By using transgenic and knockout mice, we have elucidated that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. In humans, loss-of-function mutations in the gene coding for guanylyl cyclase-B (GC-B), the specific receptor for CNP, have been proved to be the cause of acromesomelic dysplasia, type Maroteaux, one form of human skeletal dysplasias. Following these results, we have started to translate the stimulatory effect of CNP on endochondral bone growth into the therapy for patients with skeletal dysplasias. We have shown that targeted overexpression of CNP in cartilage or systemic administration of CNP reverses the impaired skeletal growth of mice model of achondroplasia, the most common form of human skeletal dysplasias.

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α-glucosidase inhibitors (αGIs) increase active glucagon-like peptide-1 (GLP-1) and reduce the total glucosedependent insulinotropic polypeptide (GIP) levels, but their ability to prevent diabetes remains uncertain. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels and improve hyperglycemia in a glucose-dependent fashion. However, the effectiveness of their combination in subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) is uncertain. The present study evaluated the effect of miglitol, sitagliptin, and their combination on glucose, insulin and incretin levels in non-diabetic men. Miglitol and sitagliptin were administered according to four different intake schedules (C: no drug, M: miglitol; S: sitagliptin, M+S: miglitol and sitagliptin). The plasma glucose levels were significantly lower for M, S and M+S than for the control. The areas under the curve (AUCs) of the plasma active GLP-1 level in the M, S, and M+S groups were significantly greater than that in the control group. The AUC of the plasma active GLP-1 level was significantly greater for M+S group than for the M and S groups. The AUC of the plasma total GIP level was significantly smaller for M+S group than for the control and M and S groups. The results of our study suggest that miglitol, sitagliptin, or their combination contributes to the prevention of type 2 diabetes.

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We previously reported that the administration of miglitol after a meal was equally effective as administration before a meal. Since glucagon-like peptide-1 (GLP-1) reportedly promotes islet cell growth and inhibits apoptosis in animal models, an increase in GLP-1 secretion might also be beneficial for islet cell function and mass in humans. Miglitol reportedly enhances GLP-1 responses and reduces glucose-dependent insulinotropic polypeptide (GIP). However, whether the effect of miglitol on these incretins is comparable when miglitol is administered before or after a meal remains uncertain. Here, we compared the effects of the pre-meal versus post-meal administration of miglitol on the plasma active GLP-1 and total GIP levels in healthy men. Miglitol was administered according to three different intake schedules in each subject (control: no drug, intake 1: drug administered just before a meal [50 mg]; intake 2: drug administered at 30 min after the start of a meal [50 mg]). The area under the curve (AUC) of the plasma GLP-1 level for the intake 1 group was significantly greater than those of the control and intake 2 groups. The AUCs of the plasma GIP level for the intake 1 and 2 groups were significantly smaller than that of the control. The administration of miglitol just before a meal, rather than after a meal, is recommended in view of the up-regulation of GLP-1.

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A 75-year-old woman was admitted to our hospital because of a poor glycemic control. She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma ACTH and cortisol levels, lack of their circadian rhythm, non-suppressibility to high-dose dexamethasone, responsiveness to CRH, but not to DDAVP, and suppression to octreotide. Pituitary MRI showed an equivocal small lesion. CT scan of the chest showed two nodular lesions in the right lung (S5, S7), while a mild uptake was noted only in S5 lesion by FDG-PET, but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy (SRS). Inferior petrosal sinus sampling revealed a gradient of plasma ACTH after CRH stimulation, consistent with the diagnosis of Cushing’ s disease. She underwent middle and inferior lobectomy of the right lung. The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive ACTH immunoreactivity, while that of S5 was cryptococcal granuloma. RT-PCR revealed abundant expressions of POMC and SSTR (-1, -2, -5), but not of CRHR and V1bR. Postoperatively, abnormal endocrine data were normalized along with improvement of hypertension and diabetes. This was a diagnostic challenging case with ectopic ACTH syndrome indistinguishable from Cushing’ s disease by various endocrine and imaging tests, among which SRS successfully localized the tumor responsible for ectopic ACTH secretion.

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A 34-year-old Japanese woman was referred to the hospital because of general fatigue and palpitations. She was diagnosed as having resistance to thyroid hormone (RTH) and Hashimoto’s thyroiditis at the age of 28. She felt general fatigue, palpitations, heat intolerance, and sweating for 6 months. Thyroid function tests demonstrated elevated levels of free triidothyronine (T3) and free thyroxine (T4) that were above detectable ranges and a completely suppressed level of TSH that was below the detectable range. Titers of anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) were positive. A 20-minute Technetium-m99 pertechnetate thyroid uptake imaging study showed an elevated value of 39.53% and a normal-shaped thyroid gland. These results indicated that Graves’ disease (GD) caused primary hyperthyroidism. Pituitary and peripheral tissues responded to the presence of excess thyroid hormone in the patient. Oral administration of methimazole was started and continued for 1 year 10 months, after which it was ceased. Two years after the cessation of methimazole treatment, level of free T4 was elevated compared to reference range, but levels of TSH and free T3 were within normal reference ranges. Titers of TRAb and TSAb remained negative for 2 years. These findings indicated that the patient’s GD was in remission. In conclusion, it is difficult to make a differential diagnosis between GD with RTH and GD alone if RTH is not diagnosed before the onset of GD. An antithyroid drug is able to cause the remission of GD with RTH.

