Obesity causes type 2 diabetes, atherosclerosis and cardiovascular diseases by inducing systemic insulin resistance. It is now recognized that obesity is related to chronic low-grade inflammation in adipose tissue. Specifically, activated immune cells infiltrate adipose tissue and cause inflammation. There is increasing evidence that activated macrophages accumulate in the hypertrophied adipose tissue of rodents and humans and induce systemic insulin resistance by secreting inflammatory cytokines. Accordingly, a better understanding of the molecular mechanisms underlying macrophage activation in adipose tissue will facilitate the development of new therapeutic strategies. Currently, little is known about the regulation of macrophage activation, although E3 ubiquitin ligase Casitas B-lineage lymphoma (Cbl)-b was identified recently as a novel negative regulator of macrophage activation in adipose tissue. Cbl-b, which is a suppressor of T- and B-cell activation, inhibits intracellular signal transduction by targeting some tyrosine kinases. Notably, preventing Cbl-b-mediated macrophage activation improves obesity-induced insulin resistance in mice. c-Cbl is another member of the Cbl family that is associated with insulin resistance in obesity. These reports suggest that Cbl-b and c-Cbl are potential therapeutic targets for treating obesity-induced insulin resistance. In this review, we focus on the importance of Cbl-b in macrophage activation in aging-induced and high-fat diet-induced obesity.

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The Japan Thyroid Association (JTA) recently published new guidelines for clinical management of thyroid nodules. This paper introduces their diagnostic system for reporting thyroid fine-needle aspiration cytology. There are two points where the new reporting system that differs from existing internationally-accepted ones. The first is the subclassification of the so-called indeterminate category, which is divided into ‘follicular neoplasm’ and ‘others’. The second is the subclassification of follicular neoplasm into ‘favor benign’, ‘borderline’ and ‘favor malignant’. It is characterized by self-explanatory terminologies as to histological type and probability of malignancy to establish further risk stratification as well as to facilitate communication between clinicians and cytopathologists. The different treatment strategies adopted for thyroid nodules is deeply influenced by the particular diagnostic system used for thyroid cytology. In Western countries all patients with follicular neoplasms are advised to have immediate diagnostic surgery while patients in Japan often undergo further risk stratification without immediate surgery. The JTA diagnostic system of reporting thyroid cytology is designed for further risk stratification of patients with indeterminate cytology. If a surgeon applies diagnostic lobectomy to all patients with follicular neoplasm unselectively, this subclassification of follicular neoplasm has no practical meaning and is unnecessary. Cytological risk stratification of follicular neoplasms is optional and cytopathologists can choose either a simple 6-tier system without stratification of follicular neoplasm or a complicated 8-tier system depending on their experience in thyroid cytology and clinical management.

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Glycated hemoglobin (HbA1c) and glycated albumin (GA) are frequently used as glycemic control markers. These markers are influenced by either altered hemoglobin metabolism or albumin metabolism. We investigated the correlation between HbA1c and GA by collecting only data that had not been affected by the turnover of either HbA1c or GA and proposed a novel equation for accurately estimating the extrapolated HbA1c (eHbA1c) value based on the GA value. Data sets for a total of 2461 occasions were obtained from 731 patients (including non-diabetes patients) whose HbA1c and GA values were simultaneously measured. Data sets obtained from patients undergoing hemodialysis, patients with hematological malignancies, pregnancy, chronic liver diseases, hyperthyroidism, steroid treatment or a blood transfusion during the past 3 months, or patients without albumin, hemoglobin, eGFR, or urinary protein measurements and data sets with an eGFR of less than 30 mL/min/1.73 m², a hemoglobin level of less than 10 mg/dL, an albumin level of below 3.0 g/mL, or a urinary protein level of 3+ were excluded. Finally, we selected 284 data sets. We then analyzed these data sets, performed a scatter plot to examine the correlation between HbA1c and GA, and established an equation describing the resulting correlation. Based on all the data points, the resulting equation was HbA1c = 0.216 × GA + 2.978 [R² = 0.5882, P < 0.001].

