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Can Exercise-mimetics-to-be skip the exercise?

For the sake of your well-being, how can you effectively and repeatedly communicate the wisdom of "exercise" to the general public so that their questions are intelligently and correctly answered? Have you ever given them a certain, if somewhat substandard, message such as 1) exercise-mimicking drugs aren't appealing, 2) very-low carbohydrate foods are superior to other special diets ± exercise, 3) it doesn't matter that endurance (aerobic) exercise is far superior to resistance (anaerobic) exercise, or vice versa?
Some may be the one and only solution for them, but some may not be effective or even harmful for others. Therefore, your correct response is, as expected, "Your question itself is very important, but the answer depends on each and every one of you.
First, they need to properly organize and clarify the purpose of their inquiry: 1) Do you want to get cosmetically skinny or a less obese body style? 2) Do you need to improve your metabolic condition before you get sick, in other words, is it preventive? 3) Is the goal to cure the most serious diseases that result from a sedentary lifestyle, and/or to ameliorate associated diseases? 4) Is your aim improvement of future drug efficacy in preparation for modifying the intracellular signaling system for dietary nutrients and the extracellular milieu?
Unlike other communicable diseases, even if oral medications and/or injections are once successful in controlling or normalizing these metabolic diseases, we do not have the weapons to get rid of them. In other words, our diseases that appear to be polygenic are accompanied by a kind of treatment resistance. This is because it is not possible to correct all possible genetic and epigenetic etiologies. In fact, postponing or reducing medication is a legitimate practice that is already routinely done. Nevertheless, in addition to these drugs, or along with them, there are strict non-pharmaceutical daily restrictions on the metabolic diseases that must be followed even by patients in the 21st century, just as they were in the days when the Greeks and Romans enjoyed their happy and creative eras.
Here, Ogawa's group thoroughly examined whether exercise intensity synergizes with the glucose co-transporter 2 inhibitor (SGLT2-i) dapagliflozin in patients with T2DM. In their RCT, 146 patients were assigned to a 24-week treatment of intensive exercise. The primary endpoint was the change in body fat distribution in each patient. Their study revealed that intensive exercise did not influence reduced fat-free mass after administration of SGLT2-i while it was able to further decrease abdominal fat, hopefully leading to greater improvements of hyperglycemia and chronic inflammation than DAPA alone in T2DM patients. It is important to emphasize that the mechanisms of action of SGLT2-i and exercise overlap, and in both cases energy production is biased toward the utilization of fat rather than glucose or glycogen. It is easy to imagine that this condition is similar to the condition of very low carbohydrate diets to treat obesity leading to T2DM. In the latter case, the recent emphasis on frailty due to lack of body protein and the many adverse reactions due to excessive lipid intake (with the exception of some ketogenic diets) is rather contrary to the benefits of reducing carbohydrates to prevent or treat T2DM.
Similar experiments have been conducted previously by others, but their conclusions were not uniform. Through somewhat different approach, one report proposed that inhibition of SGLT2 makes the improvement in insulin sensitivity by endurance exercise training uncertain, independent of the effects of aerobic exercise on fitness and body composition. Insight into such discrepancies in the quality and quantity of exercise must be of great significance, but it will be necessary to watch for the unprecedented occurrence of adverse clinical outcomes, even if they are rare.

Effects of intensive exercise combined with dapagliflozin on body composition in patients with type 2 diabetes: a randomized controlled trial

Ryotaro Bouchi, Noriyuki Sonoda, Jun Itoh, Yasuhiro Ono, Tatsuya Fukuda, Takato Takeuchi, Junji Kishimoto, Tetsuya Yamada, Yoshihiro Ogawa

Abstract

This study was aimed to evaluate the effects of intensive exercise in addition to the administration of sodium-glucose cotransporter 2 inhibitor dapagliflozin (DAPA) on body composition, including fat-free mass, in type 2 diabetes. We randomly assigned 146 patients to 24 weeks of treatment with intensive exercise, including resistance training, plus 5 mg (up to 10 mg) of DAPA daily (IT group) or DAPA alone (CT group). The primary endpoint was the difference in the change in fat-free mass from baseline to 24 weeks between the groups. The skeletal muscle mass index (SMI); metabolic profile, including HbA1c; and regional fat mass were also determined. ANCOVA was used for the group comparison, with least squares mean (LSM) differences and 95% confidence interval (CI). There was no significant difference in the change in fat-free mass (LSM difference –0.1 kg (95% CI: –0.5 to 0.4) and SMI (LSM difference –0.1 kg (95% CI: –0.2 to 0.1) between the groups. In contrast, the reduction of trunk fat mass was significantly higher in the IT group than in the CT group ((LSM difference –0.5 kg [95% CI –0.9 to –0.1]). Higher adherence to the resistance training tended to be associated with changes in HbA1c and high-sensitivity CRP levels. Our study suggests that intensive exercise do not prevent the reduction of fat-free mass after administration of SGLT2 inhibitors but can increase the reduction in abdominal fat, presumably leading to further improvements of hyperglycemia and chronic inflammation than DAPA alone in type 2 diabetes patients.


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How confidently can physicians recommend anti-thyroid drugs and when?

It is increasingly realized that miscellaneous types and degrees of liver dysfunction occur during/after PTU (propylthiouracil, one of the two thionamide drugs currently used in the routine clinical settings shown here) administration against Graves’ disease. Recently, these events are recognized as common adverse effects of PTU in addition to a well-known intractable sequelae such as ANCA (anti-neutrophil cytoplasmic antibody)-related vasculitis including impressive otitis media shown in the recent issue of EJ (1) or notorious agranulocytosis. Indeed, before such a high frequency of liver toxicity triggered by PTU is advocated, it has been widely believed that PTU is less toxic and more safely prescribed even after permitting its a little weaker potency compared with the anti-thyroid activity elicited by MMI (methimazole, another thionamide of a potential first choice in Graves’ drug therapy). However, we must seriously recall that both drugs occupied its current standard position only after serendipitous successful experience; both were originally developed as bactericidal weapons before fortuitously confirming the remarkable anti-thyroidal activity of their derivatives. As a matter of fact, we kept appreciating PTU's precious values for their anti-Graves’ efficacy for a long time because it did not bring about frequent serious adverse effects. Nonetheless, it is nowadays recognized as risky as MMI when we use PTU in early pregnancy (cf. inborn somatic anomalies) or probably even in the breast-feeding period, while both of these occasions have long been indicated to be the first and specific situations for the choice of PTU, but not MMI, to treat accompanying Graves’ morbidity more safely.
Some solid lines of evidence indicate that PTU (and MMI) is a potent immunomodulator or regulator of proinflammatory cytokines to cure Graves’ disease, but its effect and the difference between the two thionamides are still unpredictable. No systemic translational biology using these thionamides from such a viewpoint has been reported since that time, however. No direct target to be considered a possible biomarker for eradicating the disease morbidity has been postulated or discovered. In addition, no competitions or incentives developed brand-new Graves’-curing agents during these 2 to 3 decades with some exceptions. For example, prednisolone is never warranted among them chiefly due to its inability to aim at the thyroid-specific autoimmunity. Then, now is the time to break various ambiguities for which physicians had been combating for a long time without durable success and with a certain number of therapeutic failures. Not only avoiding serious troubles but also truly developing efficacious and safe medication, as-yet unknown biomarkers will certainly conquer Graves’ disease with a much better outcome after introduction of such drugs in the clinical field.
Together, our use of PTU, even in the usual ambulatory occasion in the absence of pregnancy or coexisting disease morbidity, is more and more restricted as shown above. Next-generation anti-thyroid strategy especially exploiting the deep insight into autoimmunological viewpoints including genetic and brand-new genome-wide immunological approach are eagerly awaited.

