High-normal albuminuria is strongly associated with incident chronic kidney disease in a nondiabetic population with normal range of albuminuria and normal kidney function.

BACKGROUND: Albuminuria and estimated glomerular filtration rate (eGFR) are clinically measured to evaluate the severity of chronic kidney disease (CKD). The aim of our study was to clarify the association between clinical parameters, including albuminuria and eGFR, and the risk of incident CKD in a nondiabetic population with normal range of albuminuria and eGFR. METHODS: A 10-year follow-up, retrospective cohort study involving 317 Japanese men (mean age, 42 years) with eGFR ≥ 90 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) < 30 mg/gCr was performed. Participants were free of diabetes mellitus. Multivariate logistic regression approaches were used to assess independent predictors of the incidence of CKD. RESULTS: Twenty-nine (9%) participants developed CKD (eGFR < 60 mL/min/1.73 m2 and/or UACR ≥ 30 mg/gCr) through 10 years of follow-up. At the baseline examination, age, blood pressure, UACR, and eGFR were higher in participants who developed CKD than in those without CKD. After adjustment for confounders, high-normal albuminuria (P < 0.001) and hypertension (P = 0.045) were associated with an increased incidence of CKD. From receiver-operating characteristic curves, UACR ≥ 7.0 mg/gCr was defined as high-normal albuminuria. Logistic regression analysis also showed that, in addition to presence of hypertension, UACR ≥ 7.0 mg/gCr was identified as an independent risk of incident CKD within 10 years after adjustment for age, body mass index, smoking status, and dyslipidemia [UACR: odds ratio (OR) 17.36 (95% CI 6.16-48.93, P < 0.001)]. CONCLUSION: High-normal albuminuria and hypertension are associated with incident CKD in a nondiabetic population with normal-range UACR and eGFR.

High-normal albuminuria is associated with subclinical atherosclerosis in male population with estimated glomerular filtration rate ≥60 mL/min/1.73 m2: A cross-sectional study.

BACKGROUND: Low-grade albuminuria has been considered a predictor of cardiovascular mortality. We investigated the relationship between high-normal albuminuria and subclinical atherosclerosis in non-diabetic men with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. METHODS: In this cross-sectional study, 1,756 men with eGFR ≥60 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) <30 mg/g, who attended general health checkups between April 2012 and March 2015, underwent blood sampling, urinalysis, and carotid ultrasonography. We excluded the subjects who were diabetic and/or received an anti-hypertensive drug. Carotid intima-media thickness (IMT) and the number of focal atheromatous plaques were used as indicators of subclinical atherosclerosis. Multiple linear regression analysis was performed to identify clinical factors associated with carotid IMT. Poisson regression analysis was used to assess the determinants of the carotid plaque number. RESULTS: Median UACR was 4.8 mg/g (interquartile range, 3.6-6.9 mg/g). Compared with subjects with low-normal UACR (<10.0 mg/g), subjects with high-normal UACR (10.0-29.8 mg/g) had greater IMT and higher carotid plaque number. High-normal UACR was independently associated with thickened IMT in the model adjusted for conventional cardiovascular disease risk factors. Moreover, participants with high-normal UACR were also more likely to be associated with increased plaque count (prevalence ratio: 1.06; 95% confidence interval: 1.01-1.14) after adjustment for conventional cardiovascular disease risk factors. CONCLUSIONS: Our results indicate that high-normal albuminuria is associated with both carotid IMT and plaque formation in the non-diabetic male population with eGFR ≥60 mL/min/1.73 m2.

High-normal albuminuria and incident chronic kidney disease in a male nondiabetic population.

