Shoichiro Izawa

20/(fasting C-peptide × fasting plasma glucose) is a simple and effective index of insulin resistance in patients with type 2 diabetes mellitus: a preliminary report

BackgroundWe developed a simple and new insulin resistance index derived from a glucose clamp and a meal tolerance test (MTT) in Japanese patients with type 2 diabetes mellitus.MethodsFifteen patients [mean age: 53 years, fasting plasma glucose (FPG) 7.7 mmol/L, HbA1c 7.1% (54 mmol/mol), body mass index 26.8 kg/m2] underwent a MTT and a glucose clamp. Participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity (CPR) was measured at 0 (fasting; F-CPR) and 120 min. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices (ISI) were calculated from the MTT results. The glucose infusion rate (GIR) was measured during hyperinsulinemic–euglycemic glucose clamps.ResultsThe mean GIR in all patients was 5.8 mg·kg–1·min–1. The index 20/(F-CPR × FPG) was correlated strongly with GIR (r = 0.83, P < 0.0005). HOMA-IR (r = −0.74, P < 0.005) and ISI (r = 0.66, P < 0.01) were also correlated with GIR. In 10 patients with mild insulin resistance (GIR 5.0–10.0 mg·kg–1·min–1), 20/(F-CPR × FPG) was very strongly correlated with GIR (r = 0.90, P < 0.0005), but not with HOMA-IR and ISI (r = − 0.49, P = 0.15; r = 0.20, P = 0.56, respectively). In patients with mild insulin resistance, plasma adiponectin (r = 0.65, P < 0.05), but not BMI or waist circumstance, was correlated with GIR.Conclusions20/(F-CPR × FPG) is a simple and effective index of insulin resistance, and performs better than HOMA-IR and ISI in Japanese patients with type 2 diabetes mellitus. Our results suggest that 20/(F-CPR × FPG) is a more effective index than HOMA-IR in Japanese patients with mild insulin resistance.

Utility of Shear Wave Elastography for Diagnosing Chronic Autoimmune Thyroiditis.

The aims of this study were to evaluate the utility of shear wave elastography (SWE) using acoustic radiation force impulse (ARFI) for diagnosing chronic autoimmune thyroiditis (CAT) and to verify the effect of fibrotic thyroid tissue on shear wave velocity (SWV). The subjects were 229 patients with 253 normal thyroid lobes (controls) and 150 CAT lobes. The SWV for CAT (2.47 ± 0.57 m/s) was significantly higher than that for controls (1.59 ± 0.41 m/s) (P < 0.001). The area under the receiver operating characteristics (ROC) curve for CAT was 0.899, and the SWV cut-off value was 1.96 m/s. The sensitivity, specificity, and diagnostic accuracy were 87.4%, 78.7%, and 85.1%, respectively. Levels of anti-thyroperoxidase antibodies and thyroid isthmus thickness were correlated with tissue stiffness in CAT. However, there was no correlation between levels of anti-thyroglobulin antibodies and tissue stiffness. Quantitative SWE is useful for diagnosing CAT, and it is possible that SWE can be used to evaluate the degree of fibrosis in patients with CAT.

Correlation between Quantitative Shear Wave Elastography and Pathologic Structures of Thyroid Lesions

The aim of this study was to determine the correlation between shear wave velocity (SWV) generated by acoustic radiation force impulse and the pathologic structure of thyroid lesions. A total of 599 thyroid tissue samples were divided into four groups based on pathologic structure: 254 normal thyroid tissue samples as a control, 128 with chronic autoimmune thyroiditis (CAT) that demonstrated diffuse fibrosis, 165 with benign nodules that had high cell density and 52 with papillary thyroid carcinoma (PTC) that showed high cell density and fibrosis. The mean SWVs in each group were as follows: 1.60 ± 0.18 m/s in normal thyroid, 2.55 ± 0.28 m/s in CAT, 1.72 ± 0.31 m/s in benign nodules and 2.66 ± 0.95 m/s in PTC. The SWVs of CAT and PTC were significantly higher than those of normal thyroid, (p < 0.001). SWV was significantly affected by fibrosis.

