary excretion of C-peptide. The time course of increase in serum amylase varied in these patients. In conclusion, neither the level of serum amylase nor the swelling of pancreas was associated with the onset or severity of fulminant type 1 diabetes. The pancreatic exocrine and endocrine events may occur concomitantly but independently during the course of fulminant type 1 diabetes.

Significance of IA-2 antibody in Japanese type 1 diabetes: its association with GAD antibody.

To investigate the presence and level of serum antibodies to IA-2 (IA-2A) in Japanese patients with adult type 1 diabetes in order to clarify its association with glutamic acid decarboxylase (GAD) antibody. Serum samples were obtained from 101 Japanese patients with type 1 diabetes, including 37 patients with slowly progressive form of type 1 diabetes. Serum levels of IA-2A and GADA were determined by radioimmunoassay. The study had a cross-sectional design. IA-2A and GADA were detected in 37 and 59% of these patients, respectively. Of the 37 slowly progressive form of patients, IA-2A and GADA were present in 49 and 86%, respectively (NS). GADA levels were significantly higher (P<0.05) in IA-2A positive than in IA-2A negative patients in slowly progressive form, but IA-2A levels did not differ significantly between GADA positive and GADA negative patients. Measuring IA-2A in combination with GADA is useful for the diagnosis and prognosis of type 1 diabetes in Japanese.

Gln27Glu polymorphism of the beta2 adrenergic receptor gene in healthy Japanese men is associated with the change of fructosamine level caused by exercise.

Adrenaline plays a major role in the maintenance of blood glucose level by promoting glycogenolysis during prolonged exercise predominantly via the beta2 adrenergic receptor (beta2AR). Because beta2ARs are mainly present in the muscle and liver, beta2AR gene polymorphism may affect changes in glucose metabolism caused by exercise. We, therefore, investigated the effect of beta2AR gene polymorphism on glucose metabolism in healthy Japanese men. The study group consisted of 124 unrelated healthy Japanese men who were aged 21-69 years (mean +/- S.D.: 45.3+/-11.7). They participated in an exercise program which was defined as low-moderate intensity at 20-60min per day, 2-3 days per week for 3 months. The genotype of Gln27Gln was detected in 109 subjects (87.9%), of Gln27Glu in 15 subjects (12.1%) and of Glu27Glu in none, and that of Arg16Arg, Arg16Gly and Gly16Gly in 32 (25.8%), 79 (63.7%) and 13 subjects (10.5%), respectively. There was no association between these polymorphisms and the metabolic characteristics at baseline. The change in fructosamine level as a result of exercise showed that the carrier of the Glu allele had a better response to exercise than the non-carrier. In conclusion, Gln27Glu polymorphism was associated with the change in fructosamine level resulting from exercise, but not Arg16Gly polymorphism.

Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells.

Plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherosclerosis in diabetic patients. PAI-1 is produced by endothelial cells stimulated with various inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, which induces insulin resistance. In diabetic patients, troglitazone, a thiazolidinedione, can lower the concentration of PAI-1. We investigated the TNF-alpha-induced signaling pathway that leads to PAI-1 synthesis and the target step of troglitazone in this pathway. TNF-alpha induced PAI-1 mRNA expression and protein production in human umbilical vein endothelial cells (HUVECs). A specific inhibitor for p38 mitogen-activated protein kinase, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580), and a protein kinase C inhibitor, calphostin C, had no inhibitory effects on TNF-alpha-induced PAI-1 secretion. A protein tyrosine kinase inhibitor, genistein, completely inhibited TNF-alpha-induced PAI-1 secretion, whereas an inhibitor of extracellular signal-regulated kinase (ERK) kinase, 2'-amino-3'-methoxyflavone (PD98059), and a nuclear factor-kappaB (NF-kappaB) inhibitor, emodin, partly inhibited TNF-alpha-induced PAI-1 secretion. Together, PD98059 and emodin completely inhibited TNF-alpha-induced PAI-1 secretion, suggesting that both NF-kappaB-dependent and NF-kappaB-independent pathways are involved in TNF-alpha-induced signal pathway to PAI-1 production and that the latter pathway is mediated by activation of ERK. Furthermore, we have shown that troglitazone inhibited both TNF-alpha-induced PAI-1 protein secretion and mRNA in HUVECs. Genistein, but neither PD98059 nor emodin, was additive to the inhibitory effect of troglitazone on TNF-alpha-induced PAI-1 secretion. These results indicate That ERK and NF-kappaB are possible targets of TNF-alpha and troglitazone in the regulation of PAI-1 production.

PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men.

Exercise training improves insulin sensitivity, but individual responses vary greatly. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a regulator of adipose cell differentiation and plays an important role in systemic insulin action. We investigated whether PPARgamma gene polymorphism affects insulin resistance in response to exercise in Japanese healthy men. The exercise program at an individual intensity of 50% of the maximal heart rate was performed for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical activity of 700 kcal/wk. The program was conducted for 3 months without any dietary intervention, and the clinical and metabolic characteristics were examined before and after the exercise program. Body mass index (BMI) did not change significantly after the exercise program, whereas percentage of body fat (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased significantly. Pro12Ala polymorphism in PPARgamma gene was performed on genomic DNA isolated from human leukocytes and examined with polymerase chain reaction (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the Ala allele did not correlate with fasting immunoreactive insulin (IRI) and homeostasis model assessment-insulin resistance index (HOMA-R) at baseline, but did so with the changes in IRI and HOMA-R after exercise (DeltaIRI, Pro/Pro 0.55 +/- 3.49 microU/mL v Pro/Ala -2.83 +/- 1.47 microU/mL, P <.05; DeltaHOMA-R, Pro/Pro 0.09 +/- 0.86 v Pro/Ala -0.61 +/- 0.32, P <.05). This result suggests that the Ala allele is associated with improvement in insulin resistance after exercise. We conclude that PPARgamma gene polymorphism may be a reliable indicator of whether exercise will have a beneficial effect as part of the treatment of insulin resistance syndrome.

Prediction of exercise-mediated changes in metabolic markers by gene polymorphism.

The effects of regular physical exercise on obesity-associated metabolic abnormalities vary for each individual. In this study, we investigated whether genotypes of genes associated with obesity can predict the effects of exercise on changes in metabolic markers in healthy men. Healthy Japanese men (n=106) performed the exercise program at 50% of their maximal heart rate for 20-60 min a day, 2-3 days each week for 3 months. The levels of fasting plasma glucose (FPG) and serum leptin significantly decreased after the exercise program. Polymorphisms of the beta3-adrenergic receptor (beta3AR) and uncoupling protein-1 (UCP-1) genes were analyzed with RFLP methods. In the Trp/Trp genotype of the beta3AR gene, the levels of serum leptin, FPG and fructosamine (FrAm) decreased significantly after the exercise program, but not in the Arg/Arg genotype. In the AG heterozygote and the GG homozygote of the UCP-1 gene, FPG and FrAm levels were significantly reduced, respectively. In conclusion, gene polymorphism of the beta3AR and UCP-1 was found to be associated with the exercise-mediated improvement in glucose tolerance and leptin resistance in healthy Japanese men.

Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat.

Recent reports have shown that thiazolidinediones have preventive effects on urinary albumin excretion in diabetes. However, the mechanism leading to these effects has not yet been elucidated. We studied here the effects of thiazolidinediones on albuminuria and hemodynamic and morphological changes in the kidneys of streptozotocin (STZ)-induced diabetic spontaneous hypertensive rats (SHRs). Diabetes was induced in SHRs by intravenous injection of STZ (50 mg/kg). The diabetic SHRs were divided into the following 3 groups: (1) STZ-SHRs given normal chow (STZ), (2) STZ-SHRs given chow mixed with 0.1% troglitazone (STZ + tro), and (3) STZ-SHRs given chow mixed with 0.001% pioglitazone (STZ + pio). Three groups of nondiabetic SHRs were also investigated: (4) SHR, (5) tro, and (6) pio. We evaluated the urinary albumin excretion rate (AER) every 4 weeks. After 12 weeks of treatment, the animals were killed and renal morphological examinations were performed. Thiazolidinediones did not affect blood pressure or blood glucose levels. Urinary AER were markedly increased in STZ-SHRs. After 12 weeks of treatment with thiazolidinediones, the urinary AER was significantly decreased while creatinine (Cr) clearance was left unchanged. Histologically, the loss of anionic sites of glomerular basement membranes (GBM) evaluated with polyetyleneimine was suppressed significantly in the diabetic SHRs treated with thiazolidinediones. In conclusion, administration of thiazolidinediones in diabetic SHRs decreased the urinary AER and suppressed the loss of anionic sites of GBM without affecting blood pressure, blood glucose levels, or Cr clearance. These results clarify the novel therapeutic action of thiazolidinediones on diabetic nephropathy.