BACKGROUND: High-normal albuminuria is an important risk factor for incident chronic kidney disease in diabetic populations, in contrast to an uncertain association in nondiabetic populations. This study aimed to reveal the relationship between high-normal albuminuria and incident chronic kidney disease in a Japanese nondiabetic population. METHODS: A 10-year follow-up retrospective cohort study was performed involving 1378 Japanese men (mean age 44 ± 5.3 years) without chronic kidney disease and diabetes mellitus. Chronic kidney disease was diagnosed as either estimated glomerular filtration rate < 60 mL/min/1.73 m2 or a urine albumin-to-creatinine ratio ≥ 30 mg/g. RESULTS: At baseline, age, estimated glomerular filtration rate, and the presence of hematuria, hypertension, and dyslipidemia were independently associated with the albumin-to-creatinine ratio. Among the 1378 participants, 185 (13.4%) fulfilled diagnostic criteria for chronic kidney disease over the 10-year follow-up period. Median annual estimated glomerular filtration rate decline showed a deterioration with increasing quartiles of baseline albumin-to-creatinine ratio (P = 0.004). Participants who had a baseline albumin-to-creatinine ratio in the highest quartile (5.9-28.9 mg/g) were more likely to develop micro- or macroalbuminuria (odds ratio: 16.23, 95% confidence interval 6.56-54.03), chronic kidney disease (odds ratio: 2.48, 95% confidence interval 1.64-3.82), and hypertension (odds ratio 2.06, 95% confidence interval 1.30-3.31), but not diabetes mellitus compared with those who had an albumin-to-creatinine ratio in the lowest quartile (1.3-3.6 mg/g) after adjustment for potential confounders. CONCLUSIONS: High-normal albuminuria was associated with incident chronic kidney disease in this Japanese nondiabetic male population.

Association between aerobic capacity and the improvement in glycemic control after the exercise training in type 2 diabetes.

BACKGROUND: We investigated the influence of aerobic capacity on the improvement in glycemic control achieved by long-term aerobic exercise in type 2 diabetes. METHODS: Fifty-three male patients with type 2 diabetes, recruited from outpatient clinics, wore multiple-memory accelerometers and were instructed to exercise at moderate intensity for ≥30 min on ≥3 days per week over 12 months. Peak oxygen uptake (peak [Formula: see text]) and serum glycated albumin (GA) were measured at baseline and after 3, 6, 12 months. Peak [Formula: see text] data were expressed as percentages of predicted values. RESULTS: According to the number of bouts of exercise (intensity, ≥4 METs; duration, ≥15 min), the subjects were divided into inactive (<3 times per week) or active (≥3 times per week) groups. Serum GA decreased significantly after 3, 6, 12 months only in the active group. When the subjects were assigned to four groups according to initial peak [Formula: see text] (%pred) (low-fitness or high-fitness) and the number of bouts of exercise (active or inactive), serum GA decreased significantly after 3, 6, 12 months only in the high-fitness/active group. When the subjects were also assigned to four groups according to the change in peak [Formula: see text] (%pred) (improved or unimproved) and the number of bouts of exercise (active or inactive), serum GA decreased significantly after 3 and 12 months only in the improved/active group. CONCLUSION: The improvement in glycemic control achieved by aerobic exercise was associated with both the initial and the increase in peak [Formula: see text] during aerobic exercise.

Regardless of central obesity, metabolic syndrome is a significant predictor of type 2 diabetes in Japanese Americans.

AIMS/INTRODUCTION: The impact of metabolic syndrome (MetS) on the development of type 2 diabetes has been reported in different ethnic populations. However, whether central obesity is an essential component as a diagnostic criterion for MetS remains a controversial topic. The aim of the present study was to investigate the association between MetS and the incidence of type 2 diabetes with or without central obesity in a Japanese American population. MATERIALS AND METHODS: We examined whether MetS predicts incident type 2 diabetes among 928 Japanese American participants who did not have diabetes enrolled in an ongoing medical survey between 1992 and 2007. MetS was defined on the basis of American Heart Association/National Heart, Lung, and Blood Institute criteria. The average follow-up period was approximately 6.8 years. RESULTS: During the follow-up period, 116 new cases of diabetes were diagnosed. Compared to the participants without MetS, the hazard ratio (HR) for incident type 2 diabetes was significantly higher in participants with MetS, after adjustment for sex, age and impaired glucose tolerance (HR 1.64, 95% CI 1.11-2.42). The risk of type 2 diabetes was found to be significantly higher in participants with MetS but without central obesity (HR 2.07, 95% CI 1.25-3.41), as well as in participants with MetS and with central obesity (HR 2.46, 95% CI 1.51-4.01) than in participants with neither MetS nor central obesity, after adjustment for sex, age and impaired glucose tolerance. CONCLUSIONS: These results show that the presence of MetS, with or without central obesity, could independently predict the development of type 2 diabetes in Japanese Americans.