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μ-Crystallin (CRYM) is also known as NADPH-dependent cytosolic T3-binding protein. A study using CRYM-null mice suggested that CRYM stores triiodothyronine (T3) in tissues. We previously established CRYM-expressing cells derived from parental GH3 cells. To examine the precise regulation of T3-responsive genes in the presence of CRYM, we evaluated serial alterations of T3-responsive gene expression by changing pericellular T3 concentrations in the media. We estimated the constitutive expression of three T3-responsive genes, growth hormone (GH), deiodinase 1 (Dio1), and deiodinase 2 (Dio2), in two cell lines. Subsequently, we measured the responsiveness of these three genes at 4, 8, 16, and 24 h after adding various concentrations of T3. We also estimated the levels of these mRNAs 24 and 48 h after removing T3. The levels of constitutive expression of GH and Dio1 were low and high in C8 cells, respectively, while Dio2 expression was not significantly different between GH3 and C8 cells. When treated with T3, Dio2 expression was significantly enhanced in C8 cells, while there were no differences in GH or Dio1 expression between GH3 and C8 cell lines. In contrast, removal of T3 retained the mRNA expression of GH and Dio2 in C8 cells. These results suggest that CRYM expression increases and sustains the T3 responsiveness of genes in cells, especially with alteration of the pericellular T3 concentration. The heterogeneity of T3-related gene expression is dependent on cellular CRYM expression in cases of dynamic changes in pericellular T3 concentration.

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Surgical treatment of pheochromocytoma is associated with a high risk of hemodynamic instability. To reduce the risk of perioperative complications, adequate medical treatment to normalize blood pressure and restore blood volume is required. Accurate evaluation of the circulating blood volume (CBV) in perioperative patients with pheochromocytoma is clinically important. In the present study, we adopted whole-body bioimpedance monitoring technique using the Non-Invasive Cardiac System (NICaS), which can non-invasively measure cardiac output (CO) values. NICaS-derived CO values were evaluated in eight preoperative patients with pheochromocytoma and were compared with simultaneous CBV values measured by a conventional indicator dilution method using ¹³¹I-labeled human serum albumin. In these patients with pheochromocytoma, the NICaS-derived CO values were significantly correlated with the CBV values measured by ¹³¹I-labeled human serum albumin (4.86 ± 1.05 L/min vs 4.79 ± 1.02 L; r = 0.906; P = 0.002). Sequential NICaS-derived CO values confirmed that CBV increased after preoperative treatment with an α-blocker, with or without volume loading. The results of this study indicate that NICaS can be used to accurately and non-invasively evaluate the hemodynamic status. By sequential monitoring of NICaS-derived CO values, we are able to confirm whether adequate CBV in a patient with pheochromocytoma is obtained by preoperative medical treatment with α-blockers or volume loading, to avoid perioperative complications.

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Type 1 diabetes is characterized by T-cell-mediated autoimmune destruction of pancreatic β-cells. Currently, approximately 50 type 1 diabetes susceptibility genes or chromosomal regions have been identified. However, the functions of type 1 diabetes susceptibility genes in T cells are elusive. In this study, we evaluated the correlation between type 1 diabetes susceptibility genes and T-cell signaling. The expression levels of 22 candidate type 1 diabetes susceptibility genes in T cells from nonobese diabetic (NOD), control C57BL/6 (B6), and NOD-control F1 hybrid mice were analyzed in response to 2 key immunoregulatory cytokines: interleukin-2 (IL-2) and transforming growth factor β (TGF-β). Exogenous gene expression studies were also performed in EL4 and Jurkat E6.1 T-cell lines. Significant differences in the expression of Clec16a, Dlk1, Il2, Ptpn22, Rnls, and Zac1 (also known as Plagl1) were observed in T cells derived from the 3 strains of mice, and TGF-β differentially influenced the expression of Ctla4, Foxp3, Il2, Ptpn22, Sh2b3, and Zac1. We found that TGF-β induced Zac1 expression in both primary T cells and EL4 cells and that exogenous expression of Zac1 and ZAC1 in T-cell lines altered the expression of Il2 and DLK1, respectively. The results of our study indicate the possibility that additional genetic pathways underlying type 1 diabetes susceptibility, including those involving Clec16a, Dlk1, Rnls, Sh2b3, and Zac1 under IL-2 and TGF-β signaling in T cells, may be shared between human and NOD mice.

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A 67-year-old female with hypertension and impaired glucose tolerance was admitted to our hospital because of a typical acromegalic appearance, including large, thickened bulky hands and feet, and a large prominent forehead and tongue. She did not have a Cushingoid appearance, such as a moon-face, buffalo hump, purple striae or central obesity. The laboratory data revealed a serum GH level of 4.6 ng/mL and serum insulin-like growth factor-1 level of 811 ng/mL. The oral glucose tolerance test showed no suppression of the GH values. An endocrine examination showed a lack of circadian rhythmicity of ACTH and cortisol. Cortisol was not suppressed by a low dose of dexamethasone during the suppression test, but was suppressed by a high dose of dexamethasone. A radiological study revealed two isolated adenomas in the pituitary and a left adrenal tumor. These findings strongly suggested a diagnosis of acromegaly with subclinical Cushing’s disease and a left adrenal incidentaloma. Transsphenoidal surgery was performed. Hematoxylin and eosin staining showed that the left and right pituitary adenomas were composed of basophilic and acidophilic cells, respectively. Immunohistochemical staining showed the left adenoma to be positive for ACTH and negative for GH. In contrast, the right adenoma was GH-positive and ACTH-negative. This is a rare case of independent double pituitary adenomas with distinct hormonal features. We also provide a review of the previously reported cases of double pituitary adenomas and discuss the etiology of these tumors.

