Tan Tominaga

Inflammation and insulin resistance are independently related to all-cause of death and cardiovascular events in Japanese patients with type 2 diabetes mellitus.

Insulin resistance (IR)/hyperinsulinemia and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP]) can predict cardiovascular disease. However, because IR and inflammation (IF) have not been evaluated simultaneously, it is not known whether IR and IF are independently related to cardiovascular disease. Furthermore, the combined effect of IR and IF on the prediction of cardiovascular disease is presently unknown. Thus, we measured insulin sensitivity (K index of the insulin tolerance test; KITT) and hs-CRP in 350 Japanese patients with type 2 diabetes, and followed them for 1-7 years (mean, 4.5 years). During the follow-up, 33 patients died and 53 patients developed non-fatal coronary artery disease or stroke (endpoint). Age, systolic blood pressure, current smoking, past history of cardiovascular disease, KITT, and hs-CRP independently and significantly correlated with endpoint. One-S.D. difference was associated with a significant increase of relative risk in KITT (1.45; 95% CI 1.09-1.91) and hs-CRP (1.30; 1.04-1.67). When patients were subdivided to tertile, the relative risk in the highest tertile of KITT was 1.76 (95% CI 1.01-3.11) and hs-CRP was 2.00 (1.03-3.85) compared with the patients with lowest tertile. The relative risk in the highest tertile of both KITT and hs-CRP was 5.32 (1.18-24.0) compared with the lowest tertile of both values. In conclusion, low-grade IF and IR are independently related to all-cause of death and cardiovascular disease in Japanese patients with type 2 diabetes. Coexistence of low-grade IF and IR amplify this effect.

Metabolic cardiovascular disease risk factors and their clustering in subclinical hypothyroidism

Objective  A possible association between subclinical hypothyroidism and cardiovascular disease (CVD) has been reported. Monitoring of atomic‐bomb survivors for late effects of radiation exposure at the Radiation Effects Research Foundation has provided the opportunity to examine associations between subclinical hypothyroidism and metabolic CVD risk factors. The objective of the study was to evaluate associations between subclinical hypothyroidism and metabolic CVD risk factors, and a cluster of these factors.

Risk for Progression to Overt Hypothyroidism in an Elderly Japanese Population with Subclinical Hypothyroidism

BACKGROUND Few population-based studies report the changes with time in thyroid function tests in patients with subclinical hypothyroidism. We compared the risk for developing overt hypothyroidism in patients with subclinical hypothyroidism and euthyroid controls from the same population of elderly Japanese. We also sought associations of selected parameters with the development of overt hypothyroidism in the subclinical hypothyroid and euthyroid groups. METHODS We measured thyrotropin (TSH) and free thyroxine (T4) levels at baseline examinations performed from 2000 to 2003 in the cohort of Japanese atomic-bomb survivors and identified 71 patients with spontaneous subclinical hypothyroidism (normal free T4 and TSH >4.5 mIU/L without a history of thyroid treatment, mean age 70 year) and 562 euthyroid controls. We re-examined TSH and free T4 levels an average of 4.2 years later (range, 1.9-6.9). RESULTS The risk for progression to overt hypothyroidism was significantly increased in subclinical hypothyroid patients (7.0%) compared with control subjects (1.6%) after adjusting for age and sex (odds ratio, 4.56; p=0.009). Higher baseline TSH levels were associated with progression from subclinical to overt hypothyroidism (p=0.02) in the multivariate analysis, including age, sex, antithyroid peroxidase antibody, and ultrasonography (US) findings. The analysis using binary TSH data suggested that a TSH level >8 mIU/L was a predictive value for development of overt hypothyroidism (p=0.005). On the other hand, serum TSH levels spontaneously normalized in 38 (53.5%) of the patients with subclinical hypothyroidism. In the multivariate analysis, normalization of TSH levels was associated with lower baseline TSH levels (p=0.004) and normal and homogenous thyroid US findings (p=0.04). Atomic-bomb radiation dose was not associated with subclinical hypothyroidism or its course. CONCLUSIONS Subclinical hypothyroidism was four times more likely to be associated with development of overt hypothyroidism than euthyroid controls in the sample population of Japanese elderly. TSH levels in half of the patients normalized spontaneously when assessed after an average follow-up period of 4.2 years. Baseline TSH level and thyroid US findings are potential predictors of future thyroid function in subclinical hypothyroidism.