Japanese lifestyle during childhood prevents the future development of obesity among Japanese-Americans.

OBJECTIVE: To evaluate whether a Japanese lifestyle during childhood could protect against the future development of obesity-associated metabolic diseases by comparing native Japanese with Japanese-Americans in whom genetic factors are the same. METHODS: Study subjects were 516 native Japanese and 781 Japanese-Americans who underwent medical examinations between 2007 and 2010. Japanese-Americans were divided into 444 first-generation immigrants (JA-1), who were born in Japan, and 337 second- or later-generation descendants (JA-2), who were born in the United States. The JA-2 group was then divided into the kibei subgroup (N = 79), who had moved to Japan before the age of 18 years and later returned to the United States, and the non-kibei subgroup (N = 258), who had never lived in Japan. RESULTS: The JA-2 group had the highest percentages of obesity, metabolic syndrome, and type 2 diabetes compared with native Japanese and JA-1. Furthermore, among JA-2, the prevalence of obesity and metabolic syndrome in the kibei subgroup was significantly lower than that in the non-kibei subgroup. The prevalence of diabetes in the kibei subgroup also tended to be lower than in the non-kibei subgroup. CONCLUSIONS: The prevalence of obesity and metabolic diseases differed with residence in Japan during childhood among Japanese-Americans. These findings indicate the possibility that Japanese lifestyle during childhood could reduce the future risks for obesity-associated metabolic diseases.

Low high-density lipoprotein cholesterol level is a significant risk factor for development of type 2 diabetes: Data from the Hawaii-Los Angeles-Hiroshima study.

AIMS/INTRODUCTION: A low level of high-density lipoprotein cholesterol (HDLC) is a common feature of metabolic syndrome. We have reported that Japanese-Americans who share a virtually identical genetic makeup with native Japanese, but who have lived Westernized lifestyles for decades, have lower HDLC levels and a high prevalence of type 2 diabetes compared with native Japanese. However, the impact of low HDLC level on type 2 diabetes is unclear. The aims of the present study were to evaluate whether serum HDLC level was associated with development of type 2 diabetes and if the effect might be modified by lifestyle. MATERIALS AND METHODS: We examined 1,133 non-diabetic Japanese-Americans and 1,072 non-diabetic Japanese, who underwent the 75-g oral glucose tolerance test (OGTT) and were followed for an average of 8.8 and 7.0 years, respectively. We analyzed whether serum HDLC level is a risk factor for development of type 2 diabetes based on the Cox proportional hazards model. RESULTS: After adjustment for age and sex, hazard ratios for development of type 2 diabetes per unit of serum HDLC level (mmol/L) were 0.292 (95% confidence interval [CI] 0.186-0.458, P < 0.0001) among Japanese-Americans and 0.551 (95% CI 0.375-0.88, P = 0.0023) among native Japanese. Comparable hazard ratios after further adjustment for category of OGTT and body mass index were 0.981 (95% CI 0.970-0.993, P = 0.0018) and 0.991 (95% CI 0.980-1.002, P = 0.112), respectively. CONCLUSIONS: HDLC level was associated with development of type 2 diabetes in both Japanese-Americans and native Japanese. However, these results suggest that the impact of high-density lipoprotein on glucose metabolism might be affected by lifestyle.

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.

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.

Cross-sectional and prospective study of the association between lung function and prediabetes.

