Relationship between serum cholesterol efflux capacity and glucose intolerance in Japanese-Americans.

AIM: Serum cholesterol efflux has been suggested to be a key anti-atherogenic function of reverse cholesterol transport. Meanwhile, the quantitative and qualitative alteration of the levels of lipoproteins in the serum has been reported in patients with diabetes, although it remains unclear whether the serum cholesterol efflux capacity is impaired in cases of newly diagnosed glucose intolerance. We thus assessed the relationship between the serum cholesterol efflux capacity and glucose intolerance as detected using oral glucose tolerance tests (OGTTs). METHODS: We measured the capacity of whole serum to mediate cholesterol efflux from human THP-1 macrophages in a cohort of 439 Japanese-Americans who underwent 75-g OGTTs. A multiple regression analysis was performed to examine the relationship between the serum cholesterol efflux capacity and glucose intolerance. RESULTS: The serum cholesterol efflux capacity was found to be negatively correlated with the area under the curve for the serum glucose concentration during the 75-g OGTTs in all subjects. In addition, the serum cholesterol efflux capacity was found to be modestly but significantly lower in the glucose intolerance group (31.4 ± 6.2%) than in the normal glucose tolerance group (33.2 ± 6.1%). There was also a negative association between the serum cholesterol efflux capacity and glucose intolerance after adjusting for age and sex. Moreover, this association remained significant even after further adjustments for serum total cholesterol, high-density lipoprotein cholesterol, apolipoprotein AI and C-reactive protein. CONCLUSIONS: The serum cholesterol efflux capacity is impaired in Japanese-Americans newly diagnosed with glucose intolerance. This impairment may contribute in some manner to increasing the risk of atherosclerotic disease in subjects with glucose intolerance.

5-aminolevulinic acid, a precursor of heme, reduces both fasting and postprandial glucose levels in mildly hyperglycemic subjects.

OBJECTIVE: The aim of this study was to evaluate the combined effects of 5-aminolevulinic acid phosphate (ALA-P) and iron on the glycemic index in mildly hyperglycemic adults. METHODS: This double-blind, randomized placebo-controlled trial comprised 212 subjects (ages 35-70 y, fasting plasma glucose 105-125 mg/dL or hemoglobin (Hb)A1c 6.1%-7.1%). These participants were randomly assigned to four groups receiving either one of three doses of ALA-P and iron as sodium ferrous citrate (5 mg and 0.6 mg, 5 mg and 1.8 mg, or 15 mg and 1.8 mg, respectively) or a placebo, administered orally once a day over a 12-wk period. RESULTS: Fifteen mg ALA-P plus 1.8 mg iron decreased the fasting plasma glucose level (2.32 mg/dL, 95% confidence interval [CI], 0.24-4.42, P = 0.029), serum glycoalbumin (0.22%, 95% CI, 0.02-0.42; P = 0.031), and 2h-oral glucose tolerance test levels (14.2 mg/dL, 95% CI, 1.8-26.6; P = 0.025) more than the placebo. However, the levels of HbA1c, fasting insulin, serum 1,5-anhydro-d-glucitol, and Homeostasis Model of Assessment-Insulin Resistance showed no appreciable changes. The participant numbers with impaired glucose tolerance and impaired fasting glucose decreased in the highest dosage group of ALA-P plus iron compared with the placebo group. CONCLUSION: An oral intake of ALA would be a novel approach to prevent type 2 diabetes mellitus.

Significantly high level of late-night free cortisol to creatinine ratio in urine specimen in patients with subclinical Cushing's syndrome.

OBJECTIVE: Absence of a late-night cortisol nadir is a consistent biochemical abnormality in patients with cortisol-producing adenoma. We evaluated the abnormality of late-night urinary free cortisol to creatinine ratio (late-night UFCCR) in patients with subclinical Cushing's syndrome (SCS). METHODS: Fifty-eight patients with incidentally detected adrenocortical adenomas [SCS: 9; nonfunctioning adenoma (NF): 49] were enrolled as subjects. Values measured in all patients were urinary free cortisol accumulated between 9:00 p.m. and 11:00 p.m. (late-night UFCCR), serum cortisol at 11:00 p.m. (midnight serum cortisol: MSC), serum cortisol after 1-mg overnight dexamethasone suppression test (1 mg-DST) and 24-h urinary free cortisol (UFC). RESULTS: Median late-night UFCCR value in SCS was significantly higher than that in NF (P < 0·001). Significant correlations were observed between late-night UFCCR and each of serum cortisol after 1 mg-DST and MSC (r = 0·537, P < 0·001 and r = 0·556, P < 0·001, respectively). There was no significant correlation between serum cortisol after 1 mg-DST and 24-h UFC (r = 0·211, P = 0·112). In receiver operating characteristic analysis for diagnosis of SCS, the areas under the curves of late-night UFCCR and 24-h UFC were 0·937 (95% confidence interval 0·865-1·008) and 0·726 (0·874-0·999), respectively. Late-night UFCCR cut-off value of 4·9 nmol/µmol Cre showed a sensitivity of 100% and a specificity of 76·6%. CONCLUSION: Patients with SCS showed higher late-night UFCCR values than those with NF. Late-night UFCCR was significantly correlated with autonomous cortisol production findings. Diagnostic performance of late-night UFCCR was superior to 24-h UFC. These results suggest that late-night UFCCR might represent one of the simple and reliable tests for SCS diagnosis.

