GnRH plays an essential role in neuroendocrine control of reproductive function. In mammals, the pattern of gonadotropin secretion includes both pulse and surge phases, which are regulated independently. The pulsatile release of GnRH and LH plays an important role in the development of sexual function and in the normal regulation of the menstrual cycle. The importance of GnRH pulsatility was established in a series of classic studies. Fertility is impaired when GnRH pulsatility is inhibited by chronic malnutrition, excessive caloric expenditure, or aging. A number of reproductive disorders in women with including hypogonadotropic hypogonadism, hypothlamic amenorrhea, hyperprolactinemia and polycystic ovary syndrome (PCOS) are also associated with disruption of the normal pulsatile GnRH secretion. Despite these findings, the molecular mechanisms of this pulsatile GnRH regulation are not well understood. Here, we review recent studies about GnRH pulsatility, signaling and transcriptional response, and its implications for disease.

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This study was performed to examine the efficacy and safety of the rapid- and short-acting insulinotropic SUR ligand mitiglinide given as add-on therapy for 52 weeks in type 2 diabetic patients whose blood glucose was insufficiently controlled by pioglitazone monotherapy. Type 2 diabetic patients aged ≥ 20 years with postprandial plasma glucose (PPG1 or 2) ≥ 200 mg/dL and glycated hemoglobin (HbA_1C) 6.5–<9.0% despite receiving pioglitazone 15–45 mg/day were additionally treated with concomitant mitiglinide 10 mg tid p.o. for a total treatment period of 52 weeks. In 171 patients recruited, HbA_1C was significantly reduced from 7.64 ± 0.77% at baseline to 6.84 ± 0.73%, 6.64 ± 0.64%, 6.67 ± 0.57% and 6.81 ± 0.65% at weeks 16, 28, 40, and 52, respectively. Over half the patients achieved HbA_1C target of <7.0%, and one third <6.5%. Significant reductions in fasting plasma glucose (FPG) and PPG 1 and 2 hours after a meal versus baseline were noted at all time-points evaluated. The most frequently noted adverse reactions were hypoglycemic symptoms, weight gain, and peripheral edema (all mild). In type 2 diabetic patients combination therapy with mitiglinide and pioglitazone exerted significant long-term improvements in HbA_1C, FPG, and PPG and was well tolerated. This drug combination therapy is a promising means of alleviating insufficient pancreatic insulin secretion and insulin resistance.

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We describe herein a case of thyroid storm with hypoglycemia and lactic acidosis—a rare complication of thyroid storm. The patient was a 50-year-old Japanese woman who suffered cardiopulmonary arrest an hour after hospitalization. Analysis of a blood sample obtained before her cardiopulmonary arrest yielded surprising results: Her plasma glucose level was 14 mg/dL and her lactic acid concentration had increased to 6.238 mM. Thus, if atypical thyroid storm presents with normothermic hypoglycemia, and lactic acidosis, we believe it is necessary to consider a diagnosis of thyroid storm earlier, because this condition requires emergency treatment. Moreover, it is very important to apply standard principles in the treatment of atypical cases of thyroid storm.

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The association between subclinical hypothyroidism and cardiovascular disease and the beneficial effect of levothyroxine replacement in subclinical hypothyroidism are still under debate. The present study was designed to determine whether subclinical hypothyroidism is associated with an increase in the intima-media thickness of the common carotid artery (C-IMT) and whether thyroid hormone replacement can reverse this change in the C-IMT. Patients with newly-diagnosed subclinical (n=36) and overt (n=40) hypothyroidism and healthy euthyroid individuals (n=32) participated in this study. All the patients were examined for clinical characteristics, and the serum lipid levels and the C-IMT were measured. Patients with subclinical hypothyroidism had a C-IMT measurement after 18 months of levothyroxine replacement. There were meaningful differences in total cholesterol and LDL-cholesterol levels between patients with subclinical hypothyroidism and euthyroidism. The subjects with subclinical and overt hypothyroidism had a greater C-IMT compared with euthyroid controls (0.66± 0.10 and 0.70± 0.11 vs. 0.57± 0.08 mm, respectively; P < 0.05). After 12 months of euthyroidism, 28 of 36 patients with subclinical hypothyroidism completed the follow-up study. Thyroid hormone replacement significantly decreased the C-IMT (0.67± 0.11 to 0.60± 0.10 mm; P = 0.021) and improved the lipid profile. Based on multiple regression analysis, the decrement in LDL-cholesterol was independently associated with the regression of the C-IMT. Subclinical hypothyroidism was closely related to an increased C-IMT. Thyroid hormone replacement resulted in regression of the increased C-IMT, which was attributed to the improvement in the lipid profile.