OBJECTIVES: A growing body of evidence suggests that there is a relationship between impaired lung function and the risk of developing diabetes mellitus (DM). However, it is not known if this reflects a causal effect of lung function on glucose metabolism. To clarify the relationship between lung function and the development of DM, we examined the incidence of newly diagnosed prediabetes (a precursor of DM) among subjects with normal glucose tolerance (NGT) at baseline. DESIGN: Primary analysis of an occupational cohort with both cross-sectional and longitudinal data (follow-up duration mean±SD: 28.4±6.1 months). SETTING AND PARTICIPANTS: Data were analysed from 1058 men in a cross-sectional study and from 560 men with NGT in a longitudinal study. OUTCOMES AND METHODS: Impaired lung function (per cent predicted value of forced vital capacity (%FVC) or per cent value of forced expiratory volume 1 s/FVC (FEV(1)/FVC ratio)) in relation to the ratio of prediabetes or DM in a cross-sectional study and development of new prediabetes in a longitudinal study. NGT, prediabetes including impaired glucose tolerance (IGT) and increased fasting glucose (IFG) and DM were diagnosed according to 75 g oral glucose tolerance tests. MEASUREMENTS AND MAIN RESULTS: %FVC at baseline, but not FEV(1)/FVC ratio at baseline, was significantly associated with the incidences of DM and prediabetes. Among prediabetes, IGT but not IFG was associated with %FVC. During follow-up, 102 subjects developed prediabetes among those with NGT. A low %FVC, but not FEV(1)/FVC ratio, was predictive of an increased risk for development of IGT, but not of IFG. CONCLUSIONS: Low lung volume is associated with an increased risk for the development of prediabetes, especially IGT, in Japanese men. Although there is published evidence for an association between chronic obstructive pulmonary disease and DM, prediabetes is not associated with the early stage of COPD.

Cigarette smoking decreases dynamic inspiratory capacity during maximal exercise in patients with type 2 diabetes.

To investigate the influence of cigarette smoking on exercise capacity, respiratory responses and dynamic changes in lung volume during exercise in patients with type 2 diabetes. Forty-one men with type, 2 diabetes without cardiopulmonary disease were recruited and divided into 28 non-current smokers and 13 current smokers. All subjects received lung function tests and cardiopulmonary exercise testing using tracings of the flow-volume loop. Exercise capacity was compared using the percentage of predicted oxygen uptake at maximal workload (%VO2max). Respiratory variables and inspiratory capacity (IC) were compared between the two groups at rest and at 20%, 40%, 60%, 80% and 100% of maximum workload. Although there was no significant difference in lung function tests between the two groups, venous carboxyhemoglobin (CO-Hb) levels were significantly higher in current smokers. %VO2max was inversely correlated with CO-Hb levels. Changing patterns in respiratory rate, respiratory equivalent and IC were significantly different between the two groups. Current smokers had rapid breathing, a greater respiratory equivalent and a limited increase in IC during exercise. Cigarette smoking diminishes the increase in dynamic IC in patients with type 2 diabetes. As this effect of smoking on dynamic changes in lung volume will exacerbate dynamic hyperinflation in cases complicated by chronic obstructive pulmonary disease, physicians should consider smoking habits and lung function when evaluating exercise capacity in patients with type 2 diabetes.

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.

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.

The influence of lung function on exercise capacity in patients with type 2 diabetes.

Patients with type 2 diabetes have impaired exercise capacity. While numerous factors are known to contribute to impaired exercise capacity, the role of lung function remains unclear. We conducted the present study to investigate the influence of lung function on exercise capacity in patients with type 2 diabetes. Cardiopulmonary exercise testing was carried out in 31 male patients with type 2 diabetes without diabetic complications or cardiopulmonary diseases. Patients with abnormal spirometry results such as a percentage of predicted forced vital capacity (%FVC) < 80% and/or a ratio of forced expiratory volume in one second (FEV1) to FVC (FEV1/FVC) < 70% were excluded from the study. We used the percentage of predicted maximal oxygen uptake (%VO2max) as an index of exercise capacity. The correlations between %VO2max and lung function and other factors known to be associated with impaired exercise capacity were then assessed. Univariate analysis revealed %VO2max correlated significantly with percentage of predicted FEV1 (%FEV1), duration of type 2 diabetes, regular exercise habits, and systolic and diastolic blood pressures. In a multivariate analysis, %FEV1 and regular exercise habits were found to be independent determinants of %VO2max. A mild reduction in %FEV1, which may be a complication of diabetes, is associated with impaired exercise capacity in patients with type 2 diabetes. When evaluating spirometric values in patients with type 2 diabetes, a reduction in %FEV1 should be noted even when both %FVC and FEV1/FVC are within normal limits.