Propylthiouracil-induced otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis: a ‍case report and review of the literature

Marino Hiruma, Yoshiyuki Sasano, Natsuko Watanabe, Ai Yoshihara, Satoshi Ishii, Yuichiro Yaguchi, Jaeduk Yoshimura Noh, Kiminori Sugino, Koichi Ito

Abstract

Propylthiouracil (PTU)-induced otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is an extremely rare adverse event associated with anti-thyroid drugs and is not well recognized. A 42-year-old woman with Graves’ disease undergoing PTU therapy for 8 years visited our hospital because of earache and congested feeling in her left ear. Blood tests, a computed tomography scan and pure tone audiometry revealed otitis media and moderate mixed hearing impairment. Antibiotics, ear drops with antibiotics and painkillers were administered. However, her earache and hearing loss gradually got worse and symptoms of facial nerve palsy appeared. At several weeks after initiation of the treatment, a high serum level of myeloperoxidase (MPO)-ANCA, 75.6 U/mL, was revealed. After excluding other causes, she was diagnosed with OMAAV. PTU was suspected as the cause of her OMAAV and was immediately discontinued, and prednisolone was started. Hearing impairment in her left ear gradually got better and showed substantial improvement. Facial nerve palsy disappeared. Although PTU-induced OMAAV is an extremely rare disease, it is important to recognize the disease, as delayed treatment can lead to irreversible hearing loss, hypertrophic pachymeningitis, and subarachnoid hemorrhage. When patients taking anti-thyroid drugs, especially PTU, are diagnosed with refractory otitis media or hearing loss, it is possible that OMAAV might be the cause and thus serum ANCA levels should be evaluated.


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Pandemic stressor

New findings revealed by a single resource in a short period would be acceptable only when semi-quantitative, but not accurately countable parameters are analyzed in a cohort group, since the latter approach usually takes one or more years to achieve its goal. With this concept in mind, “stress”, a clear-cut marker when it is present or absent, is thought difficult to be represented as numerical numbers for its severity. On the other hand, the effects of stress itself would be rather easily understood in the worthy topic in diabetes field without quantitative analyses during or in response to the current early phase of COVID-19 pandemic, while its destination is unsure even now. Considering the above descriptions, we wish to introduce the report by Munekawa et al, which concluded that many patients with diabetes experienced stress and lifestyle changes due to the COVID-19 pandemic, and these changes were associated with increased body weight and HbA1c levels. They may form only tips in the iceberg consisting of large numbers of coefficients including HbA1C, sleep, exercise, age, snack over-intake, and so on. Undoubtedly, all these parameters are more or less related to the stress curated from their questionnaires. But because of their inherent countability, they cannot be expressed as statistically significant something such as fold-differences with this small sample size at this moment. On the other hand, unlike these parameters, stress cannot be measured in a truly quantitative matter, which might make the analysis dealing with stress more vague but also more focused and flexible if dealt with great caution as shown here.
In conclusion, unless COVID-19 happens to be proven to reduce the numbers of diabetic endemic, we have to explore and reach our first and probably tentative goal to block the spread of diabetic. This holds true even when your enemy is pandemic of something other than COVID-19. I believe that their findings should be handled as an invaluable source of information from Japan for future discussion. During this processes, COVID-19-specific topics including cytokine storm, coagulopathy and age-dependent severity of the diseases would be intensively studied in the context of diabetic milieu.

Effect of coronavirus disease 2019 pandemic on the lifestyle and glycemic control in patients with type 2 diabetes: a cross-section and retrospective cohort study

Chihiro Munekawa, Yukako Hosomi, Yoshitaka Hashimoto, Takuro Okamura, Fuyuko Takahashi, Rena Kawano, Hanako Nakajima, Takafumi Osaka, Hiroshi Okada, Saori Majima, Takafumi Senmaru, Naoko Nakanishi, Emi Ushigome, Masahide Hamaguchi, Masahiro Yamazaki, Michiaki Fukui

Abstract

To investigate the acute effects of the coronavirus disease 2019 (COVID-19) on the lifestyle and metabolic parameters in patients with type 2 diabetes mellites. This cross-sectional and retrospective cohort study induced 203 patients who completed a questionnaire regarding stress levels and lifestyles. Data regarding stress levels, sleep time, exercise, and total diet, snack, and prepared food intake were obtained from the questionnaires. The changes in the body weight or HbA1c levels were determined by comparing the values at the time the questionnaire was administered to those noted 3 months ago. Increased levels of stress and decreased exercise levels were reported in approximately 40% and >50%. During the COVID-19 pandemic. There was a negative correlation between stress and exercise (r = –0.285, p < 0.001) and a positive correlation between stress and prepared food intake (r = 0.193, p = 0.009). Decreased exercise levels (r = –0.33, p < 0.001) and increased snack consumption (r = 0.24, p = 0.002) were associated with increased body weight. Furthermore, increased total diet intake (r = 0.16, p = 0.031) was associated with increased HbA1c levels. These relationships remained significant for patients aged <65 years and patients who did not engage in regular exercise. Many patients experienced stress and lifestyle changes due to the COVID-19 pandemic, and these changes were associated with increased body weight and HbA1c levels.


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In chronic or sustained asymptomatic SIADH (syndrome of inappropriate secretion of anti-diuretic hormone), emergent therapy is not always warranted before steadily correcting hyponatremia with a focus on fluid intake restriction. Nonetheless, such a morbidity eventually dampens QOL of the patients, if untreated. On the other hand, acute phase hyponatremia due to SIADH of miscellaneous origins including certain malignant neoplasms are often difficult to deal with or even diagnose safely. Moreover, in some SIADH, the medical staff experience confusion as to whether to treat it extensively or not. In addition, unnecessarily heavy water restriction as intensive treatment may lead to unanticipated dehydration with potentially fatal consequences.
Recently, these struggles were gradually alleviated by the successful introduction and widespread and careful use of oral anti V2-antagonist (tolvaptan) after the diagnosis of SIADH. Now, in this issue of Endocrine Journal, Arima and colleagues summarized their cohort study to determine the efficacy and safety of oral tolvaptan tablets (7.5-60 mg/day) for 30 days in Japanese patients with hyponatremia secondary to SIADH. We wish this article will be of great help in treating one of the most common electrolyte disturbances, hyponatremia, by not only endocrine experts but also those who are preparing to become first-line medical professionals with profound knowledge in body fluid physiology.