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Lymph node metastasis is an important clinicopathological feature of papillary thyroid carcinoma (PTC). PTC having clinically apparent lateral node metastasis detectable on preoperative imaging studies (N1b) is known to show a dire prognosis. However, N1b cases include various levels of biological aggressiveness, depending on the size, number, laterality and invasiveness of metastatic nodes. We investigated differences in the prognoses of 621 N1b patients based on these features and compared their prognoses with those of 4297 patients without clinically apparent metastasis (N0) and 125 patients with clinically apparent central node metastasis only (N1a). Disease-free survival (DFS) and cause-specific survival (CSS) of N1b or N1a patients were significantly worse than those of N0 patients, but the prognosis of N1b patients did not differ from that of N1a patients. In the subset of N1b patients, metastatic nodes larger than 3cm, extranodal extension, or 5 or more clinically apparent metastatic nodes independently affected DFS and a combination of the former two features also showed an effect on CSS on multivariate analysis. Prognosis of N1b patients who had none of these features did not differ from that of N1a patients. It is therefore suggested that N1b patients having metastasis larger than 3cm, those showing extranodal extension, and those having 5 or more clinically apparent metastasis should regarded as high-risk, and that careful surgical treatment and postoperative follow-up are necessary.

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Type 1A diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. The HLA-DR and -DQ genes are well established as being associated with increased risk for type 1 diabetes. Moreover, polymorphisms in CTLA4 have been reported to be associated with susceptibility to type 1 diabetes and autoimmune thyroid disease (AITD). In both Caucasian and Japanese populations, the lifetime risk in siblings of type 1 diabetic probands is much higher than that in general populations. However, in Japan, where the prevalence of type 1 diabetes is less than one-tenth that of most Caucasian populations, it is rare for type 1 diabetes to develop in three or more siblings within a family. Here, we report a Japanese family in which type 1 diabetes occurred in three siblings amongst four sisters. Three probands of type 1 diabetes had the same combination of HLA haplotypes, DRB1^*0405-DQB1^*0401/ DRB1^*0802-DQB1^*0302, which occurs significantly more often in type 1 diabetes patients than in control subjects in the Japanese population. With respect to the rs3087243 (+6230G>A) polymorphism of CTLA4, the first sister had type 1 diabetes and AITD and had the GG genotype, whereas the second and third sisters, who had type 1 diabetes without AITD, had the AG genotype. This is the first report of a family in which type 1A diabetes developed in three siblings. We performed genetic analysis of HLA-DR, -DQ, and CTLA4 in all family members. Even in a country where the prevalence of type 1 diabetes is low, diabetic proband siblings should be monitored for the onset of type 1 diabetes.

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Obesity and systemic oxidative stress are closely related. However data concerning the relationships between oxidative stress and body fat mass distribution are sparse. Anthropometric and metabolic profile was evaluated in 148 clinically healthy middle-aged women to assess the correlations between oxidative stress, fat mass distribution, adipokines, and inflammatory markers. Systemic oxidative stress was assessed by urinary creatinine-indexed 8-epi-prostaglandin F-_2α (8-epi-PGF_2α). Body fat mass distribution was examined by dual-energy X-ray absorptiometry (DXA). Lipid profile, adipokines and inflammatory markers including leptin, adiponectin, high sensitive C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α) were determined. We found body mass index (BMI), waist circumference (WC), both central and peripheral DXA-derived regional fat mass (FM) accumulations were positively correlated with 8-epi-PGF_2α. Leptin, hsCRP and PAI-1also positively associated with 8-epi-PGF_2α. After adjustment for BMI and WC, lower-body FM, total FM and PAI-1 retained significant association with 8-epi-PGF_2α. Mutliple linear regression analyses indicated lower-body FM and PAI-1 were the two important predicators of 8-epi-PGF_2α. These results suggest that DXA-derived regional FM indices, especially low extremity adiposity, are more closely associated with systemic oxidative stress than indirect anthropometric indices. Positive associations between 8-epi-PGF_2α and PAI-1, hsCRP, leptin support the notion that oxidative-stress-induced dysregulation of inflammation and adipokines may mediate the obesity-related metabolic derangement.

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The biohazards caused by the viral delivery of pancreatic duodenal homeobox gene 1 (Pdx1) to the murine liver limits its application. We aimed to evaluate the feasibility of hydrodynamics-based transfection (HBT) with Pdx1 in improving hyperglycemia. Murine hepatocellular carcinoma (Hepa1-6) cells were transfected with the Pdx1-expressing plasmid, pcDNA3.1/V5-His A (pcDNA)-Pdx1. Hepatic delivery of pcDNA-Pdx1 or pcDNA in streptozocin- induced diabetic mice was achieved by HBT. The sequential serum glucose and alanine aminotransferase (ALT) levels were assessed. On the 3^rd day after transfection, the transfection efficiency in the Hepa1-6 cells and the mice livers was 5% and 0.35 %, respectively. At 1 wk after HBT, asides from hepatic expression of insulin, the diabetic mice transfected with pcDNA-Pdx1 had a significantly lower sugar (211 ± 61.6 vs. 413 ± 62 mg/dL; p = 0.002) level than those transfected with pcDNA; however, the difference diminished afterward. No significant difference in the ALT levels was observed between the 2 groups. No mortality was noted in the mice transfected with pcDNA-Pdx1. The hypoglycemic effect of Pdx1 delivered by HBT was transient and associated with negligible complications. In studies on the short-term biological effects of Pdx1 in vivo, HBT is a potential alternative to viral delivery of Pdx1 to the murine liver.