[Macroangiopathy compared between native Japanese and Japanese-Americans: findings from the Hawaii-Los Angels-Hiroshima Study].

We have conducted medical surveys of Japanese-Americans, in whom westernization of life style occurred earlier and more intensively, in order to clarify the impact of westernization of life style on diseases in Japanese. This survey is started in Hawaii in 1970, and Los Angeles in 1978. We clarified that the prevalence of obesity, which leads to insulin resistance, is higher in Japanese-Americans than that in Japanese, and that insulin resistance which is associated with diabetes, hypertention, and dyslipidemia could increase macroangiopathy such as ischemic heart disease and stroke in Japanese-Americans. The mortality rate of Japanese-Americans with diabetes from ischemic heart disease increased to be similar extent to that of Caucasian in the U.S. It could be concluded that Japanese-Americans are at high risk for macroangiopathy.

Aldosterone synthase (CYP11B2) C-344T polymorphism affects the association of age-related changes of the serum C-reactive protein.

Aldosterone participates in vascular and myocardial inflammation either directly or indirectly through blood pressure (BP). Aldosterone synthase (CYP11B2) C-344T polymorphism may influence the severity of systemic inflammation. A total of 398 Japanese Americans (152 men and 246 women, age 19-92 years) from the Hawaii-Los Angeles-Hiroshima study were enrolled. BP and serum levels of C-reactive protein (CRP) were measured, and the CYP11B2 C-344T polymorphism, rs1799998, was determined. No influence of the polymorphism on baseline characteristics such as systolic, diastolic and mean BP, pulse pressure or serum CRP levels was observed. In all genotypes, systolic BP showed a significantly positive correlation with age (TT (n=178): r=0.283, P<0.001; TC (n=164): r=0.213, P=0.006; and CC (n=56): r=0.289, P=0.031). However, the regression coefficients of systolic BP with age were not different across genotypes. According to the results of univariate and multivariate analyses with adjustment for BP, the serum CRP level increased with age only in subjects with the CC genotype (P=0.027 and P=0.004, respectively), and elevation of serum CRP was mainly observed in the elderly population (aged >or=60 years). Moreover, the regression coefficient of CRP levels with age was significantly steeper in subjects with the CC genotype than in those with the TC or TT genotype (P=0.028). The CC genotype of the CYP11B2 C-344T polymorphism was associated with an age-dependent increase in the serum CRP level independent of BP, and may contribute to a cardiovascular phenotype by promoting vascular inflammation.

Improvement of hypercortisolism by ß-blocker therapy in subclinical Cushing's syndrome associated with ACTH-independent macronodular adrenocortical hyperplasia.

