HbA1c levels Measured by Enzymatic Assay and Immunoassay during Off-Site Health Checkups Are Both Lower than Those Measured by On-Site HPLC Assay.

It has already been reported that HbA1c levels measured by immunoassay (IA) (IA-HbA1c) during off-site health checkups present falsely lower results. We also reported that HbA1c levels measured by enzymatic assay (EA) (EA-HbA1c) during off-site health checkups are lower. In the present study, we compared IA-HbA1c levels or EA-HbA1c levels during off-site health checkups with on-site high-performance liquid chromatography (HPLC)-HbA1c levels using the same samples. Subjects were 88 non-diabetic individuals who had health checkups in Nishinomiya Municipal Central Hospital. Subjects with a history of diabetes mellitus and those with HPLC-HbA1c ≥ 6.5% were excluded. IA-HbA1c levels (Study 1) or EA-HbA1c levels (Study 2) in the health checkups were compared with on-site HPLC-HbA1c levels using the same samples. Both IA-HbA1c levels and EA-HbA1c levels had positive correlations with HPLC-HbA1c levels (p <0.0001 for both), although both were significantly lower than HPLC-HbA1c levels (p <0.0001 for both). The degrees of reductions in the IA-HbA1c levels and EA-HbA1c levels compared with HPLC-HbA1c levels were almost same to each other. Similarly to IA-HbA1c levels, EA-HbA1c levels during the health checkups were lower than HPLC-HbA1c levels. It was demonstrated that HbA1c levels decrease similarly if measured by either EA or IA during off-site health checkups.

Effects of alogliptin on the ratio of glycated albumin to HbA1c in patients with type 2 diabetes mellitus.

The ratio of glycated albumin (GA) to HbA1c (the GA/HbA1c ratio) has been used as a glycemic control indicator that reflects postprandial plasma glucose levels or glycemic variability. In this study, we investigated the effects of alogliptin, a DPP-4 inhibitor, on the GA/HbA1c ratio in patients with type 2 diabetes mellitus. Thirty-eight patients with type 2 diabetes mellitus whose glycemic control was stable were enrolled, and alogliptin (12.5 or 25 mg/day) was then administered to them for 24 weeks. HbA1c and GA levels both significantly decreased after 24 weeks (P < 0.0001), whereas the GA/HbA1c ratio did not (P = 0.129). No correlation was observed between the change in the GA/HbA1c ratio (the ΔGA/HbA1c ratio) and HbA1c or GA level before the administration of alogliptin; however, a negative correlation was found between the ΔGA/HbA1c ratio and the GA/HbA1c ratio before the administration of alogliptin (R = -0.322, P = 0.049). Although the GA/HbA1c ratio in the low-value group (<2.80) was not significantly affected by the administration of alogliptin, that in the high-value group (≥2.80) significantly decreased (P = 0.008). The administration of alogliptin significantly decreased the GA/HbA1c ratio in the high-value group after 24 weeks. Alogliptin may be more useful for patients with high postprandial plasma glucose levels than in those with low postplandial plasma glucose levels.

Association of urine acidification with visceral obesity and the metabolic syndrome.

Urine acidification is induced by metabolic acidosis which is associated with a high intake of protein-rich diet. The purpose of this study was to investigate the relationship of urine acidification with visceral obesity and the metabolic syndrome. We recruited 1,051 male subjects who underwent health examinations at the Health Care Center in Kinki Central Hospital. Subjects who were treated for hypertension, dyslipidemia, diabetes mellitus, and hyperuricemia and had the past history of chronic liver disease, chronic kidney disease and cancer, were excluded in this study. All subjects were administered to urine pH, blood and physical examinations. Lower urine pH was associated with higher serum urea nitrogen which reflects high intake of protein-rich diet, whereas it had no relation to serum creatinine. Lower urine pH was also associated with an increase in waist circumference, homeostasis model assessment-R, fasting plasma glucose, HbA1c, serum triglyceride, serum uric acid and with a decrease in high density lipoprotein cholesterol. Urine pH was not associated with mean blood pressure. Urine acidification is a characteristic of visceral obesity and the metabolic syndrome. High intake of protein-rich diet may contribute urine acidification, which is associated with various metabolic abnormalities in visceral obesity.

The thiazolidinedione drug troglitazone up-regulates nitric oxide synthase expression in vascular endothelial cells.

Endothelial dysfunction is a phenomenon often observed in diabetic patients, which is a cause for vascular complications of diabetes mellitus. Endothelium-derived nitric oxide (NO) is responsible for vasodilatation, and NO-dependent vasodilatation is diminished in diabetic patients. In the present study, we evaluated the effects of thiazolidinediones (TZDs), antidiabetic drugs known to improve insulin resistance and to have vasodilating properties, on endothelial NO synthase (eNOS) expression in cultured vascular endothelial cells. Human umbilical vein endothelial cells were treated with the TZDs troglitazone and pioglitazone, or the peroxisome proliferator-activated receptor (PPAR) gamma activator 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-dPGJ2). The expression of eNOS protein and its mRNA was determined by Western and Northern blot analyses, respectively. The effect of alpha-tocopherol that possesses structural similarity to troglitazone was also examined. Troglitazone up-regulated eNOS protein and its mRNA levels, whereas pioglitazone and 15-dPGJ2 failed to increase their levels. By contrast, alpha-tocopherol also increased in eNOS protein and mRNA. These results suggest that troglitazone up-regulates eNOS expression probably through its 6-hydroxychromanes structure but not activating PPARgamma.