Open-label, multicenter, dose-titration study to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone

Hiroshi Arima, Koichi Goto, Tomohisa Motozawa, Makoto Mouri, Ryo Watanabe, Takahiro Hirano, San-e Ishikawa

Abstract

The purpose of this study was to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This multicenter, open-label, dose-escalation, phase III study enrolled Japanese patients (20–85 years old) with hyponatremia secondary to SIADH who were unresponsive to fluid restriction. Oral tolvaptan was administered for up to 30 days, initially at 7.5 mg/day, but escalated daily as necessary, based on the serum sodium concentration and safety, over the first 10 days until the optimal maintenance dose was determined for each patient (maximum 60 mg/day). The primary endpoint was the proportion of patients with normalized serum sodium concentration on the day after the final tolvaptan dose. Secondary endpoints included the mean change in serum sodium concentration from baseline on the day after the final dose. Sixteen patients (male, 81.3%; mean ± standard deviation age 71.9 ± 6.1 years) received tolvaptan treatment and 11 patients completed the study with one patient re-administered tolvaptan in the treatment period. Serum sodium concentrations normalized in 13 of 16 (81.3%) patients on the day after the final tolvaptan dose. The mean change in serum sodium concentration from baseline on the day after the final dose was 11.0 ± 4.3 mEq/L. Adverse events considered related to tolvaptan (10 [62.5%] patients) were generally of mild to moderate severity. Oral tolvaptan corrects hyponatremia in Japanese patients with SIADH with a similar efficacy and safety profile as that noted in non-Japanese patients.


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Just an accidental error?

We sometimes encounter endocrine diseases where a certain fixed group of endocrine tissues is similarly involved. Why is there a limited repertoire in such lesions? Medullary thyroid carcinoma and pheochromocytoma are neoplasms common to MEN (Multiple Endocrine Neoplasia)-2, and both are triggered by the heritable activation of protooncogene, RET. Then, what determines RET-dependence? Is there any pathogenetic commonality between activated RET and loss of menin, another culprit of MEN modality (MEN-1), while the latter shows a somewhat different tumorigenic organ tropism? Could this be a mere reflection of partly shared ontogenic organogenesis in each MEN or among two MENs? In the Journal, Manso et al. provided one more unsolved, but closely related puzzle. They described a unique case of a man affected not only by MEN-2a but also by APS (Autoimmune Polyglandular Syndrome) type 2. Unlike type 1 APS in which AIRE (Autoimmune Regulator Gene) mutation is responsible, type 2 APS-causing genes are not yet specified except that it would be deeply involved in autoimmune susceptibility in certain endocrine organs probably distinct from those affected in type 1 APS. The patient developed Hashimoto’s thyroiditis, diabetes mellitus type 1 and AAD (Autoimmune Addison’s Disease). Moreover, his past history revealed that he first developed medullary thyroid cancer, followed by bilateral pheochromocytoma on the adrenals. They found on adrenal histology bilateral cortical atrophy in the presence of a lymphocytic infiltration, confirming the presence of AAD. Their report is the first case in humans concerning the association between APS and MEN. Their findings suggest that adrenal medullary tumor can develop even on an adrenal gland with cortical atrophy due to autoimmune adrenalitis. Co-susceptibility of autoimmune and neoplastic diseases in the endocrine organs (thyroid, adrenal, endocrine pancreas and other candidates such as pituitary and parathyroid) caused by a limited number of a genetic mutation(s) is undoubtedly never a trivial issue. Especially, when compared with APS type 1, endocrine organs involved in APS type 2 are more similar to those seen in MEN-2. Several but not mutually exclusive (genetic) hits during a certain developmental period of common ancestral endocrine organogenesis would lead to two distinct, but perhaps intermingling pathological changes, namely autoimmunity or tumorigenesis.

First proof of association between autoimmune polyglandular syndrome and multiple endocrine neoplasia in humans

Jacopo Manso, Simona Censi, Maurizio Iacobone, Francesca Galuppini, Gianmaria Pennelli, Corrado Betterle, Caterina Mian

Abstract

Autoimmune Addison’s disease (AAD) is a rare condition occurring either in isolation or associated with other autoimmune diseases as part of an autoimmune polyglandular syndrome (APS) type 1, 2 or 4. Multiple endocrine neoplasia (MEN) type 1, 2 or 4 is a hereditary autosomal dominant cancer syndrome. Medullary thyroid carcinoma and pheochromocytoma are neoplasms common to MEN-2a and MEN-2b. We describe a unique, complex case of a man resulted affected by both APS-2 and MEN-2a. The patient developed Hashimoto’s thyroiditis, diabetes mellitus type 1 and AAD, despite testing negative for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OHAb). Moreover, he had also a family history for MEN-2a and he first developed medullay thyroid cancer, then bilateral pheochromocytoma on the adrenal substrate of an AAD. On adrenal histology we found complete bilateral cortical atrophy in the presence of a lymphocytic infiltration and fibrosis, confirming an ACA and 21-OHAb-negative AAD. This datum is the first documented in a living individual and confirms that the absence of autoantibodies is not incompatible with an autoimmune dis‍ease and confirms that AAD is a cell-mediated autoimmune disease limited to the adrenal cortex and sparing medullary. In the light of a literature review concerning the association between APS and MEN, this is the first proven case to be reported in humans. Finally, our findings suggest that adrenal medullary tumor can develop even on an adrenal gland with cortical atrophy due to autoimmune adrenalitis.


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Irisin and Respiration

In addition to the identification of many myokines in recent years, the discovery of one fascinating molecule, namely, irisin, is now establishing its unique position by showing that there is crosstalk between not only brain and adipose tissue but also brain and muscle cells. Such partnerships play an unforeseen role as a metabolic arranger or refresher through the intricate action on the mitochondrial biogenesis even to prolong physiological life span. Its true significance is not yet fully understood, but its important role as a muscle browning, which itself is reminiscent of the close interaction between adipose tissue and muscle cells, is being revealed. Such crosstalk includes beta3 adrenergic activity, cachexia, and exercise-induced mitochondrial metabolism. In addition, the broad linkage with irisin observed in neural activities such as brain recognition and osteoclast behavior is also becoming increasingly attractive. For example, in ex vivo, human adult brain cortical slices express irisin, which activates the cAMP-PKA-CREB memory pathway in response to exogenous recombinant irisin. It is also possible that irisin acts on osteoclast alpha integrin to exert exercise-induced bone strengthening effects. Today, the broad spectrum of activity of the irisin extends to other promising areas of obesity, sleep, and apnea, but remains an ambiguous debate; a recent report by Huang et al. in Endocrine Journal found that serum irisin levels were significantly correlated with OSA (obstructive sleep apnea) severity, independent of BMI (body mass index) or PA (physical activity). Whatever the ultimate outcome of this controversy, we believe that these intensive lines of irisin research shed new light on metabolic and behavioral neuroscience.

Association of the serum irisin level with obstructive sleep apnea: a body mass index- and physical activity-matched study

Weijun Huang, Yupu Liu, Huajun Xu, Huaming Zhu, Jian Guan, Hongliang Yi, Jianyin Zou

Abstract

Obesity is strongly correlated with the pathogenesis of obstructive sleep apnea (OSA); myokines may play important roles in this condition. We performed a body mass index- (BMI) and physical activity- (PA) matched study to explore the relationship between the irisin level and OSA. Ninety-six consecutive participants were recruited. After matching in terms of BMI and PA, 28 OSA patients and 28 healthy controls were finally included. Whole-night laboratory-based polysomnography was used to identify OSA. The Recent Physical Activity Questionnaire and Epworth Sleepiness Scale Questionnaire were employed to assess PA over the past 4 weeks, and daytime sleepiness. We measured serum irisin, fasting blood glucose, and insulin levels in blood samples. The serum irisin concentrations differed significantly between the control, mild OSA, moderate OSA, and severe OSA groups (p < 0.001) and correlated significantly with the apnea/hypopnea index (AHI) (r = –0.787, p < 0.001). All of age, BMI, neck, waist and hip circumferences, fasting blood glucose level, and the Epworth Sleepiness Scale and PA scores were associated with irisin levels (p < 0.05). After adjustment for these factors, the serum irisin level was independently correlated with the AHI (r = –0.428, p = 0.002). On forward logistic regression analysis, the association remained significant in the final multiple regression model (β = –0.107, p < 0.001). The serum irisin concentration was significantly correlated with OSA severity, independently of BMI and PA. Further studies are needed to determine the molecular mechanisms in play.


