Adult growth hormone deficiency (GHD) is a well defined clinical condition, which is characterized by abnormal body composition, impaired physical activity and decreased quality of life. In addition, in recent years, growing interest has been shown towards cardiovascular risks in adult patients affected by GHD. In this regard, GHD is widely known to be associated with increased mortality, likely due to the increase of risk factors, such as central obesity, impaired lipid and glucose profiles and other less-known risk factors, such as inflammatory cytokines, endothelial dysfunction and oxidative stress. However, very few papers have recently discussed this topic. In this review, the aim is to clarify this issue by discussing evidence regarding the effects of adult GHD on metabolic and cardiovascular profiles.

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This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (-0.9% [-7.5 mmol/mol] and -0.7%, [-5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control.

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Autoimmune thyroid diseases (AITDs), including Graves’ diseases (GD) and Hashimoto’s thyroiditis (HT), are the most common autoimmune diseases, and are mainly mediated by T cells that produce cytokines and chemokines in abnormal amounts. Few reports have described the circulating chemokines active in AITDs. Recently, we used a new multiplex immunobead assay to simultaneously measure cytokines and chemokines in small volume serum samples from patients with AITDs. We measured 23 selected serum chemokines in patients with GD (n=45) or HT (n=26), and healthy controls (n=9). GD patients were further classified as either untreated, intractable, or in remission, while HT patients were classified as either hypothyroid or euthyroid. Of the 23 serum chemokines assayed, only the serum level of IP-10 (CXCL10/interferon-γ-inducible protein 10) was elevated, depending on disease activity, in GD or HT compared with healthy controls. However, the serum level of IP-10 was also increased in both untreated GD patients and hypothyroid HT patients, suggesting that levels of this cytokine may not be affected by disease specificity. In conclusion, autoimmune inflammation in patients with AITD is closely related to the level of the serum chemokine, IP-10. Therefore, IP-10 might be a good biomarker for tissue inflammation in the thyroid, but not a useful biomarker for predicting disease specific activity, the progression of AITDs, or responsiveness to treatment because of its independence from thyroid function or disease specificity.

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In general, juvenile differentiated thyroid carcinoma (DTC) demonstrate indolent characteristics and favorable prognosis are observed in comparison with many other carcinomas. However, recurrence is frequent, necessitating additional treatment, including radioactive iodine (RAI) therapy. In this report, the probability of recurrence, prognostic factors, treatment, and outcomes in both juvenile- and adult-onset DTC were analyzed and compared. At our institution, a total of 1552 DTC patients underwent thyroidectomy and/or lymph node dissection. The patients included 23 in their teens, 118 in their twenties, and 1412 in their thirties or older. The risk factors for distant metastases for DTC were male gender, follicular carcinoma, size of the PTC primary tumor, cervical lymph node metastases from PTC, and the presence of more than two distant metastatic foci. Patients with the highest risk underwent RAI ablation in line with institutional guidelines. Although the overall outcome in our juvenile patients was excellent, during follow-up, 4 (17.4%) of the 23 patients developed recurrent disease: 91.3% achieved complete remission, 4.35% partial remission, and 4.35% stable disease, with no disease-related deaths. Among the 118 patients in their twenties to thirties, 1 (0.8%) experienced progressive disease and disease-related death. A younger age at diagnosis and less radical primary surgery without subsequent RAI ablation are factors strongly predictive of distant metastases in patients with juvenile-onset DTC. To reduce the rate of relapse and improve surveillance for recurrent disease, total thyroidectomy followed by RAI appears to be the most beneficial initial treatment for patients with high- and intermediate-risk juvenile DTC.

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Few articles have described fluctuations in glutamic acid decarboxylase antibody (GADAb) levels after a diagnosis of slowly progressive type 1 diabetes (SPIDDM). Here, we present a case in which GADAb levels exponentially increased after initiating and stopping insulin. A 64-year-old female patient newly diagnosed with SPIDDM was admitted and started multiple daily insulin injections. The patient’s GADAb titer was 6.9 U/mL (normal: <1.4 U/mL) and the patient had a type 1 diabetes susceptible HLA class II haplotype known in the Japanese population as: DRB1*04:05-DQB1*04:01. When the patient’s “honeymoon period” set in, hypoglycemia was observed and the dose of insulin was reduced. Two months after the diagnosis, 1 unit of insulin glargine/day was being injected and the patient demonstrated good glycemic control. Subsequently, the patient’s home doctor recommended that insulin injections be stopped. Three months after the diagnosis, the patient’s GADAb titer suddenly increased to 1600 U/mL. The patient’s GADAb titer decreased but was still positive (40 U/mL) 36 months after diagnosis. HbA1c levels were maintained below 7%, and oral glucose tolerance tests at 10, 26, and 36 months after diagnosis suggested that the patient had preserved insulin secretion. To the best of our knowledge, this is the first report that describes exponential increases in GADAb after initiating and stopping insulin in a patient with SPIDDM.