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Reactive C-cell hyperplasia (CCH) has been observed in cases of autoimmune Hashimoto’s thyroiditis; however, its occurrence in Graves’ disease, the other major autoimmune disorder, has not yet been investigated. On the other hand, although Carcinoembryonic Antigen (CEA) serum levels have been reported elevated in patients with autoimmune thyroid disease (ATD), the source of CEA production at the cellular level is not elucidated. The aim of this study was to evaluate CCH and CEA immunohistochemical expression and comparatively analyze them in 136 ATD cases (107 Hashimoto’s and 29 Graves’ disease cases) and 20 cases of nodular hyperplasia (NH). Immunohistochemistry using monoclonal antibodies to chromogranin and CEA was performed. A scoring system for CCH and semiquantitative evaluation for CEA expression were applied. C-cell hyperplasia was absent in NH cases. In contrast, it was detected in 11% of ATD cases being more frequently observed in Hashimoto’s (12.1%) than Graves’ disease (6.8%) CCH associated to male sex and older age of Hashimoto’s patients. CEA was detected only in ATD cases (33.8%), in C-cells and in follicular cells as well, being more frequently detected in Graves’ (44.8%) than Hashimoto’s (30.8%) disease. An interesting finding was an emerging possible association of CEA expression with oxyphilic change but not with C-cell hyperplasia in Hashimoto’s thyroiditis. No significant correlation was established between CCH and CEA follicular cell expression in neither disease. In conclusion, C-cell hyperplasia and CEA expression may be encountered in the setting of Hashimoto’s thyroiditis and Graves’ disease.

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Mutations in the GPR54 gene have already been identified as a cause of idiopathic hypogonadotrophic hypogonadism and central precocious puberty (CPP) in certain patients. However, currently there is only a limited amount of data available regarding KISS1 gene mutations or polymorphisms. The aim of this study is to identify KISS1 gene mutations or polymorphisms in Korean girls with CPP. 101 Korean girls with CPP were recruited as the patient group, and 51 healthy Korean female adults as the control group. All coding exons and exon-intron boundaries of the KISS1 gene were sequenced. The relationships between identified sequence variations and CPP were evaluated via the comparison of allele frequencies between the two groups. Different clinical characteristics were also compared between the subgroups with or without a certain variation in the patient group. Eight polymorphisms were identified in the KISS1 gene. Although two of them were novel, those polymorphisms could not lead to amino acid changes. p.P110T was detected less frequently in CPP patients than in the controls (P = 0.022). Moreover, the CPP patients with p.P110T evidenced lower peak FSH values under GnRH stimulation than those without p.P110T (P = 0.002). The allele frequencies of several polymorphisms in the Korean population were identified in this study. An infrequent polymorphism in the KISS1 gene, p.P110T, appeared to be meaningful. This polymorphism was suggested to exert a protective effect on pubertal precocity, even though more evidence will be required to confirm the accurate function.

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Thyroid dysfunction has been known to be closely associated with increased vascular events. The aims of the present study included determining the prevalence of subclinical thyroid disease and relationships between normal ranges of thyroid function and internal carotid artery steno-occlusion (ICS) in patients with ischemic stroke. From March 2007 to February 2008, 382 consecutive patients with ischemic stroke referred to the neurovascular ultrasound laboratory were analyzed. ICS was defined as greater than 50% luminal narrowing or complete obstruction in at least 1 internal carotid artery. Subclinical thyroid disease was determined by free thyroxine (fT4) and thyroid stimulating hormone (TSH) measurements. After the exclusion of patients with abnormal levels of thyroid hormones, normal ranges of fT4 were classified into 3 groups: low-normal (fT4, 11.0~12.3 pmol/L), mid-normal (12.4~15.4), and high-normal (15.5~24.0) thyroid groups. There were 17 patients (4.5%) with subclinical hypothyroidism and 6 (1.6%) with subclinical hyperthyroidism. There were 301 patients (78.8%) with normal fT4 and TSH levels, and among them, 67 patients (22.3%) had ICS. There was a significantly higher percentage of ICS in the low-normal thyroid group than in the other groups. By multivariate regression analysis, the low-normal fT4 group had an OR of 2.80 (95% confidence interval, 1.39-5.66) for ICS compared to the mid-normal group. In patients with ischemic stroke, the prevalence of subclinical thyroid disease was similar to the general population, and in euthyroid patients, low-normal thyroid function was independently associated with a higher percentage of ICS.