Clinical and Molecular Features of a TSH-Secreting Pituitary Microadenoma

We describe a case of a thyroid stimulating hormone (TSH)-secreting pituitary microadenoma, and report the systematic gene expression profile of the surgically- removed tumor. A 50-year-old woman was referred to our hospital because she had high TSH, free-T4, and free-T3 levels, and a pituitary tumor that was visualized with magnetic resonance imaging. Her basal TSH level was high even after a high T3 loading dose, and increased following administration of thyroid releasing hormone (TRH) even after administration of a high dose of exogenous T3. Her clinical symptoms and peripheral markers for T3 were responsive to exogenous T3. There was no thyroid hormone receptor (TR) β gene mutation. The patient was diagnosed with a TSH-secreting pituitary adenoma, and trans-sphenoid surgery was performed. The histologic features and immunophenotype were consistent with a TSH-secreting pituitary adenoma. Reverse transcription-polymerase chain reaction analysis of pituitary hormones, pituitary-specific transcription factors, receptors, and transcriptional cofactors of clinical significance was performed on the removed tumor. The tumor expressed TSH, growth hormone, prolactin, α-subunit, pituitary transcription factor-1 (pit-1) but not proopiomelanocortin (POMC), prophet of pit-1 (prop-1) and pituitary cell-restricted T box factor (Tpit). TRβ and TRH-receptor gene expression was normal. Three steroid receptor coactivators (SRC)-1, SRC-2, and SRC-3 were expressed. Nuclear receptor corepressor (N-CoR)2 was absent in the tumor, whereas nuclear receptor corepressor (N-CoR1) was expressed. Somatostatin receptor type 1 expression was significantly decreased, whereas type 4 receptor was expressed, which are unusual characteristics for pituitary tumors. The gene expression pattern in the tumor might have a role in the clinical features of this case.

Impact of Fibrotic Tissue on Shear Wave Velocity in Thyroid: An Ex Vivo Study with Fresh Thyroid Specimens

We sought to elucidate the correlation between shear wave velocity (SWV) and fibrosis in thyroid by precisely assessing pathological structures inside 5 × 5 mm2 regions of interest (ROIs) of resected specimens, under conditions that excluded physical artifacts. The materials were unselected thyroid and lymph node specimens resected during thyroid surgery. Immediately after surgery, fresh unfixed thyroid and metastatic lymph node specimens were suspended in gel phantoms, and SWV was measured. Upon pathological examination of each specimen, the extent of fibrosis was graded as none, moderate, or severe. A total of 109 specimens were evaluated: 15 normal thyroid, 16 autoimmune thyroiditis, 40 malignant nodules, 19 benign thyroid nodules, and 19 metastatic lymph nodes. When all specimens were classified according to the degree of fibrosis determined by pathological imaging, the mean SWV was 1.49 ± 0.39 m/s for no fibrosis, 2.13 ± 0.66 m/s for moderate fibrosis, and 2.68 ± 0.82 m/s for severe fibrosis. The SWVs of samples with moderate and severe fibrosis were significantly higher than those of samples without fibrosis. The results of this study demonstrate that fibrosis plays an important role in determining stiffness, as measured by SWV in thyroid.

Autoantibody against WD repeat domain 1 is a novel serological biomarker for screening of thyroid neoplasia

Thyroid nodules are common among adults, and accurate diagnosis is critical in for management decisions. Ultrasound and fine needle aspiration cytology are the most common methods to evaluate nodules, but they are not practical for screening large numbers of patients because of cost and time considerations.

