One-year real-life efficacy of sitagliptin revealed importance of concomitant pioglitazone use in Japanese patients with type 2 diabetes mellitus.

AIMS: Dipeptidyl-peptidase 4 inhibitors have become one of the most popular antidiabetic drugs. However, what kind of combinations with other drugs were advantageous was not known. Here, we tried to elucidate it in a real-life clinical setting. METHODS: We retrospectively studied efficacies of sitagliptin in 87 Japanese patients with type 2 diabetes mellitus for 52 weeks. We divided subjects into excellent, effective and unresponsive subgroups according to glycemic responses to sitagliptin. RESULTS: In the excellent and effective groups the minimum HbA1c values were attained at 16 weeks while HbA1c levels in the unresponsive group kept increasing during the study period. There was a significant difference in the baseline HbA1c values between the excellent and unresponsive groups (p=0.02). Interestingly, the mean doses of pioglitazone were highest in the excellent group and lowest in the unresponsive group (p=0.02). When we compared the effective and unresponsive groups, the mean doses of sulfonylureas were constantly higher in the effective group than in the unresponsive group (p=0.05). CONCLUSIONS: These data suggest that the baseline HbA1c value can be a factor that predicts the extent of HbA1c reduction and reveal a possibility that the concomitant use of pioglitazone augments glycemic responsiveness to sitagliptin.

Serum from methimazole-treated patients induces activation of aryl hydrocarbon receptor, a transcription factor that binds to dioxin-response elements.

BACKGROUND: The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by xenobiotic substances such as dioxin. After activation, it binds to dioxin response elements of DNA, thereby inducing transcription of a variety of xenobiotic metabolizing enzymes. To investigate whether AhR-activating substances accumulate in patients with endocrine disorders, we tested serum samples for AhR-stimulating activity. METHODS: Serum AhR-stimulating activity was evaluated by exposing the HepG2 cells transiently transfected with an AhR-responsive reporter plasmid to serum samples. On the basis of preliminary findings that implicated methimazole (MMI), wild-type and AhR-null mice were treated with MMI, and their plasma AhR-stimulating activities and thyroxine levels were quantified. RESULTS: In 28 randomly chosen patients, 7 out of 10 Graves' disease patients exhibited increased serum AhR-stimulating activity. The increased activity did not correlate with thyroid hormone status. However, we hypothesized that it might be caused by MMI. Subsequent analyses revealed that in 25 of 26 MMI-treated Graves' patients, serum samples collected after the MMI treatment had significantly higher AhR-stimulating activity compared to samples obtained when the same patients were not on MMI. By contrast, serum AhR-stimulating activity was unchanged in samples from the seven patients on propylthiouracil (PTU) compared to serum taken before the PTU treatment. In vitro experiments demonstrated that an MMI metabolite 3-methyl-2-thiohydantoin, but not MMI, activated AhR. MMI increased plasma AhR-stimulating activities and reduced plasma thyroxine concentrations, in both wild-type and AhR-deficient mice. CONCLUSIONS: Graves' patients taking MMI have increased serum AhR-stimulating activity, which is unrelated to thyroid hormone status, but correlates with MMI treatment. The AhR activation is likely caused by 3-methyl-2-thiohydantoin. Further studies are required to determine the potency of 3-methyl-2-thiohydantoin as an AhR activator and the significance of the differences between MMI and PTU observed in this study.

Increased serum apolipoprotein B48 concentration in patients with metabolic syndrome.

AIM: Postprandial hyperlipidemia is characterized by an increase of chylomicron remnants (CM-R), and is a risk factor for atherosclerosis. Apolipoprotein (apo) B48 exists exclusively in chylomicroms and CM-R, and fasting plasma levels of apo B48 may reflect high postprandial levels of chylomicrons and/or CM-R. We hypothesized that fasting apo B48 levels may be increased in metabolic syndrome. METHODS: We investigated 1,349 inhabitants (528 men and 821 women aged 62.4+/-12.8 y; mean+/-S.D.) of two towns in rural Hokkaido, who underwent health checks in 2005. RESULTS: The fasting apo B48 level was significantly higher in males than females (geometric mean 1.92; 95% CI 1.802.04 microg/mL, vs. 1.69; 95% CI 1.611.76 microg/mL; p< 0.001). Ln (apo B48) showed a significant positive correlation with total cholesterol and ln (triglycerides), and a negative correlation with HDL-cholesterol. The correlation between ln (apo B48) and ln (triglycerides) was strong. Apo B48 was significantly higher in men and women with than without metabolic syndrome. Regression analysis revealed that ln (apo B48) was significantly associated with age, BMI, total cholesterol, HDL cholesterol, LDL cholesterol, and ln (triglyceride). CONCLUSION: Fasting apo B48 levels are raised in individuals with metabolic syndrome.

Isolation and characterization of apolipoprotein B48-containing lipoproteins with a monoclonal antibody against apolipoprotein B48.