Insulin resistance and coronary risk factors in Japanese type 2 diabetic patients with definite coronary artery disease

Insulin resistance is known as an important risk factor for coronary artery disease (CAD). However, CAD-related mortality in Japanese type 2 diabetics is lower than in Caucasians. To investigate whether insulin resistance is related to CAD in Japanese type 2 diabetics, we measured insulin sensitivity and several coronary risk factors in Japanese patients with type 2 diabetes with and without CAD. Thirty-three patients with definite CAD and 33 age- and sex-matched patients without CAD (control) were studied. Insulin sensitivity was assessed by the K index of insulin tolerance test (KITT). Clinical characteristics, classical risk factors, lipoprotein (a), and insulin sensitivity were compared between the two groups. Patients with CAD had a significantly longer duration of diabetes (9.0 +/- 1.4 vs. 5.5 +/- 0.9 years, P < 0.05, respectively), were mostly hypertensive (69.7 vs. 39.4%, P < 0.05), and more likely to be treated with insulin (45.5 vs. 18.2%, P < 0.05) compared with the control. Concerning the metabolic parameters, patients with CAD had a significantly higher insulin resistance than control (2.40 +/- 0.15 vs. 3.23 +/- 0.17%/min, P < 0.01, respectively), higher triglyceride (1.39 +/- 0.10 vs. 1.05 +/- 0.05 mmol/l, P < 0.05), lower HDL cholesterol (1.05 +/- 0.05 vs. 1.28 +/- 0.06 mmol/l, P < 0.05), and higher lipoprotein (a) (27.5 +/- 4.3 vs. 17.4 +/- 2.0 mg/dl, P < 0.05). Multiple logistic regression analysis indicated that hypertension, insulin resistance, high lipoprotein (a) and triglyceride, and low HDL cholesterol were independently related to CAD. Our results suggest that insulin resistance per se is a significant risk factor for CAD in Japanese patients with type 2 diabetes.

Elevation of Serum Pro-Gastrin - Releasing Peptide in Patients with Medullary Thyroid Carcinoma and Small Cell Lung Carcinoma

Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells of the thyroid gland and produces a variety of peptides such as calcitonin (CT) and gastrin-releasing peptide (GRP). Here we measured serum levels of pro-gastrin-releasing peptide (Pro-GRP), a more stable precursor of GRP, in 15 patients with MTC (4 males, 11 females) who did not show any clinical or radiologic signs of small cell lung cancer. Serum Pro-GRP levels were elevated in 80% (12/15) patients. Significant correlation was observed between serum Pro-GRP and CT (r = 0.52) and carcinoembryonic antigen (CEA) (r = 0.56). Serum Pro-GRP levels also correlated with tumor size (r = 0.70). Serum Pro-GRP levels also decreased below the cut-off range in one patient after surgical resection. Our data suggest that Pro-GRP, which is considered to be a specific marker for small cell lung carcinoma, seems to be also helpful and additional marker for the diagnosis and monitoring the response to therapy in patients with MTC in addition to calcitonin as the main tumor marker.

Effects of Radiation on the Longitudinal Trends of Hemoglobin Levels in the Japanese Atomic Bomb Survivors

Abstract Wong, F. L., Yamada, M., Tominaga, T., Fujiwara, S. and Suzuki, G. Effects of Radiation on the Longitudinal Trends of Hemoglobin Levels in the Japanese Atomic Bomb Survivors. Radiat. Res. 164, 820–827 (2005). The late effects of radiation on the hematopoietic system have not been fully evaluated. We examined the long-term effects of radiation exposure on hemoglobin levels in the Japanese atomic bomb survivors over a 40-year period from 1958 to 1998. Compared to the unexposed survivors, the mean hemoglobin levels for those exposed to a bone marrow dose of 1 Gy were significantly reduced by 0.10 g/dl (95% CI: 0.04 to 0.16) or 0.67% at 40 years of age (P < 0.0001) and by 0.24 g/dl (95% CI: 0.08 to 0.40) or 1.8% at 80 years of age. Radiation effects are greater for smokers than for nonsmokers at age less than 35 years (P < 0.01), although cigarette smoking was associated with increased hemoglobin levels. Sex and birth cohort differences in radiation effects were not found after adjusting for smoking. The radiation-induced reduction in hemoglobin levels could not be explained by the presence of certain anemia-associated diseases. 