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Caffeine, in stark contrast to cigarette smoking, is likely to ameliorate one potentially serious trouble in Graves’ orbits.

Eyes in Graves’ sometimes give her/his friends charming impression, but it’s still a formidable area of not only an ophthalmologists but also experts of general medicine including thoughtful endocrinologists. It often gives patients not only difficulty in visual acuity but overall eye movement disturbances as well as miscellaneous inflammatory processes on neighboring systems. On one hand, euthyoid Graves’ patients suffer from only eye problem without other systemic sympathomimetic troubles and even spontaneously show curing tendency as the Graves’ morbidity declines. However, there remain certain patients in whom their eye troubles in addition to severe cardiotoxic symptoms remarkably impairs their quality of life without taking advantage of any effective medical procedures. Moreover, its underlying pathogenesis such as the way how anti-TSH receptor antibody works in a restricted facial area remains still enigmatic.
In the recent issue of the Journal, Ko et al. found that caffeine inhibited oxidative stress and adipogenesis, the main presumptive culprits of Graves’ ophthalmopathy (GO). In the in vitro mechanism of GO, superoxide radicals stimulate orbital fibroblasts to proliferate and differentiate into mature adipocytes. Notably, cigarette smoking, likely the most important environmental factor associated with GO occurrence and progression, may act by stimulating the ROS (reactive oxygen species) generation. Accordingly, several in vitro studies indicated the therapeutic merit of antioxidants in primary cultured orbital fibroblasts from GO patients. Although caffeine is known to function as a free radical remover, it exhibits both antioxidant and pro-oxidant properties depending on its dose. Of interest, they reported that orbital fibroblasts were resistant to the generation of ROS at the highest concentration (5 mM) of caffeine without causing cell injury. They also showed that drugs with antioxidant effects significantly suppressed adipocyte differentiation in the same cells with the aid of various transcription factors including C/EBP. These results are reminiscent of recent studies depicting that ROS are important in regulating mitotic clonal expansion during adipogenesis and adipocyte differentiation by accelerating mitotic clonal expansion.
Together, we are encouraged to examine such a beneficial effect of caffeine in a wide patient cohort of the well-controlled euthyroid period of GO patients.

Anti-oxidative and anti-adipogenic effects of caffeine in an in vitro model of Graves’ orbitopathy

JaeSang Ko, Ji-Young Kim, Jae-woo Kim, Jin Sook Yoon

Abstract

Oxidative stress and adipogenesis play key roles in the pathogenesis of Graves’ orbitopathy (GO). In this study, the therapeutic effects of caffeine on the reduction of oxidative stress and adipogenesis were evaluated in primary cultured GO orbital fibroblasts in vitro. Orbital fibroblasts were cultured from orbital connective tissues obtained from individuals with GO. Intracellular reactive oxygen species (ROS) levels induced by hydrogen peroxide or cigarette smoke extract and the expression of anti-oxidative enzymes were measured after caffeine treatment. After adipogenic differentiation and caffeine treatment, cells were stained with Oil Red O and the levels of peroxisome proliferator activator γ (PPARγ), C/EBPα, and C/EBPβ were determined by western blot analysis. Hydrogen peroxide and cigarette smoke extract increased the levels of intracellular ROS and anti-oxidative enzymes, which decreased in a dose-dependent manner upon pretreatment with caffeine in GO orbital fibroblasts. Oil Red-O staining results revealed a decrease in lipid droplets; furthermore, PPARγ, C/EBPα, and C/EBPβ protein expression levels were inhibited upon treatment with caffeine during adipocyte differentiation. In conclusion, caffeine decreased oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. These findings may contribute to the development of new types of caffeine-containing pharmacological agents for use in the management of GO.


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Along with pancreatic cancers, certain glioblastomas, small cell lung carcinomas, undifferentiated thyroid cancers and so on, ovarian cancer in general remains very intractable even in the recent revolutionary era which began to obtain the curative clues for cancer in general. Indeed, several cell-targeted anti-cancer drugs and immune checkpoint inhibitors gave us unprecedented, remarkable outcomes for not a few numbers of malignant neoplasms. On the other hand, any benign cancers of endocrine origins can be transformed into outrageous counterparts. To elucidate the underlying mechanism, among all, we have to find a driver molecule(s) or its equivalent gene(s) for the above cancers to open a new and broad avenue for conquering such malignancies. Current oncologists are quite sure that every cancer is able to survive and proliferate by addicting to such a driver(s). In this issue of Endocrine Journal, Inoue's group started to fully characterize the genome of ovarian cancers by using one of the next generation genome-reading methods, RNA-sequencing analysis (RNA-Seq). So far, there are few reports of RNA-seq-based mutation analysis of ovarian cancers. Their analysis of 32 clinical ovarian specimens from 24 patients identified novel mutations in TP53, BRCA1, BRCA2, ARID1A, PIK3CA, KRAS, PTEN, CTNNB1, and other HR-related genes such as ATM. However, these might be only tips of a huge unexplored iceberg. We look forward encountering the unforeseen players through a series of these analyses within several years. Hopefully, such a finding happens to be accompanied by a debut of a novel powerful newcomer(s)whose participation in the field fruitfully expands the scope of our biological view.

Identification of novel mutations of ovarian cancer-related genes from RNA-sequencing data for Japanese epithelial ovarian cancer patients

Saya Nagasawa, Kazuhiro Ikeda, Kuniko Horie-Inoue, Sho Sato, Satoru Takeda, Kosei Hasegawa, Satoshi Inoue

Abstract

Ovarian cancer has the highest mortality rate among gynecological cancers. Gene mutations are involved in the carcinogenesis, metastasis, and therapeutic response in ovarian cancer. However, the variety and proportion of gene mutation is not fully analyzed in Japanese ovarian cancer patients, especially, in those with recurrent tumors. In the present study, RNA-sequencing was performed for 32 clinical ovarian specimens obtained from 24 Japanese patients (24 primary cancer specimens and 8 recurrent specimens paired with corresponding primary cancer specimens). Mutations in 24 primary specimens were analyzed by comparing the sequence data mapped on RefSeq genes with those in the public online databases BRCA Exchange, COSMIC, ClinVar, and cBioportal. Mutations were observed in TP53 in 16 specimens (67%), BRCA1 in 9 (38%), BRCA2 in 13 (54%), ARID1A in 3 (13%), PIK3CA in 2 (8%), KRAS in 1 (4%), PTEN in 1 (4%), and CTNNB1 in 1 (4%), excluding synonymous mutations. Among those identified muations, 13 of 14 mutations in TP53, 10 of 11 mutations of BRCA1, 10 of 23 mutation positions of BRCA2, none of 7 mutations of ARID1A, 1 mutation of PIK3CA, and 1 mutation of CTNNB1 were consistent with those reported in the public online databases; however, the other mutations identified were novel. Comparison between matched-paired specimens of primary and recurrent tumors revealed the changes of mutational status in expressed RNAs. RNA-sequencing-based mutation analysis will be useful to reveal ethnic differences of gene mutations in ovarian cancer and to understand the contribution of gene mutations to recurrence.