AIM: Remnant lipoproteins are well known to play a pivotal role in atherosclerosis. In patients with postprandial dyslipidemia, metabolic pathways for exogenous lipoproteins are generally disturbed, resulting in accumulation of chylomicron remnants. Although it has been difficult to make a specific antibody against apolipoprotein B48 (apoB48) , a constituent of exogenous lipoproteins, we succeeded in creating a specific monoclonal antibody against apoB48. In this study, we isolated apoB48-containing lipoproteins from lipoproteins with a density less than 1.019 g/mL using this anti-apoB48 monoclonal antibody (4C8). METHODS: Apolipoproteins and lipids were analyzed to confirm whether apoB48-containing lipoproteins are isolated from other lipoproteins. The characteristics of apoB48-containing lipoproteins in the plasma of patients were compared with type 2 diabetes mellitus and non-diabetic patients. Furthermore, the uptake of apoB48-containing lipoproteins by THP-1 cells (a human acute monocytic leukemia cell line) , HepG2 cells (a human hepatoma cell line) , and human umbilical vein endothelial cells (HUVEC) was investigated. Also, the expression of apoB48 receptors in these cells was tested with RT-PCR. RESULTS: Apolipoprotein analysis of 4C8-bound lipoproteins indicated the isolation of apoB48-containing lipoproteins, because the content of apoB100 was quite low (less than 5%) . Compared with lipoproteins that were not bound to the antibody, apoB48-containing lipoproteins had a higher content of triglycerides. There was no significant difference in the composition of apoB48-containing lipo-proteins between patients with and without type 2 diabetes. Uptake of fluorescence-labeled apoB48-containing lipoproteins by THP-1-derived macrophages and HepG2 cells, but not by HUVEC, was observed. The specificity of this uptake was confirmed because the fluorescent signal was competed out by an excess amount of the same unlabeled lipoproteins. RT-PCR revealed the expression of apoB48 receptors in THP-1 and HepG2 cells but not in HUVEC. These results suggest that specific uptake of apoB48-containing lipoproteins may occur via apoB48 receptors. CONCLUSION: ApoB48-containing lipoproteins have a higher triglyceride content and are taken up into THP-1-derived macrophages and HepG2 cells by a specific pathway.

Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome.

BACKGROUND AND AIM: We have previously shown that serum plasmalogen levels positively correlate with HDL, and significantly decrease with aging, and may be related to LDL particle size. The objective of the present study was to investigate the effects of increased serum plasmalogens on lipidosis, particularly the appearance of atherogenic small dense LDL (sdLDL), of subjects with hyperlipidemia and metabolic syndrome (MetS). METHODS AND RESULTS: The effects of increased serum plasmalogen levels, induced by 2 wk of myo-inositol treatment, on several clinical and biochemical parameters were examined in 17 hyperlipidemic subjects including some with MetS. After myo-inositol treatment, significant increases in plasmalogen-related parameters, particularly ChoPlas, and significant decreases in atherogenic cholesterols including sdLDL, were observed. Among the hyperlipidemic subjects treated with myo-inositol, compared to subjects without MetS, subjects with MetS had a significant increase in plasmalogens and a tendency towards reduced sdLDL, high sensitivity C-reactive protein (hsCRP), and blood glucose levels. Correlation analyses between the measured parameters showed that plasmalogens, as well as HDL, function as beneficial factors, and that sdLDL is a very important risk factor that shows positive correlations with many other risk factors. CONCLUSION: These results suggest that increased plasmalogen biosynthesis and/or serum levels are especially effective in improving MetS among hyperlipidemic subjects with MetS.

Plasmalogens in human serum positively correlate with high- density lipoprotein and decrease with aging.

AIM: The objective of the present study was to propose plasmalogens as a beneficial factor in human plasma by showing a highly positive correlation with high-density lipoprotein (HDL) and a significant reduction with aging. METHODS: For 148 elderly subjects suspected of coronary artery disease (CAD), clinical characteristics such as coronary stenosis, hyperlipidemia, abnormal glucose tolerance, and hypertension were investigated, and serum biochemical markers including plasmalogens were determined. RESULTS: Serum plasmalogens levels tended to fall in significant coronary stenosis and abnormal glucose tolerance. Correlative analyses among serum biochemical markers revealed that plasmalogens positively correlate with HDL-related values, particularly apolipoprotein A-I (apo A-I), and that the molar ratio of choline plasmalogen (ChoPlas) to ethanolamine plasmalogen (EtnPlas) correlates positively with low-density lipoprotein (LDL) particle size, and negatively with apo A-II and fasting triglyceride (TG) levels. Comparison of plasmalogens in elderly subjects with those of 119 healthy young subjects showed a marked decrease in serum plasmalogens levels by aging. CONCLUSION: These results suggest that serum plasmalogens, antioxidant phospholipids, function as a beneficial factor as well as HDL, and that the measurement of serum plasmalogens is useful in clinical diagnosis.