Prevalence of Cardiovascular Disease and Its Risk Factors in Primary AldosteronismNovelty and Significance: A Multicenter Study in Japan

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K+ ⩽3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and β cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls. We recruited 30 participants (12 T2DM and 18 non-diabetic healthy controls). Participants underwent a meal tolerance test during which plasma glucose, insulin and serum C-peptide immunoreactivity were measured. We performed a hyperinsulinemic-euglycemic clamp and measured the glucose-disposal rate (GDR). The fasting serum levels of adiponectin, insulin-like growth factor-1, irisin, autotaxin, FABP4 and interleukin-6 were measured by ELISA. We found a strong negative correlation between FABP4 concentration and GDR in T2DM (r = -0.657, p = 0.020). FABP4 also was positively correlated with insulin secretion during the meal tolerance test in T2DM (IRI (120): r = 0.604, p = 0.038) and was positively related to the insulinogenic index in non-DM subjects (r = 0.536, p = 0.022). Autotaxin was also related to GDR. However, there was no relationship with insulin secretion. We found that serum FABP4 concentration were associated with insulin resistance and secretion in T2DM. This suggests that FABP4 may play an important role in glucose homeostasis.

Implication of intracellular localization of transcriptional repressor PLZF in thyroid neoplasms

BackgroundPromyelocytic leukaemia zinc finger (PLZF) is a transcriptional repressor that was originally isolated from a patient with promyelocytic leukaemia. PLZF also affects key elements for cell cycle progression, such as cyclin A, and can affect the tumourigenicity of various cancers. Thus far, the behaviour of PLZF in thyroid carcinoma remains unclear.MethodsWe analysed the expression profile of PLZF in different types of benign and malignant thyroid lesions as well as in normal thyroid tissue. Specifically, we examined PLZF expression in normal thyroid (N; n = 4), adenomatous lesion (AL; n = 5), follicular adenoma (FA; n = 2), papillary thyroid carcinoma (PTC; n = 20), and anaplastic thyroid carcinoma (ATC; n = 3) samples. PLZF expression was estimated by western blotting and immunohistochemical (IHC) staining.ResultsPLZF was expressed in all samples of thyroid lesions examined. In N, AL, and FA, PLZF was mainly localized in the nucleus. In contrast, in PTC and ATC, PLZF was mainly expressed in the cytosol with high intensity. In more detail, the cytoplasmic IHC scores in PTC with capsular invasion (CI) and lymph node (LN) metastasis were higher than those in PTC without CI and LN metastasis.ConclusionsPLZF shows different subcellular localizations among PTC, ATC, and other thyroid lesions. Furthermore, high cytoplasmic expression of PLZF may be correlated with CI and LN metastasis in thyroid carcinoma. The present report is the first to describe the implications of intracellular PLZF expression in thyroid carcinomas.

Body mass index ≥23 is a risk factor for insulin resistance and diabetes in Japanese people: A brief report

Background Screening for undiagnosed type 2 diabetes mellitus is recommended for Asian Americans with a body mass index ≥23. However, the optimal body mass index cut-off score for predicting the risk of diabetes mellitus in Japanese people is not well known. The aim of this study was to determine the best body mass index cut-off score for predicting insulin resistance and diabetes mellitus in the Japanese population. Methods This study had two parts, a clinical investigation and a retrospective observational investigation. In the clinical part of the study, 58 participants (26 with type 2 diabetes mellitus and 32 non-diabetics) underwent a hyperinsulinemic-euglycemic clamp from which their glucose disposal rate was measured. For the retrospective part of the study, medical check-up data from 88,305 people in the Tottori Prefecture were analyzed for clinical evidence of diabetes mellitus. The optimal BMI cut-off scores for prediction of insulin resistance and diabetes mellitus were determined. Results In the clamp study, the optimal body mass index cut-off score to predict insulin resistance in non-diabetic patients was 22.7. All participants with type 2 diabetes mellitus were insulin resistant, and the optimal body mass index cut-off score for prediction of severe insulin resistance was 26.2. When the data from the type 2 diabetic and the non-diabetic participants were combined, the optimal body mass index cut-off score for prediction of insulin resistance was 23.5. Analysis of 88,305 medical check-up records yielded an optimal body mass index cut-off score for prediction of diabetes mellitus of 23.6. Conclusions These results suggest that having a body mass index ≥23 is a risk factor for insulin resistance and diabetes mellitus in the Japanese population.