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How safe now?

We now know that pheochromocytoma, not rare but not so familiar in the clinic at present, should be treated with intense preoperative and intraoperative workup to result in successful and peaceful outcome. Once believed as one of the riskiest operations in the endocrine surgery, widely well-recognized cautious pretreatment to prevent deadly dehydration during the tumor resection made such a memory only a nightmare in the past. Then, how safe is the curative operation of pheochromocytoma as a current therapeutic maneuver statistically? In this issue, Bai et al performed an elegant study to systematically organize current status of the risk predictors including BMI, CHD (coronary heart disease), tumor size, and preoperative use of crystal/colloid fluid. In this process, they developed a rather unique and sophisticated nomogram and found that the use of such a nomogram is quite beneficial to predict the probability of IHD (intraoperative hemodynamic instability). Validation of the usefulness of their nomogram for pre- and intra-operative prediction of IHD with pheochromocytoma is eagerly awaited.

Development and validation of a clinical model to predict intraoperative hemodynamic instability in patients with pheochromocytomas surgery

Song Bai, Bin Wu, Zichuan Yao, Xianqing Zhu, Yunzhong Jiang, Hongyan Wang

Abstract

Although currently the primary strategy for the treatment of pheochromocytomas is surgery, it is associated with a high risk of intraoperative hemodynamic instability (IHD), even with adequate preoperative medical preparation, which may result in life-threatening situations. The aim of this study was to develop and validate a nomogram for preoperative prediction of IHD related to pheochromocytoma surgery. The development cohort consisted of 283 patients with pheochromocytoma who underwent unilateral laparoscopic or open adrenaletomy at our center between January 1, 2007 and December 31, 2016. The clinicopathological characteristics of each patient were recorded. The least absolute shrinkage and selection operator binary logistic regression model was used for data dimension reduction and feature selection, while multivariable logistic regression analysis was used to develop the prediction model. An independent cohort consisting of 119 consecutive patients from January 1, 2017 to December 31, 2018 was used for validation. The performance of the prediction model was assessed in regards to discrimination, calibration, and clinical usefulness. The predictors of this model included body mass index, coronary heart disease, tumor size, and preoperative use of crystal/colloid fluid. For the validation cohort, the model showed good discrimination with an area under the receiver operating characteristic of 0.767 (95% CI, 0.667–0.857) and good calibration (unreliability test, p = 0.852; Hosmer–Lemeshow test, p = 0.9309). Decision curve analysis demonstrated that the model was clinically useful. This nomogram to facilitate preoperative individualized prediction of IHD in patients with pheochromocytoma may help to improve the perioperative strategy and treatment outcome.


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A curious course of hypercalcemia but not hypophosphatemia after discontinuation of denosumab; Is FGF23 a culprit?

In this issue, Uchida and Nakazato’s group reported a case of a woman with sustaining hypercalcemia after scheduled cessation of denosumab, a potent anti-RANKL antibody to prevent bony events related to her breast cancer successfully treated five years ago. During this period, prominent hypercalcemia with normal serum phosphorus in the presence of unexpectedly high level of serum FGF23 appeared. After ruling out other possible plausible contributors for such cooccurrence of hypercalcemia and elevated serum FGF23 concentration, the authors speculated a large continuous phosphorus load by massive bone resorption triggered by discontinuation of denosumab yielded high plasma levels of FGF23. During the course, reduction of bone resorption with zoledronic acid normalized circulating FGF-23 and hypercalcemia. We are quite sure this case has a lot of implications for the unsolved pathophysiology of FGF23 and other calciotropic substances and coexisting morbidities. While many questions are remaining, we stress here that very similar events were reported in at least five other cases so far.

Elevated levels of circulating fibroblast growth factor 23 with hypercalcemia following discontinuation of denosumab

Taisuke Uchida, Hideki Yamaguchi, Chinami Kushima, Tadato Yonekawa, Masamitsu Nakazato

Abstract

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.


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Never direct, but surely related?

The traditional and prevailing view teaches us that serum TSH concentration is likely to be a powerful predictor of malignancy in thyroid neoplasms. Meta-analyses of many studies showed that the proportion of thyroid cancer in patients with thyroid nodules with decreased serum TSH levels was lower than those with normal or high serum TSH conditions. Furthermore, a positive association between serum TSH and aggressive variants of PTC (a representative of thyroid cancer; papillary type) was recognized regardless of the demonstration of autoimmunity. All these findings suggest that TSH plays a crucial role in thyroid cancer initiation and aggressiveness. However, strictly speaking, whether TSH is one and only culprit of real-world PTC pathogenesis in addition to its occurrence remains unsolved. (Herein, we will not deal with other suspicious carcinogens including radioactive iodine.) What if a significant number of PTCs obtained from credible and unbiased statistical studies exhibited a rise in insignificant levels of TSH? Guo et al. in the recent issue of EJ addressed these issues by demonstrating that hyperinsulinemia and higher TPOAb levels might be other risk factors of PTC, but not disease severity in Chinese patients. Insulin and IGFs are in one sense a plausible candidate for malignant cell transformation, but no further clues were provided at present. The relationship between autoimmunity and carcinogenesis is still an untouchable area. Clearly, additional longitudinal and observational studies with a large sample size are needed to evaluate the effects of hyperinsulinemia and TPOAb level on the development and progression of PTC. Elucidation of its underlying mechanism(s) would help to develop new anticancer drugs targeted to the intracellular signal transduction players commonly and hopefully involved in this process.

Hyperinsulinemia and thyroid peroxidase antibody in Chinese patients with papillary thyroid cancer

Xiaoyan Guo, Xinyan Chen, Ce Zhang, Jiahuan Zhang, Chunyu Zhang

Abstract

This study aimed to investigate if hyperinsulinemia and/or insulin resistance was correlated with the occurrence of papillary thyroid cancer (PTC) in a group of Chinese patients. 258 inpatients were included in the study. According to the postoperative pathology results, all subjects were divided into PTC (n = 153) and control groups (with benign thyroid nodules, n = 105). Body mass index (BMI), fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), thyroid-stimulating hormone (TSH), FT4, FT3, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb), serum uric acid (UA), and lipid levels. Fasting insulin levels, HOMA-IR values, TPOAb levels, serum TSH levels, and serum uric acid levels in the PTC group were higher than those in the control group (p < 0.05). However, no significant differences in age, gender, BMI, history of hypertension, and the levels of fasting plasma glucose, FT3, FT4, TGAb, total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein were observed between the two groups (p > 0.05). After the multiple logistic regression analysis, the occurrence of PTC was positively associated with fasting insulin (odds ratio [OR] = 1.048, 95% confidence interval [CI]: 1.003–1.096, p = 0.037) and TPOAb levels (OR = 1.001, 95% CI: 1.000–1.002, p = 0.032). Moreover, TPOAb level was positively correlated with vague margin (r = 0.126, p = 0.045) and negatively correlated with homogeneous echo (r = –0.179, p = 0.004). However, fasting insulin levels were not correlated with pathological characteristics of PTC. Hyperinsulinemia and higher TPOAb levels might be the risk factors of PTC, but not disease severity in Chinese patients.