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Parathyroid carcinoma is a rare tumor associated with poor prognosis, thus early preoperative recognition and surgical resection are critical. However, because of a lack of definitive diagnostic markers and typical clinical features, it is difficult to diagnose this disease in its early stages and it is often misdiagnosed as parathyroid adenoma. Additionally, little is known about the molecular pathogenesis of parathyroid carcinoma because of its rarity. To better understand the molecular genetics of parathyroid carcinoma in the Chinese population, we undertook gene expression profiling of eight parathyroid tumors (five parathyroid adenomas and three parathyroid carcinomas) and five normal parathyroid samples. Differential gene sets between the groups were identified, which may serve as diagnostic biomarkers. Using both gene and protein expression, we demonstrated that CD24, HMOX1, VCAM1 and KCNA3 are useful markers for parathyroid carcinoma. Our findings provide insights into the molecular mechanisms of parathyroid tumorigenesis and may help to improve the diagnosis and treatment of parathyroid carcinoma.

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Type 2 diabetic (T2D) patients exhibit fasting relative hyperproinsulinemia owing to pancreatic β-cell dysfunction. To clarify the mechanism underlying this hyperproinsulinemic state, we evaluated the activities of the endopeptidases prohormone convertase (PC) 1/3 and PC2 in T2D patients. Fasting blood levels of intact proinsulin (IPI), total proinsulin (t-PI) and C-peptide were measured simultaneously, and intravenous glucagon loading was performed to investigate the dynamics of circulating proinsulin-related molecules released from pancreatic β-cells in 12 healthy volunteers and 18 T2D patients. Taking advantage of the 95% cross-reactivity between proinsulin and des-31,32-proinsulin (des-31,32-PI) with the human proinsulin radioimmunoassay kit used in this study, we estimated PC1/3 and PC2 activities using the following formulas: des-31,32-PI = (t-PI–IPI)/0.95; PC1/3 activity = des-31,32-PI/IPI; and PC2 activity = C-peptide/des-31,32-PI. C-peptide responses to glucagon were slightly lower among T2D patients. IPI and the IPI/C-peptide ratio were significantly higher in T2D patients (p<0.05 and p<0.01, respectively). There was no difference in des-31,32-PI levels or PC2 activity between the two groups. However, PC1/3 activity was significantly lower in T2D patients than in the control group (p<0.01). We propose that decreased activity of PC1/3 rather than PC2 in pancreatic β-cells is involved in the impaired proinsulin processing, resulting in elevated IPI levels in T2D patients.

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Shear wave elastography (SWE) using acoustic radiation force impulse (ARFI) is a novel ultrasonography technique. The aim of this study was to investigate the clinical usefulness of quantitative SWE for differentiating thyroid nodules. For phantom study, we measured the shear wave velocities (SWVs) of the four spheres of 2- and 1-cm diameters with varying hardness. For clinical study, the SWVs of normal thyroid glands and thyroid nodules, that were classified as benign or malignant according to either cytological or pathological findings, were measured. The SWVs of each thyroid patient were compared with that of a normal thyroid and each other. In phantom study, the SWVs for the 2-cm spheres correlated with the hardness of the targets, whereas the values for the 1-cm spheres did not. In clinical study, 112 nodules identified in 167 patients and 94 normal thyroid glands were analyzed according to the criteria for the study. The nodules included 84 benign nodules, and 28 papillary carcinoma. The mean SWVs of each group were 1.64 ± 0.47 m/s for normal thyroid, 1.88 ± 0.62 m/s for benign nodules and 2.67 ± 0.76 m/s for papillary carcinoma. The SWVs of papillary carcinoma were significantly higher than those of benign nodules (P < 0.001). The area under the ROC curve was 0.809 with a cut-off value of 2.01 m/s. The sensitivity and specificity were 85.7% and 62.0% respectively. Results showed that SWE provides new information on tumor characteristics, such as hardness and larger nodules tended to provide stable measurements.