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Cushing’s disease is primarily caused by adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Pituitary tumor-transforming gene 1 (PTTG1) expression, a hallmark of pituitary tumors, stimulates pituitary cell proliferation. Histone deacetylases (HDACs) play an important role in regulating gene transcription and HDAC inhibitors induce cellular differentiation and suppress tumor cell proliferation. HDAC inhibitors also repress PTTG1 mRNA levels. Trichostatin A (TSA) is a potent cell-permeable HDAC inhibitor that blocks cell cycle progression. In the present study, we determined the effect of TSA on ACTH production and cellular proliferation in mouse AtT-20 corticotroph tumor cells. TSA decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and reduced ACTH levels in the culture medium of these cells. The TSA-induced decreases in POMC mRNA levels were not modulated when TSA and dexamethasone were simultaneously administered. Drug treatment also decreased AtT-20 cell proliferation, induced apoptosis, and increased the percentage of cells in G0/G1 phase using flow cytometry. TSA decreased PTTG1 mRNA levels. Furthermore, PTTG1 knockdown inhibited cellular proliferation. Its knockdown also inhibited POMC mRNA and ACTH levels. TSA inhibits ACTH production and corticotroph tumor cell proliferation. TSA may inhibit cellular proliferation, and ACTH synthesis and secretion by decreasing PTTG1 expression.

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The cardiovascular effects of short-term overt hypothyroidism are not well known. We investigated proprotein convertase subtilisin/kexin type 9 (PCSK9), soluble lectin-like oxidized LDL receptor 1 (sLOX-1) and the ankle brachial index (ABI) in thyroid cancer patients with short-term overt hypothyroidism due to thyroid hormone withdrawal (THW). Twenty-one patients requiring radioactive iodine (RAI) ablation or scanning and 36 healthy control subjects were enrolled. Patients were evaluated in the subclinical thyrotoxic phase when they were on suppressive levothyroxine therapy and in the overt hypothyroid phase due to THW for four weeks. PCSK9, sLOX-1, lipids and ABI were measured in the patient and control groups. Total cholesterol, LDL cholesterol, triglycerides and Apo B levels were increased in short overt hypothyroidism compared with the control group (p<0.001). PCSK9 levels increased before THW and after THW in the patients compared to control group (p<0.001, p=0.004, respectively). sLOX-1 levels were not different between patients with short term overt hypothyroidism and control group (p=0.27). ABI was found to be significantly decreased in patients with thyroid cancer before and after THW compared to control group (p=0.04, p=0.002 respectively). PCSK9 levels were correlated negatively with ABI (r=-0.38, p=0.004). In conclusion; our study demonstrated that patients with differentiated thyroid cancer both before and after THW which is a short term overt hypothyroid phase, had increased PCSK9 levels and decreased ABI. Short term overt hypothyroidism also leads to increased HDL, LDL, total cholesterol, Apo A and Apo B levels.

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The goal of this study was to assess the safety and efficacy of 0.75 mg of dulaglutide, a once weekly glucagon-like peptide-1 receptor agonist, in Japanese patients with type 2 diabetes (T2D) on a single oral hypoglycemic agent (OHA). In this phase 3, nonrandomized, open-label, parallel-group, 52-week study, safety and efficacy of once weekly dulaglutide 0.75 mg were assessed in Japanese patients with T2D on a single OHA (sulfonylureas [SU], biguanides [BG], α-glucosidase inhibitors [AGI], thiazolidinedione [TZD], or glinides [GLN]). A total of 394 patients were treated with study drug, and 92.9% completed the 52-week treatment period. The most frequent treatment-emergent adverse events were nasopharyngitis and gastrointestinal disorders, including constipation, diarrhea, and nausea. Incidences of hypoglycemia varied across the combination therapy groups: incidence was greater in patients receiving SU compared with other combinations. No severe hypoglycemic episodes occurred during the study. Increases from baseline in pancreatic and total amylase, lipase, and pulse rate were observed in all 5 combination therapy groups. Significant reductions from baseline in HbA1c were observed in all 5 combination therapy groups (-1.57% to -1.69%, p < 0.001 for all). Mean body weight changes from baseline varied across the combination therapy groups: a significant increase was observed in combination with TZD, there were no significant changes in combination with SU or GLN, and significant reductions were observed in combination with BG or AGI. Once weekly dulaglutide 0.75 mg in combination with a single OHA was overall well tolerated and improved glycemic control in Japanese patients with T2D.