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IgG4-positive plasma cell infiltration into multiple organs or tissues, such as the pancreas and salivary glands, associated with increased serum levels of IgG4 is a characteristic finding seen in IgG4-related disease. Affected organs may appear tumorous as a result of chronic inflammatory processes accompanied with progressive fibrosis. Recent cases of this disorder in which the pituitary gland was affected include cases of diffuse enlargement of the pituitary and/or its stalk associated with central diabetes insipidus and/or impaired anterior hormone production. Here we report two such cases, as well as two additional previously undiagnosed cases found in our database. In order to make a correct diagnosis of pituitary lesion involvement with IgG4-related disease, the clinical background and concomitant disorders should be carefully taken into consideration and the measurement of serum levels of IgG4 seems to be useful.

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The inverse association between plasma B-type natriuretic peptide (BNP) levels and body mass index (BMI) has been reported in Western populations. Here we analyzed the relationship between plasma BNP and obesity in a general urban Japanese population. We recruited 1,759 subjects without atrial fibrillation or history of ischemic heart disease aged 38-95 years (mean age ± standard deviation 64.5 ± 10.9 years, 56.1% women, mean BMI 22.8 ± 3.1 kg/m²) from the participants in the Suita Study between August 2002 and December 2003. In multivariable regression analyses adjusted for age, systolic blood pressure, pulse rate, serum creatinine, left ventricular hypertrophy in ECG, the inverse relationships between BNP levels and BMI (kg/m²) was found in both sexes (both p<0.001). Multivariable-adjusted mean plasma BNP levels in the group of BMI<18.5, 18.5≤BMI< 22, 22≤BMI<25, and 25≤BMI were 23.4, 17.9, 14.0 and 13.0 pg/mL, respectively (trend p<0.001). The negative association of body fat (percentage and mass), skin fold thickness, or waist circumference with BNP levels was observed the negative associations in both sexes (p<0.01). Among the obesity indices, body fat mass is most tightly associated with BNP. In conclusion, plasma BNP was inversely associated with obesityrelated markers such as body fat mass, skinfold thickness and waist circumferences after adjusted for relevant covariates in a Japanese population.

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We report two patients with vitamin D deficiency due to unbalanced diet. The patients initially presented with severe hypocalcemia, normophosphatemia and markedly elevated serum PTH levels. Although nutritional vitamin D deficiency was suspected from their history of gastrointestinal problems and dietary restriction, we conducted Ellsworth- Howard test to exclude the possibility of pseudohypoparathyroidism (PHP). Both patients showed no incremental response of urinary phosphate excretion. However, the urinary cAMP response to exogenous PTH was different between the two. Case 1 showed a blunted response (5-fold and 1.54 μ mol/h increase) and case 2 showed a normal response (39-fold and 3.04 μ mol/h increase). According to the criteria of Ellsworth-Howard test, the data of case 1 was compatible with PHP type I, and of case 2 with PHP type II. The final diagnosis of vitamin D deficiency was established in both patients based on very low serum 25-hydroxyvitamin D levels (less than 5 ng/mL) and the effect of treatment. After calcium supplementation with or without vitamin D, their biochemical abnormalities disappeared. They maintained normocalcemia without medication after correction of their unbalanced diet. The present study indicated that patients with vitamin D deficiency occasionally showed biochemical findings suggestive of PHP and that such patients could exhibit not only PHP type II pattern of response to exogenous PTH but also of type I pattern. Thus our clinical observation suggests the complexity of PTH resistance in vitamin D deficiency and underscores the importance of diet to prevent the disorder.

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Pheochromocytoma (PCC) and paraganglioma (PGL) are tumors of the autonomic nervous system. The former is a tumor that occurs in only adrenal glands, and the latter can be found in the head and neck or in the thorax and abdomen. In PCC and PGL, genetic mutations account for approximately 30% of functional (secrete catecholamines) and nonfunctional cases. In addition to RET, VHL and NF-1, genes encoding succinate dehydrogenase complex subunit B (SDHB), subunit C (SDHC), and subunit D (SDHD) are recognized as susceptibility genes for PCC and PGL. Recently, PCC and PGL caused by genetic mutations of SDHB, SDHC and SDHD were established as hereditary pheochromocytoma paraganglioma syndrome (HPPS). Approximately 15% of all PCCs and PGLs are recognized as HPPS. Among these three susceptibility genes, SDHB and SDHD are known to be strongly related to HPPS. The aim of this study was to analyze SDHB and SDHD mutations in PCC and PGL patients. Among 18 patients, we identified a novel heterozygous nonsense mutation at codon 168 resulting in a CAG (glutamine) to TAG (stop) substitution (Q168X) in the SDHB gene in a patient diagnosed with solitary sporadic PGL. A number of studies have reported that SDHB mutation-associated disease demonstrates a higher rate of malignancy. However, all seven patients diagnosed with malignancy in this study did not have genetic mutation of SDHB and only one patient with no malignant sign had genetic mutation of SDHB. Further accumulation of cases is necessary to confirm the association between SDHB mutation and malignant potential.

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