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Strategies for increasing functional beta cell mass are effective for diabetes therapy. Although controversy remains on the existence of facultative beta cell progenitors in the adult pancreas, most evidence does not support such a possibility. One of the greatest physiological increases in beta cells has been detected in the maternal pancreas during pregnancy, following neonatal period and in the setting of insulin resistance. However, no systematical analysis on the beta cell growth in this period has been ever performed. Here we analyzed beta cell replication by quantifying BrdU incorporated beta cells at different time points in the pregnant mice. Similarly, we evaluated the possible involvement of beta cell neogenesis (differentiation from progenitor cells) by analyzing expression of Neurog3, a key determinant of pancreatic endocrine cell neogenesis during embryogenesis, in the exocrine pancreas. We found a dynamic increase in beta cell replication, but failed to detect beta cell neogenesis, demonstrating that beta cell growth in the maternal pancreas during pregnancy is predominantly attributable to beta cell replication, rather than beta cell neogenesis.

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Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that usually results from paternally and maternally transmitted mutations in genes for steroidogenic enzymes. Recent studies on steroid 21-hydroxylase deficiency, the most common form of CAH, have revealed that a small percentage of patients have a non-carrier parent; uniparental disomy (UPD) and de novo mutations were reported as disease-causing mechanisms in these patients. However, it remains unknown whether UPD and de novo mutations underlie other forms of CAH. Here, we report a male patient with steroid 11β-hydroxylase deficiency (11OHD) born to a non-carrier mother. The patient was identified by an elevated 17-hydroxyprogesterone level at a neonatal mass-screening test. His clinical features were comparable to those of previously reported patients with 11OHD. Direct sequencing of CYP11B1 identified a homozygous IVS7+1G>A mutation in the patient, which was not shared by his mother. Comparative genomic hybridization of the patient detected UPD of chromosome 8 [UPD(8)]. Microsatellite analysis indicated non-maternal origin of the UPD(8) and confirmed parentage of other chromosomes. This study shows for the first time that 11OHD can be caused by UPD in the presence of a non-carrier parent. Awareness of such rare cases should improve the accuracy of genetic counseling for families with CAH. Our data support the importance of UPD as an underlying mechanism of autosomal recessive disorders.

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Insulin autoantibodies can be produced by insulin injections but rarely cause severe side effects such as glucose instability and insulin allergy. We study the characteristics of insulin autoantibody-positive diabetic patients with a medical history of insulin therapy using single and multiple (adjusted for age, sex, type of diabetes) logistic regression analyses. Associations between insulin autoantibodies and age, sex, type of diabetes, HbA1c, and serum creatinine were not significant, but the association between insulin autoantibodies and duration of insulin use was significant. Unadjusted and adjusted odds ratios were 1.08 (1.02–1.14) and 1.07 (1.01–1.14), respectively. Unadjusted and adjusted odds ratios for protamine-containing insulin were 3.08 (1.49–6.34) and 4.27 (1.90–9.58), respectively. The adjusted odds ratios for premixed biphasic insulin and intermediate-acting insulin were 2.21 (1.03–4.73) and 2.35 (1.01–5.49), respectively. Associations between insulin autoantibodies and any insulin analog were not significant. These results suggest that protamine-containing insulin and duration of insulin use are risk factors for the production of insulin autoantibodies. If patients with poorly controlled diabetes have a history of protamine-containing insulin therapy over a long time, the appearance of insulin autoantibodies should be monitored.

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A novel clinical entity related to autoimmune polygladular syndrome (APS) termed “anti–PIT-1 antibody syndrome” is characterized by a presence of circulating autoantibody against the pituitary-specific transcriptional factor-1 (PIT-1) with acquired specific defect in GH, PRL, and TSH. Although autoimmunity to PIT-1 has been suggested, the underlying mechanisms remain to be elucidated. Sialic acid acetylesterase (SIAE) plays a crucial role in regulating the threshold of autoantibody production of B-cells and the defective variants of SIAE are associated with an increased risk of various autoimmune diseases such as type 1 diabetes (T1DM). To explore the link between anti–PIT-1 antibody syndrome and SIAE, we analyzed SIAE gene in 3 patients with anti–PIT-1 antibody syndrome and 200 healthy control subjects, and compared the prevalence of single nucleotide polymorphisms. Intriguingly, we found A467V SIAE variants (c.1400C>T, rs7941523) in a heterozygous state in all the patients with anti-PIT-1 antibody syndrome, while we detected in 6 % of control subjects, in which the prevalence was significantly increased in the patients (P<0.0005). Considering the physiological function of SIAE and the clinical features of anti-PIT-1 antibody syndrome, present data imply a novel aspect of the pathogenesis in this disease.

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