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This study aimed to investigate early and late outcomes of patients who underwent neurosurgical procedures for the preoperative diagnosis of Cushing’s disease (CD). Clinical, endocrine, imaging, and histologic data from 252 patients undergoing pituitary surgery at Toranomon Hospital through the end of 2012 were entered into a database and statistically analyzed. In 22 of these patients (8.7%; positive venous sampling in 15 and negative venous sampling in 7 patients), tumors were invisible on magnetic resonance imaging (MRI) and 42.9% of them achieved remission. In the remaining 230 patients, 93.5% of those with microadenomas (n=154) and 71.1% of those with macroadenomas (n=76) achieved early postoperative remission, with recurrence rates of 2.7% and 14.8%, respectively, during a 72.5-month median follow-up. In multivariate analyses, cavernous sinus invasion (CSI; odds ratio [OR], 13.0), type of surgery (OR, 4.0), and tumor size (OR, 2.7) were significant preoperative factors affecting early postoperative results, whereas peak cortisol levels ≥9.4 μg/dL in response to corticotropin-releasing hormone (CRH) and CSI were significant factors predicting recurrence. Tumor recurrence was more common in patients with non-densely granulated adenomas than in patients with densely granulated adenomas. We propose that the higher remission and lower recurrence rates in this series are due to our surgical strategies, including extracapsular tumor removal, aggressive resection of tumors with CSI, extended transsphenoidal surgery (TSS), or a combined approach for large/giant adenomas. Appropriate multimodal treatments, including radiotherapy, medication, and repeated surgery in patients with persistent or recurrent CD, could result in better overall outcomes than previously achieved.

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Annexin A5 (ANXA5), a member of the structurally related family of annexin proteins, is expressed in pituitary gonadotropes. We previously reported that ANXA5 expression is stimulated by gonadotropin-releasing hormone (GnRH). In the present study, we investigated ANXA5 expression in the anterior pituitary gland of GnRH-deficient mutant hypogonadal (hpg) mice. RT-PCR demonstrated that luteinizing hormone β subunit (LHβ) and ANXA5 mRNA levels were both lower in the pituitary gland of hpg mice than in wild-type mice. Immunohistochemistry showed that ANXA5 expression throughout the pituitary gland was very low in hpg mice, suggesting that ANXA5 is diminished in gonadotropes and also in other cell types. Subcutaneous administration of a GnRH analogue, des-gly10 (Pro9)-GnRH ethylamide (1 μg/day for 7 days), augmented the expression of LHβ and ANXA5 in the pituitary gland in hpg mice. However, LHβ- and ANXA5-positive cells did not show exactly matched spatial distributions. These findings suggest that GnRH is necessary for constitutive ANXA5 expression in the pituitary gland, not only in gonadotropes but also in other pituitary gland cell types. A close relationship between ANXA5 and LHβ expression was confirmed. It is suggested that a significant role of ANXA5 in the physiologic secretion of LH.

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Dapagliflozin is a SGLT2 (Sodium/Glucose cotransporter 2) inhibitor that reduces circulating glucose levels in type 2 diabetic patients by blocking the SGLT2-dependent reabsorption of glucose in the kidney. Dapagliflozin is metabolized by UGT1A9 (UDP Glucuronosyltransferase 1 family, Polypeptidase A9), suppressing its SGLT2 inhibitor activity. However little information is available on whether dapagliflozin acts in the absence of dapagliflozin metabolism. Treatment with 0.5μM dapagliflozin significantly reduced the number of HCT116 cells, which express SGLT2 but not UGT1A9. This was independent of SGLT2 inhibition, as the SGLT2 inhibitor phlorizin had no effect. Dapagliflozin also enhanced Erk phosphorylation but without changing levels of uncleaved and cleaved PPAR and uncleaved caspase-3, suggesting that the cause of the decrease in HCT116 cell number was apoptosis independent cell death. Taken together, these data indicate a new potential role for dapagliflozin as an anticancer reagent in tumor cell populations that do not express UGT1A9.

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