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So far, our prescription of a newcomer drug with a novel direction seems to lead to the fruitful outcome even when such a tool is once thought quite epoch-making. Not only by the disposal of excess glucose into the urine, sodium glucose cotransporter 2 inhibitors (sGLUT2is) are known to possess incredibly wide range of beneficial effects on diabetic patients. Such functions include anti-obesity effects by several distinct means, elevating insulin sensitivity, attenuation of anti-insulin counterregulatory substances and so on. Nevertheless, there remains a strict limitation to the use of such drugs especially for people of old age, with renal dysfunction and susceptibility to infection. Now, Kosugi and Inoue's group revealed that such pleiotropic functions depend, at least in part, on the concomitant improved action of other hormone (which is never a sole cytokine), FGF21. Since FGF21 has several promising effects on lipid metabolism and weight management, both will partially compensate for the functional pitfalls of insulin during modern sedentary life. Together with cardio- and reno-protective attractive effects of sGLUT2i, its therapeutic potential would encompass multifaceted roles as a super-reliever for oral antidiabetic-resistant with/without exogenous insulin-demanding diabetic patients. Now sGLUT2i treatment would potentially shed new brilliant light on the further development of drugs subsequent to metformin, incretin-related agents and/or thiazolidinedione.

Effects of Sodium-glucose cotransporter 2 inhibitor (dapagliflozin) on food intake and plasma fibroblast growth factor 21 levels in type 2 diabetes patients

Rieko Kosugi, Eiji Nakatani, Kensuke Okamoto, Saeko Aoshima, Hidekazu Arai, Tatsuhide Inoue

Abstract

The objective of this study was to investigate whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) treatment in patients with type 2 diabetes induced compensatory hyperphagia by reducing fibroblast growth factor 21 (FGF21) secretion. This prospective study was performed in 26 type 2 diabetes patients treated with dapagliflozin (5 mg/day). Hormonal factors associated with glucose metabolism, dietary intakes estimated by brief self-administered diet-history questionnaire (BDHQ), body weight (BW), and body composition were measured at baseline, and 4 and 12 weeks after dapagliflozin. At 12 weeks, HbA1c levels and BW decreased significantly (both p < 0.0001). BMI at baseline was predictive to baseline log10 (FGF21) (p = 0.037). This study showed no change in FGF21, but insulin and glucagon levels decreased significantly (both p < 0.05). Although hyperphagia was found in 10 patients (38.5%), defining hyperphagia as >20% increase in carbohydrate intake, dapagliflozin treatment induced no hyperphagia, when analyzed by all subjects, and there was no significant association between changes in FGF21 levels and carbohydrate intake. On the other hand, a positive correlation between changes in FGF21 levels or carbohydrate intake and BW was observed (both p < 0.005). Taken together, this study demonstrates that the intervention to maintain the reduced levels in FGF21 is beneficial for BW reduction in type 2 diabetes patients treated with SGLT2i.


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We now know that human genome consists of twenty thousands of protein-coding genes whose numbers are never remote from those in mice, flies or even E. Coli. Then, what makes us a true human is currently believed to lie outside such genomic region. Here comes a concept of non-coding transcripts including microRNA (miR) or long-non-coding (lnc)RNA scattering all over the human genome, which occupy three hundred millions of base pairs/haploid genome. It is not exaggerated to say that their function is so divergent and unique---indeed, their sequence is not conserved even among their close species---that there are no systematic descriptions representing or categorizing their way of action in the cells.
Here, Zhuang et al. reported in this issue of Endocrine Journal the mechanisms of one such miR, miR-181c, in the apoptosis of human endometrial carcinoma cells in relation to estrogen and its receptor signal. In this process, they elegantly showed a crosstalk between ER and a signal transduction molecule, PI3K-PTEN system. While many yet-unknown paradigms are left open, their report would surely shed some light on the clarification of NR-related oncogenesis.

MiR-181c affects estrogen-dependent endometrial carcinoma cell growth by targeting PTEN

Lili Zhuang, Hongmei Qu, Jianxiang Cong, Huangguan Dai, Xiaoyan Liu

Abstract

MicroRNAs (miRNAs), which is a type of non-coding and single-stranded small molecule RNA, bind either completely or incompletely to 3’-UTR of the target gene mRNA to inhibit mRNA translation or degradation. In our study, we aimed to explore the roles and mechanisms of miR-181c in the apoptosis of RL95-2 human endometrial carcinoma cells. Cell activity and apoptosis were detected by cell counting Kit-8 (CCK-8) assay and flow cytometry (FCM), respectively. Related mRNAs and proteins expression was determined by quantitative real-time reverse transcription PCR (qRT-PCR) and western blot assays, respectively. The binding capacity of PTEN-3’-UTR and miR-181c was assessed by luciferase reporter assay. The obtained results suggested that E2 evidently increased the cell activity of RL95-2 cells. In addition, miR-181c inhibitor suppressed the cell viability and enhanced the apoptosis capacity of E2-induced RL95-2 cells and distinctly reduced the miR-181c expression. We also found that miR-181c could bind to PTEN-3’-UTR and miR-181c inhibitor up-regulated the expression level of PTEN in E2-induced RL95-2 cells. Besides, overexpression of PTEN markedly promoted the apoptosis of E2-induced RL95-2 cells through regulating the Bax and Bcl-2 expression, and modulated the expression of AKT pathway, p53 and Cyclin D. In conclusion, our findings revealed that miR-181c affected the estrogen-dependent endometrial carcinoma cell growth by targeting PTEN. The potential effects of miR-181c on the apoptosis of E2-induced RL95-2 cells suggest that miR-181c could be an effective target for endometrial carcinoma therapies.


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Fat accumulation in the adipose tissue per se might not be very harmful even in the presence of overall obesity while ectopic fat deposition in liver and muscle is one of the most troublesome consequences of insulin resistance and T2DM. How insulin resistance is involved in these processes is still controversial; one of the crucial functions of insulin is inhibition of lipolysis and increased lipid production and storage both in adipose tissues.
In this issue, Lu et al. reported that there exists a close relationship between the pancreatic fat content (PFC) and insulin secretion / resistance in T2DM patients. Then the authors postulate that PFC might represent an unprecedented potential risk factor for the development of T2DM by exploiting 3p-Dixon technology.

What does pancreatic fat mean?

Maybe nobody correctly answers this question at present.
Of interest, the authors found that the relations between PFC and insulin sensitivity and insulin resistance are only observed in male T2DM subjects, but not in female T2DM subjects and non-diabetic subjects.
To explore whether PFC is an independently determinant of β-cell dysfunction and insulin resistance, they performed a partial correlation analysis to adjust for BMI, age and LFC (liver fat content). They found that the relations still exist. Therefore, it is possible to speculate that PFC plays an important role in β-cell dysfunction and insulin resistance independently, but pancreatic fat remains to be further characterized.
There are some limitations of this work; the sample size was relatively small and some of the subjects had been treated with insulin, which might have affected the accuracy of the β-cell function determination. Furthermore, they suggested the use of HOMA-β to respond to insulin secretion may affect the results of the experiment. Now, a large-scale comparison between the surface area of both visceral adipose tissue and pancreatic fat is eagerly awaited.