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Somatic mutations of the thyrotropin receptor (TSHR) gene and the gene encoding the α subunit of the stimulatory GTP-binding protein (Gsα) are the main cause for autonomously functioning thyroid nodules (AFTN) in iodine-deficient regions of the world. In iodine-sufficient regions, including Japan, the genetic relevance of AFTN is unclear. In a series of 45 Japanese subjects with AFTN, exons 9 and 10 of the TSHR and exons 7-10 of Gsα , where the activating mutations have been found, were analyzed using direct sequencing. We found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsα gene. The most frequent mutation in TSHR was Met453Thr (10 cases), followed by clustered residues from codons 630 through 633 on TSHR (7 cases). Mutations of Gsα were detected at codon 201 in 5 cases and at codon 227 in 2 cases. No patients had coexistent TSHR and Gsα mutations in the same nodule. All mutated residues but one, which was deleted at codon 403 on the TSHR gene, are constitutively active. The prevalences of a germline polymorphism of Asp727Glu on the TSHR gene and incidental papillary thyroid carcinoma in thyroid surgical specimens were similar to those reported in other studies. In the present study, more than half of the cases with AFTN had a somatic activating mutation either of the TSHR or Gsα gene, despite their high iodine intake.

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The present study was conducted to examine the effect of administration of conophylline (CnP) and betacellulinδ4 (BTCδ4) on the β-cell mass in neonatal streptozotocin-treated rats (neonatal STZ rats). STZ (100 μg/g) was injected into neonatal rats, and then CnP (2 μg/g) and/or BTCδ4 (200 pmol/g) were administered to neonatal STZ rats for 1 week. The plasma glucose concentration was monitored, and an intraperitoneal glucose tolerance test (ipGTT) was performed on day 8 and at 8 weeks after the STZ injection. In neonatal STZ rats treated with control solution (S group), the plasma glucose concentration increased for several days after the STZ injection, returned to nearly normal levels, and then increased gradually after six weeks of age. Eight weeks after the STZ-injection, the plasma glucose concentration was increased significantly compared to that of normal rats. The glucose response to ipGTT was significantly reduced in neonatal STZ rats treated with CnP (CnP group), BTCδ4 (δ4 group) and CnP+BTCδ4 (CnP+δ4 group). The β-cell mass and the insulin content of the pancreas were significantly increased in the CnP group and δ4 group. The effect of CnP+δ4 was greater than that of CnP alone or BTCδ4 alone. CnP+BTCδ4 significantly increased the number of PDX-1-positive ductal cells and the number of insulin/BrdU double-positive ductal cells. These results indicate the efficacy of CnP and BTCδ4 in increasing the β-cells mass of neonatal STZ-treated rats.

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We describe here a patient with torsade de pointes associated with recurrent ampulla cardiomyopathy, who was later proven to suffer from idiopathic AC TH deficiency. A 70-year-old man was admitted to our hospital for bacterial pneumonia. A cardiac examination performed on admission revealed ampulla cardiomyopathy, which improved spontaneously as the pneumonia was cured. Two months after discharge, he was transferred to our hospital for relapse of the pneumonia. After the second admission, the pneumonia subsided with antibiotic treatment and his general condition ameliorated gradually. However, on the 20^th hospital day, he was found lying on the floor in a prone position in cardiopulmonary arrest. Cardiac telemetry monitoring showed torsade de pointes worsening to ventricular fibrillation, and immediate cardiac defibrillation was performed. The electrocardiogram after successful defibrillation showed inverted T waves in the chest leads with long QT intervals, and subsequent emergent coronary catherization revealed the recurrence of ampulla cardiomyopathy. Thereafter, endocrinological examinations for the diagnosis of sustained hyponatremia demonstrated secondary adrenal insufficiency caused by idiopathic AC TH deficiency. The cardiomyopathy resolved promptly after steroid hormone replacement without relapse as did the hyponatremia. Patients with ampulla cardiomyopathy or ventricular fibrillation without apparent etiology should be examined for adrenal function. If begun as soon as adrenal insufficiency is diagnosed, immediate steroid replacement therapy can prevent the deterioration and relapse of cardiac involvement.

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We report a 66-year-old woman with a mixed corticomedullary tumor of the left adrenal gland. The patient was found to harbor an adrenal incidentaloma while investigated for a spigelian hernia. Due to the atypical radiological features and the relatively large size of the adrenal lesion she underwent a left adrenalectomy following endocrine testing to exclude a functional lesion. Subclinical Cushing’s syndrome was suggested by the failure to obtain adequate cortisol suppression (less than 1.8 μg/dL) following dexamethasone administration pre-operatively; cortisol suppression was restored postoperatively following the excision of the tumor. Histology was consistent with a corticomedullary mixed adenoma, a lesion for which, there is paucity of published data regarding its natural history and long term outcome. The finding of this case highlights the importance of this extremely rare entity which should be included in the long list of causes of adrenal incidentaloma since cases with intra-operative complications have been described. The previously reported reappearance of this tumor in the contralateral adrenal gland emphasizes the need for prolonged follow-up.

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