A 61-year-old man with hypertension and diabetes was referred for the evaluation of multiple bilateral adrenal tumors. While Cushingoid features were not apparent, an elevated cortisol level in response to a low-dose dexamethasone suppression test (187.7 nmol/l), an elevated urinary cortisol level (170.9 nmol/day), and a weak response to a cosyntropin-releasing hormone (CRH) provocation test were observed. Furthermore, the serum cortisol level increased in response to a posture test or isoproterenol infusion. Accordingly, the patient was diagnosed as having ACTH-independent macronodular adrenal hyperplasia (AIMAH) with subclinical Cushing's syndrome associated with the aberrant expression of ß-adrenergic receptors. After 2 months of propranolol therapy, the serum cortisol responses to a posture test and isoproterenol infusion, the cortisol level in response to a low-dose dexamethasone suppression test (102.1 nmol/l), and the urinary cortisol level (165.9 nmol/day) all normalized. While the suppression of cortisol secretion was sustained for 24 months, glucose metabolism and adrenal size were unaffected. To our knowledge, this is the first report of AIMAH accompanied by subclinical Cushing's syndrome associated with the aberrant expression of ß-adrenergic receptors. Furthermore, propranolol inhibited cortisol hypersecretion in the present case. Additional cases or controlled studies are needed to determine the potential effect of propranolol on metabolic disorders and adrenal size in patients with AIMAH.

Combined acromegaly and subclinical Cushing disease related to high-molecular-weight adrenocorticotropic hormone.

A 36-year-old man with a 1-year history of diabetes mellitus was referred to the authors' hospital for further endocrinological evaluation of acromegaly. On physical examination, typical acromegalic features but no typical cushingoid features were observed. The clinical diagnosis of growth hormone (GH)-producing pituitary adenoma was confirmed by MR imaging findings, nonsuppression of serum GH levels during a 75-g oral glucose tolerance test (trough GH 6.33 ng/ml), and elevated serum insulin-like growth factor-I levels (1361.3 ng/ml). Moreover, autonomic adrenocorticotropic hormone (ACTH) secretion was suspected, based on inadequate suppression of ACTH or cortisol levels by an 0.5-mg overnight dexamethasone suppression test. Analysis of the patient's plasma by using the gel filtration method revealed the presence of a high-molecular-weight (HMW) form of ACTH known to exhibit low biological activity. Transsphenoidal adenomectomy was performed for the pituitary tumor. Immunohistochemical investigation of the resected specimen showed strong and diffuse immunoreactivity to GH and focal immunoreactivity to ACTH. Although there have been a few cases of pituitary adenoma that produced GH and ACTH concomitantly, this is the first report of the detection of HMW ACTH in patients with GH- and ACTH-producing adenomas. Furthermore, the previous cases also did not exhibit typical cushingoid features. It is suggested that the secretion of ACTH in patients with concurrent GH- and ACTH-secreting adenomas might consist of the HMW form and that the HMW ACTH is consequently associated with a subclinical Cushing state.

Airflow limitation in smokers is associated with subclinical atherosclerosis.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality from cardiovascular disease. Although a close association between COPD and atherosclerosis has been speculated, such scientific information is limited. OBJECTIVES: To evaluate subclinical atherosclerosis in smokers with airflow limitation. METHODS: The subjects of this study were healthy middle-aged men. Smokers with airflow limitation (n = 61) and age-matched control smokers (n = 122) and control never-smokers (n = 122) without airflow limitation were included in the present study. Subjects with diabetes, acute infection, and respiratory disease other than COPD were excluded beforehand. All subjects underwent chest radiogram, spirometry, blood sampling, and carotid ultrasonography. We determined carotid intima-media thickness and focal atheromatous plaque as indicators of subclinical atherosclerosis. MEASUREMENTS AND MAIN RESULTS: Mean carotid intima-media thickness was greater in smokers with airflow limitation than in control smokers (P < 0.01) and control never-smokers (P < 0.005). Focal carotid plaque was significantly more prevalent in smokers with airflow limitation than in control never-smokers (P < 0.005). Multivariate analyses showed significant associations between thickened intima-media thickness and decreased percent predicted FEV(1) (P = 0.001) and between plaque and log(10) C-reactive protein (P = 0.013) independent of age, pack-years of smoking, body mass index, peripheral mean arterial pressure, heart rate, glucose, and low-density lipoprotein cholesterol. CONCLUSIONS: Smokers with airflow limitation had exaggerated subclinical atherosclerosis. This study suggests that middle-aged men who are susceptible to COPD may also be susceptible to vascular atherosclerosis by smoking, and atherosclerotic change starts early in the disease process of COPD.