Pancreatic fat content is associated with β-cell function and insulin resistance in Chinese type 2 diabetes subjects

Ting Lu, Yao Wang, Ting Dou, Bizhen Xue, Yuanyuan Tan, Jiao Yang

Abstract

The pathogenesis of type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction. Earlier studies reported that increased levels of pancreatic fat may lead to the development of β-cell dysfunction and insulin resistance. The present study aimed to demonstrate the relationship between pancreatic fat content (PFC) and insulin secretion and insulin resistance in Chinese subjects with T2DM. Seventy-eight T2DM subjects and 35 non-diabetic volunteers were recruited in this study. All subjects were subjected to an oral glucose tolerance test (OGTT). We also measured PFC and liver fat content (LFC) by three-point Dixon method (3p-Dixon), and we examined the relations between PFC and OGTT-derived parameters. T2DM subjects had higher PFC than non-diabetic subjects (p < 0.01). PFC was correlated with body mass index (BMI), liver fat content (LFC) and age in two groups, however, it was only positively associated with insulin secretion, insulin resistance, early- and late-phase insulin secretion in male T2DM subjects, but not in non-diabetic and female T2DM subjects. After adjusting for BMI, LFC and age, the association still existed (all p < 0.05). Furthermore, the relationship was more obvious in male T2DM subjects with a shorter course of disease. PFC was associated with β-cell dysfunction and insulin resistance in subjects with T2DM and was more obvious in male T2DM subjects with shorter duration of diabetes. Therefore, PFC might represent a potential risk factor for the development of T2DM.


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To examine in detail that vitamin D deficiency is prevalent among children in Japan in accordance with the numerous recent reports from abroad, Kubota et al. conducted a nationwide epidemiologic survey of symptomatic, not only with low serum 25(OH)D levels, vitamin D deficiency to systematically clarify its incidence rate among Japanese children. They found the overall annual incidence rate of 1.1 per 100,000 children under 15 years of age. Roughly compared with the figures in other countries, the current number is never low. Therefore, their report persuasively confirmed that supplementation with vitamin D in infants and pregnant women, as well as food fortification with vitamin D and calcium should be considered to prevent symptomatic vitamin D deficiency in Japan as well as in other countries.

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan

Takuo Kubota, Hirofumi Nakayama, Taichi Kitaoka, Yosikazu Nakamura, Seiji Fukumoto, Ikuma Fujiwara, Yukihiro Hasegawa, Kenji Ihara, Sachiko Kitanaka, Satomi Koyama, Satoshi Kusuda, Haruo Mizuno, Keisuke Nagasaki, Koji Oba, Yuko Sakamoto, Noriyuki Takubo, Toshiaki Shimizu, Yusuke Tanahashi, Kosei Hasegawa, Hirokazu Tsukahara, Tohru Yorifuji, Toshimi Michigami, Keiichi Ozono

Abstract

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145–222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9–1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7–4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.


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It has been controversial whether or not 1 mg overnight dexamethasone suppression test (DST) is superior to 0.5 mg DST in diagnosing subclinical adrenal Cushing syndrome. Sasaki et al. addressed this issue by measuring plasma dexamethasone concentration using liquid chromatography tandem mass spectrometry. Their results clearly showed that 1 mg DST dexamethasone suppression test is superior to 0.5 mg DST. This information is useful for the diagnosis of subclinical adrenal Cushing syndrome.

In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing’s syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry

Yosuke Sasaki, Takuyuki Katabami, Shiko Asai, Hisashi Fukuda, Yasushi Tanaka

Abstract

The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing’s syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS.


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Nakamura et al. investigated the complication of X-linked hypophosphatemia (XLH) other than skeletal and dental diseases. They examined retrospectively medical records of 22 patients with XLH, and found that hypertension was associated with XLH in 6 patients. The average onset of hypertension was 29.0 years and secondary hyperparathyroidism preceded the development of hypertension. In patients with hypertension, eGFR was significantly reduced compared to that of those without hypertension. These results suggest that early-onset hypertension is one of complications in patients with XLH.

Hypertension is a characteristic complication of X-linked hypophosphatemia

Yoshie Nakamura, Masaki Takagi, Ryojun Takeda, Kentaro Miyai, Yukihiro Hasegawa

Abstract

X-linked hypophosphatemia (XLH) is a group of rare disorders caused by defective proximal tubular reabsorption of phosphate. Mutations in the PHEX gene are responsible for the majority of cases. There are very few reports of long-term complications of XLH other than skeletal and dental diseases. The aim of this study was to identify the phenotypic presentation of XLH during adulthood including complications other than skeletal and dental diseases. The clinical and biochemical phenotype of 22 adult patients with a PHEX gene mutation were examined retrospectively from their medical records. 6 patients had hypertension. The average age of hypertension onset was 29.0 years. Secondary hyperparathyroidism preceded the development of hypertension in 5 patients. 1 patient developed tertiary hyperparathyroidism. 15 patients had nephrocalcinosis. 2 patients had chronic renal dysfunction. Patients with hypertension had a significantly lower eGFR (p=0.010) compared to patients without hypertension. No significant difference was found in any other parameters. To examine the genotype-phenotype correlation, 10 adult males were chosen for analysis. No significant genotype-phenotype correlation analysis was revealed in any of the complications. However, there was a possibility that the age at nephrocalcinosis onset was younger in the non-missense mutation group than in the missense mutation group (p=0.063). This study corroborated the view that early-onset hypertension could be one of the characteristic complications seen in XLH patients. Considering the limited number of our patients, further study is necessary to address a potential cause of hypertension. XLH patients require careful lifelong treatment.


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Matsuzawa et al. investigated the involvement of regulatory T cells in the pathophysiology of Graves' ophthalmopathy (GO). They analyzed peripheral blood mononuclear cells from patients with Graves' disease with overt GO, those with Graves' disease without GO (non-GO), and healthy controls. They found that GO had significantly higher frequency of effector T cells than non-GO and healthy controls. Regarding disease activity, patients with improved GO had lower frequencies of regulatory T cells than patients with stable or deteriorated GO. They conclude that expanded population of effector T cells may be associated with pathogenesis of GO and that decreased regulatory T cells in peripheral blood may predict a good clinical outcome.

Implications of FoxP3-positive and -negative CD4+ CD25+ T cells in Graves’ ophthalmopathy

Kazuhiko Matsuzawa, Shoichiro Izawa, Tsuyoshi Okura, Shinya Fujii, Kazuhisa Matsumoto, Kyoko Shoji, Risa Nakamura, Keisuke Sumi, Yohei Fujioka, Akio Yoshida, Chiaki Shigemasa, Masahiko Kato, Kazuhiro Yamamoto, Shin-ichi Taniguchi

Abstract

Graves’ ophthalmopathy (GO) is a common manifestation of Graves’ disease (GD); however, its pathogenesis is not well understood. Recently, the dysregulation of regulatory T cells (Tregs) has been thought to be closely associated with the pathogenesis and clinical symptoms of autoimmune disease. We therefore evaluated whether T cell subsets, including Tregs, are associated with GO pathogenesis and clinical symptoms. In this observational study we evaluated 35 GD patients with overt ophthalmopathy (GOs) and 28 patients without ophthalmopathy (non-GOs). Fifteen healthy euthyroid patients served as healthy controls (HCs). Peripheral blood mononuclear cells from GOs, non-GOs and HCs were analyzed for CD4, CD25, and FoxP3 expression using flow cytometry. We also evaluated their correlation with disease activity according to the clinical activity score (CAS) and magnetic resonance imaging (MRI) findings. Disease severity was evaluated using the NOSPECS score, and clinical progression of GO was followed for 24 weeks. The main outcome measures were the frequencies of FoxP3-positive and -negative CD4+ CD25+ T cells at study outset, namely Tregs and effector T cells (Teffs), respectively. GOs had higher frequencies of Teffs (30.8±8.4%) than non-GOs (19.4±7.1%) and HCs (22.7±7.9%). Notably, patients with improved GOs had lower frequencies of Tregs (5.8±1.1%) than patients with stable or deteriorated GOs (7.3±1.2%), although ophthalmic and radiological parameters were not significantly different at the start of the study. In conclusion, an expanded Teff population may be associated with GO pathogenesis. Additionally, decreased Tregs in peripheral blood may predict a good clinical outcome.