Associations between small dense LDL, HDL subfractions (HDL2, HDL3) and risk of atherosclerosis in Japanese-Americans.

AIM: Small dense low-density lipoprotein (sdLDL) has been suggested to be more atherogenic than large buoyant LDL. High-density lipoprotein (HDL) consists of two major subfractions (HDL2, HDL3), and just as controversy remains regarding which of the two is the more powerful negative risk factor for atherosclerosis, associations between sdLDL and these HDL subfractions are unclear. METHODS: We measured sdLDL cholesterol (sdLDL-C), HDL2 cholesterol (HDL2-C) and HDL3 cholesterol (HDL3-C) by a newly developed method in 481 Japanese-Americans who were not using lipid-lowering medication, and examined the associations of these cholesterol concentrations with variables related to atherosclerosis. RESULTS: In multivariate analysis, sdLDL-C was positively correlated with the body mass index (BMI), fasting glucose and insulin, 2-h glucose, HOMA-IR, high sensitivity C-reactive protein (hsCRP), and carotid artery intima-media thickness (IMT) after adjustment for age and sex. In particular, sdLDL-C was positively correlated with IMT, even after adjustment for sex, age, smoking status, hypertension, diabetes mellitus and hsCRP. HDL2-C was more closely inversely correlated than total HDL-C with BMI, fasting glucose and insulin, 2-h glucose, HOMA-IR, and hsCRP, whereas HDL3-C was not correlated with these factors. Additionally, HDL2-C was more closely correlated than total HDL-C or HDL3-C with sdLDL-C, LDL-C, triglycerides (TG), and apolipoprotein B (apoB). CONCLUSIONS: SdLDL-C was closely associated with insulin resistance and glucose tolerance, lending credence to its potential as a useful risk marker in assessing carotid artery IMT and the present degree of atherosclerosis in Japanese-Americans. The findings also suggest that subjects with higher HDL2-C levels were better protected from atherosclerosis.

Reduction of serum lipids by the intake of the extract of garlic fermented with Monascus pilosus: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND & AIMS: A dietary supplement containing garlic fermented with Monascus pilosus (MGFE) may be useful to decrease the lipid concentrations in serum without serious adverse effects. The aim of the study was to assess whether MGFE decreases serum lipid contents in volunteers with mild hyperlipidemia in a randomized, double-blind, placebo-controlled, parallel-group trial. METHODS: Healthy subjects (n = 55) with serum triglyceride concentrations of 120-200mg/dL were randomly assigned to take either MGFE or placebo capsules for 12 wk. RESULTS: A borderline, but not significant effect, to decrease triglyceride concentrations in serum (approximately 15% reduction at maximum, P = 0.062, in time × treatment interaction effect) was observed by the MGFE intake for 12 wk. The decreased reading exhibited a significant difference at wk-8 between the MGFE and placebo groups (unpaired t test, P = 0.007). The total cholesterol (P = 0.003) and LDL cholesterol (P = 0.001) contents in the serum and the LDL/HDL ratio (P < 0.001) were significant in time × treatment interaction effects by the MGFE intake. However, no alteration in the body fat percentage and abdominal circumference was observed. CONCLUSIONS: The intake of MGFE decreased triglyceride and cholesterol in serum with no appreciable adverse effects in normal to mildly hyperlipidemic individuals, suggesting that it may be effective to improve and prevent the metabolic syndrome. This clinical trial was registered with Clinicaltrials.gov as NCT00938249.

Resistance to thyroid hormone accompanied by Graves' disease.

Resistance to thyroid hormone (RTH) is characterized by elevated serum levels of thyroid hormones and normal or slightly increased serum thyrotropin (TSH) levels. Recently it has been suggested that chronic TSH stimulation in RTH activates intrathyroidal lymphocytes, leading to thyroid damage and autoimmune thyroid disease (AITD). Therefore, individuals with RTH have an increased likelihood of AITD compared to unaffected relatives. We here report a 33-year-old woman in whom we diagnosed Graves' disease and treated her with thiamazole (MMI). For two years, her TSH levels were suppressed when thyroid hormones were elevated and conversely they were increased when thyroid hormones levels were decreased. These findings were common for a clinical course during treatment for Graves' disease with anti-thyroid drug. However, three years after the initiation of MMI therapy, she had a normal or gradually elevated serum TSH level even though the level of thyroid hormones never decreased, indicating inappropriate secretion of TSH. We concluded she had RTH clinically, and we demonstrated by direct sequence analysis a mutation of the TRß gene, causing replacement of a glycine (G) with arginine (R) at codon 251. The finding of an elevated TSH level without decreased thyroid hormones should suggest the presence of RTH during therapy of Graves' disease.