Vascular endothelium as a target of beraprost sodium and fenofibrate for antiatherosclerotic therapy in type 2 diabetes mellitus.

Diabetes mellitus is an important risk factor for cardiovascular morbidity and mortality. The metabolic abnormalities caused by diabetes mellitus induce vascular endothelial dysfunction that predisposes patients with diabetes mellitus to atherosclerosis. Two mega clinical trials showed that intensive glycemic control does not have favorable effects on reducing macrovascular events although it demonstrated significant reductions in microvascular complications. It is becoming worthwhile to clarify the beneficial effects of tight controls on blood pressure, serum lipids, and postprandial hyperglycemia to prevent atherosclerosis in patients with type 2 diabetes mellitus. Here, we focus on vascular endothelium as a target of the prostaglandin I2 analog beraprost sodium and the peroxisome proliferators-activated receptor alpha activator fenofibrate for the prevention and treatment of atherosclerosis in patients with type 2 diabetes mellitus. Beraprost sodium lowered circulating vascular cell adhesion molecule- 1 (VCAM-1) concentration and prevented the progression of carotid atherosclerosis in type 2 diabetic patients, probably through inhibiting VCAM-1 expression in vascular endothelium. Fenofibrate up-regulated endothelial nitric oxide synthase expression, which may explain its effects to improve endothelium-dependent vasodilatation and to prevent the progression of coronary atherosclerosis. The approaches to target the molecules expressed in vascular endothelium will become important for preventing the atherosclerosis in type 2 diabetes mellitus.

Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids.

We have recently shown that long-term use of inhaled corticosteroids decreases bone mineral density (BMD) of the lumbar spine in postmenopausal asthmatic women. The present study aimed to evaluate the efficacy of alendronate in comparison with that of alfacalcidol (1-alpha-hydroxyvitamin D(3)) for the treatment of BMD reduction in postmenopausal asthmatic patients who had inhaled corticosteroid therapy without regular use of systemic corticosteroids. Twenty-eight postmenopausal asthmatic patients with BMD T score of -1.0 or less were randomized to receive alendronate (5 mg/d) or alfacalcidol (1 microg/d). Bone mineral density was determined at baseline and 12 months after the treatment, and biochemical markers of bone metabolism were measured at baseline and after 6 and 12 months of treatment. The mean (+/-SD) BMD values at the lumbar spine, the total hip, and the Ward's triangle significantly increased by 4.9 +/- 4.5% (P = .0005), 2.4 +/- 2.2% (P = .0005), and 3.6 +/- 5.2% (P = .02) at 12 months in the alendronate group, whereas the corresponding values did not significantly change in the alfacalcidol group. In the alendronate group, urinary N-telopeptide (NTx), serum osteocalcin, and serum alkaline phosphatase concentrations significantly decreased, and serum intact parathyroid (PTH) level significantly increased, from baseline at both 6 and 12 months. In the alfacalcidol group, urinary NTx showed modest but significant decrease, although the extent of the change was smaller than that in the alendronate group. We concluded that alendronate was effective to improve reduced BMD in postmenopausal asthmatic patients on inhaled corticosteroid therapy through the mechanism of inhibiting bone resorption.

Peroxisome proliferator-activated receptor alpha agonists increase nitric oxide synthase expression in vascular endothelial cells.

OBJECTIVE: There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor alpha (PPARalpha) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPARalpha activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells. METHODS AND RESULTS: Bovine aortic endothelial cells were treated with the PPARalpha activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPARalpha action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment. CONCLUSIONS: PPARalpha activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPARalpha-mediated cardiovascular protection.

Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts.

Insulin and IGFs are potent inducers of skeletal muscle differentiation. Although PI3K is known to be involved in skeletal muscle differentiation, its downstream targets in this process are not clearly defined. We investigated the roles of Akt and mammalian target of rapamycin (mTOR) in skeletal muscle differentiation. LY294002, a pharmacological inhibitor of PI3K, and the immunosuppressant rapamycin inhibited insulin-induced differentiation of C2C12 myoblasts. LY294002 and rapamycin suppressed myosin heavy chain expression and myotube formation. Transient reporter assays showed that both inhibitors repress muscle creatine kinase (MCK) and myogenin gene transcription. Heterologous expression of Akt1/PKB(alpha) potently suppressed MCK gene transcription without affecting myogenin gene transcription, whereas heterologous expression of Akt2 increased myogenin and MCK gene transcription. Finally, overexpression of myogenin rescued the inhibitory effect of rapamycin on MCK gene transcription, whereas it failed to rescue the inhibitory effect of LY294002 and Akt1. These results suggest that insulin regulates myogenic differentiation chiefly at the level of myogenin gene transcription via PI3K and mTOR. PI3K activity, but not mTOR, may regulate transcriptional activity of myogenin. Our data also suggest that Akt1 and Akt2 play distinct roles in myogenic differentiation.