Apolipoprotein B and insulin resistance are good markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND It is widely known that low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerosis. However, recent studies reported that serum levels of apolipoprotein B (Apo B) and Apo B to apolipoprotein A-1 (Apo A-1) ratio were better predictors of atherosclerotic vascular disease compared with LDL-C. In this study, we investigated that Apo B concentrations and insulin resistance (HOMA-R) can be good markers of carotid atherosclerosis in patients with type 2 diabetes. METHODS Sixty-six type 2 diabetic patients with carotid atherosclerosis and 66 age- and sex-matched patients without carotid atherosclerosis were compared. The usefulness in risk assessment of LDL-C, Apo B, and HOMA-R for carotid atherosclerosis were estimated by receiver-operating characteristics (ROC) curve analysis. The percentage of carotid atherosclerosis in combination with two of these markers was calculated. RESULTS Type 2 diabetic patients with carotid atherosclerosis had significantly higher body mass index, higher blood pressure, higher LDL-C, and Apo B, and higher HOMA-R. The ranking of the area under the ROC curve was Apo B, HOMA-R, and LDL-C (0.70, 0.69, and 0.66, respectively). The percentage of patients with carotid atherosclerosis and high LDL-C was 60.7%, high LDL-C+high HOMA-R was 77.4%, and high Apo B+high HOMA-R was 90.9%, respectively. The usefulness of these combinations was significantly better than that of LDL-C alone (p<0.05 and p<0.01, respectively). CONCLUSIONS In conclusion, the combination of Apo B and HOMA-R is a superior marker of carotid atherosclerosis compared with LDL-C alone in patients with type 2 diabetes.

NOR-1: a nitric oxide releasing agent for calibrating low levels of nitric oxide by the chemiluminescence method.

Nitric oxide (NO) is formed in small amounts in vivo and is rapidly oxidized by interacting with oxygen, making measurement of its level difficult. The chemiluminescence assay is the most widely used method for detecting NO and is extremely sensitive to very small amounts of NO. However, it is difficult to prepare small amounts of NO to be used as a standard for NO analysis. NOR-1, a derivative of NOR-3, is a newly discovered NO donor with rapid NO-releasing activity. We assessed the dynamics of NO release and decomposition using NOR-1. Our results demonstrate that NOR-1 is stable in dimethylsulfoxide (DMSO) and is able to dilute at lower concentration (to picomolar levels) by DMSO without decomposition. NOR-1 released persistently 1.4 more excess of NO with 15 min of incubation. There was a linear relationship between the concentration of NOR-1 and that of NO released from NOR-1 (r =0.997) These findings suggest that NOR-1 is a useful reagent for the calibration of lower NO detection.

A case of Sjögren’s syndrome presenting as hypokalemic myopathy due to distal renal tubular acidosis

We report a case of hypokalemic myopathy with distal renal tubular acidosis which leads to the diagnosis of Sjögren’s syndrome (SS). A 67-year-old man was admitted to our department for progressive muscle weakness and myalgia. Laboratory data demonstrated hypokalemia with hyperchloremic acidosis, elevated muscle enzyme and inability to acidify urine. Findings of interstitial nephritis, which is consistent with renal tubular acidosis in SS, were found on renal biopsy. Remarkable changes of the renal tubule, including tubular atrophy, dilatation and intratubular casts, were observed. Potassium replacement therapy normalized the marked elevated urinaryβ2-microglobulin excretion as well as the improvement of muscle symptoms. Taken together with our findings, it it suggested that sustained hypokalemia may partly contribute to the exacerbation of the pre-existing renal tubular disorder in SS.