Improvement of constipation and liver function by plant-derived lactic acid bacteria: a double-blind, randomized trial.

OBJECTIVE: Lactic acid bacteria (LAB) contribute to human health; however, the probiotic properties vary among strains classified into the same species. The primary objective of this study was to evaluate the effects of yogurts made by different types of LAB on the gastrointestinal system. The yogurts were also evaluated by measuring serum lipid contents and liver functional indicators as a secondary objective. METHODS: Healthy human adults (n = 68) with some complaints with regard to intestinal health, including constipation and diarrhea, were randomly assigned to receive one of three types of yogurt in a double-blind manner: type A, a yogurt made by plant-derived LAB (mainly Lactobacillus [Lb.] plantarum SN35N); type B, a yogurt made by plant-derived LAB (mainly Lb. plantarum SN13T); and type C, a yogurt made by animal-derived LAB (mainly Lactococcus lactis A6 and Streptococcus thermophilus 510) as a control. The subjects consumed 100 g of yogurt daily for 6 wk. Data were collected from clinical visits at 2-wk intervals and by diaries used to record defecation and health conditions. RESULTS: Drastic and constant increments of defecation frequency in subjects with constipation were observed with type A and B yogurts but not with type C yogurt. Type B and C yogurts resulted in decreases in total and low-density lipoprotein cholesterol. The serum concentrations of liver functional parameters were improved by the type B yogurt (12-25% reduction). CONCLUSION: The present study suggests that Lb. plantarum SN13T exhibits a superior probiotic effect on constipation in addition to improving the serum lipid contents and liver function.

The single nucleotide polymorphism upstream of insulin-induced gene 2 ( INSIG2) is associated with the prevalence of hypercholesterolaemia, but not with obesity, in Japanese American women.

Insulin-induced gene 2 (insig-2) protein is known to play important roles in cholesterol and TAG metabolism both in vivo and in vitro. One particularly interesting single nucleotide polymorphism (SNP), rs7566605, located 10 kb upstream of INSIG2 was reported to have the strongest association with obesity among 86 604 SNP, while the relationship with dyslipidaemia is uncertain. Eight hundred and eighty-five Japanese Americans (347 men and 538 women) and 378 Japanese (182 men and 196 women) were enrolled, and the rs7566605 SNP, which is consistent with either G or C, was determined. We investigated the association between the rs7566605 SNP and the prevalence of hypercholesterolaemia or hypertriacylglycerolaemia, or obesity parameters, as assessed by BMI, waist girth and percentage body fat. There were no significant differences in BMI, waist girth and percentage body fat according to the genotype in each of the four groups, which was divided by population and sex. The prevalence of hypercholesterolaemia was significantly different between the genotypes in Japanese American female subjects (GG, 62.2 %; GC, 57.1 %; CC, 42.1 %; P = 0.021), but not in the other subjects. In Japanese American women, the subjects with the CC genotype had a 0.43-fold decreased risk (95 % CI 0.24, 0.80) for hypercholesterolaemia compared with the GG genotype after adjustment for age, percentage body fat, smoking status and hormone replacement therapy. The CC genotype of the rs7566605 SNP is suggested to be a protective genetic factor against the progression of hypercholesterolaemia on a high-fat diet, especially in Japanese female subjects.

Gene-environment association of an ITGB2 sequence variant with obesity in ethnic Japanese.

Mice lacking the integrin alphaMbeta2 (Mac-1, CD11b/CD18) develop an obese phenotype on western diet rich in fat. However, no association has been found between variations in the human genes encoding the integrin alphaMbeta2 and obesity. This study was aimed to investigate the association between a single-nucleotide polymorphism (SNP) (rs235326) in the gene encoding human integrin beta2 subunit (ITGB2) with obesity. Our subject cohort comprised 651 people of Japanese ethnicity, of which 274 were Japanese Americans living in Hawaii, and the remaining 377 were native Japanese, two populations in the same genetic background with or without westernized life style. We genotyped the rs235326 polymorphism using a TaqMan assay. In the Japanese-American population, the risk of obesity was found to be 3.29-fold higher (a 95% confidence interval of 1.25-8.67, P = 0.02) in TT homozygotes than in C carriers, using a recessive model and logistic regression analysis that had been adjusted for age. This association was not found in native Japanese individuals. These results indicate that the rs235326 polymorphism in the ITGB2 gene is associated with obesity in Japanese living in the United States whose diet has become "westernized."