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Ono et al. reported a new method to induce fatal hypothyroidism in rabbits. They performed total thyroidectomy using a surgical microscope. After the total thyroidectomy, severe signs of hypothyroidism were observed. Most of the thyroidectomized rabbits died within 14 weeks presumably due to heart failure. This is an interesting animal model for fatal hypothyroidism and may be useful to establish a guideline for the treatment of myxedema coma, a life-threatening endocrine crisis.

A rabbit model of fatal hypothyroidism mimicking “myxedema coma” established by microscopic total thyroidectomy

Yosuke Ono, Masanori Fujita, Sachiko Ono, Sho Ogata, Shoichi Tachibana, Yuji Tanaka

Abstract

Myxedema coma (MC) is a life-threatening endocrine crisis caused by severe hypothyroidism. However, validated diagnostic criteria and treatment guidelines for MC have not been established owing to its rarity. Therefore, a valid animal model is required to investigate the pathologic and therapeutic aspects of MC. The aim of the present study was to establish an animal model of MC induced by total thyroidectomy. We utilized 14 male New Zealand White rabbits anesthetized via intramuscular ketamine and xylazine administration. A total of 7 rabbits were completely thyroidectomized under a surgical microscope (thyroidectomized group) and the remainder underwent sham operations (control group). The animals in both groups were monitored without thyroid hormone replacement for 15 weeks. Pulse rate, blood pressure, body temperature, and electrocardiograms (ECG) were recorded and blood samples were taken from the jugular vein immediately prior to the thyroidectomy and 2 and 4 weeks after surgery. The thyroidectomized rabbits showed a marked reduction of serum thyroxine levels at 4 weeks after the surgical procedure vs. controls (0.50±0.10 vs. 3.32±0.68 μg/dL, p<0.001). Additionally, thyroidectomized rabbits exhibited several signs of hypothyroidism such as hypothermia, systolic hypotension, bradycardia, and low voltage on ECGs, compared with controls. Of the 7 rabbits with severe hypothyroidism, 6 died from 4 to 14 weeks after the thyroidectomy possibly owing to heart failure, because histopathologic examinations revealed a myxedema heart. In summary, we have established a rabbit model of fatal hypothyroidism mimicking MC, which may facilitate pathophysiological and molecular investigations of MC and evaluations of new therapeutic interventions.


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In this review article, Horii and Hatada overviewed application of genome editing by using the CRISPR/Cas system. Using this new technology, it is rather easy to prepare knockout cells or animals. Additionally, this method enables us to generate multiple mutations and knock-in. In this article, application of the CRISPR/Cas system for the pluripotent stem cells and for preparation of genome-edited animals is presented.

Production of genome-edited pluripotent stem cells and mice by CRISPR/Cas

Takuro Horii, Izuho Hatada

Abstract

Clustered regularly at interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) nucleases, so-called CRISPR/Cas, was recently developed as an epoch-making genome engineering technology. This system only requires Cas9 nuclease and single-guide RNA complementary to a target locus. CRISPR/Cas enables the generation of knockout cells and animals in a single step. This system can also be used to generate multiple mutations and knockin in a single step, which is not possible using other methods. In this review, we provide an overview of genome editing by CRISPR/Cas in pluripotent stem cells and mice.


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Genome editing technology is a breakthrough in the field of life science and enables us to perform gene targeting in easy and reproducible ways. In this article, Hatada and Horii reviewed history, principles and application of the CRISPR/Cas9 system. Future prospects of the genome editing are also presented.

Genome editing: A breakthrough in life science and medicine

Izuho Hatada, Takuro Horii

Abstract

Genome editing technologies represent a major breakthrough that has dramatically altered strategies in a wide range of biological studies. Genome editing simplifies and accelerates the creation of animal disease models and enables construction of models in most animal species, even those that are not amenable to conventional gene targeting technology.


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Ozturk and colleagues investigated the prevalence of metabolic syndrome in patients with normocalcemic primary hyperparathyroidism (NC-PHPT) and compared to that in patients with hypercalcemic primary hyperparathyroidism (HC-PHPT). Compared to patients with HC-PHPT, patients with NC-PHPT had similar prevalence of metabolic syndrome, glucose intolerance and hypertension. Compared to control age- and gender-matched subjects, patients with NC-PHPT had significantly higher prevalence of glucose intolerance and hypertension. Patients with NC-PHPT should be followed up carefully because of the metabolic consequences.

Patients with normocalcemic primary hyperparathyroidism may have similar metabolic profile as hypercalcemic patients

Feyza Yener Ozturk, Selvinaz Erol, Muhammed Masum Canat, Savas Karatas, Idris Kuzu, Sezin Dogan Cakir, Yuksel Altuntas

Abstract

Primary hyperparathyroidism is well known to be associated with cardiovascular morbidity and mortality. However, it is unclear whether normocalcemic primary hyperparathyroidism (NC-PHPT) and hypercalcemic primary hyperparathyroidism (HC-PHPT) share the same risk factors. We aimed to determine prevalence of metabolic syndrome in NC-PHPT and compare metabolic syndrome parameters and insulin resistance in NC-PHPT subjects with those in HC-PHPT and control subjects. After excluding patients with secondary hyperparathyroidism, the study enrolled 25 patients with NC-PHPT, 24 patients with HC-PHPT and 30 age-gender matched controls. All participants were evaluated using the International Diabetes Federation (IDF)-2006 metabolic syndrome criteria. Compared with HC-PHPT patients, NC-PHPT patients had similar prevalence of metabolic syndrome, glucose intolerance, and previous history of hypertension/anti-hypertensive medications, but compared with controls, NC-PHPT patients had significantly higher prevalence of glucose intolerance and previous history of hypertension/anti-hypertensive medications. Not serum calcium but PTH concentration was found to be significantly higher in those with glucose intolerance. Serum fasting triglyceride concentration and waist circumference were found to be positively correlated only with serum PTH concentration. In conclusion, patients with NC-PHPT may be prone to similar metabolic disturbances linked to higher cardiovascular risk like patients with HC-PHPT. Although NC-PHPT is thought to occur early in the development of the classical disease, it should be monitored regularly because of its metabolic consequences.


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Hayashi et al. reported a patient with type 2 diabetes associated with anti-insulin antibody. The patient was treated with insulin but the glycemic control was poor characterized by frequent episodes of nocturnal hypoglycemia and daytime hyperglycemia. Administration of a DPP4 inhibitor was not effective whereas ipragliflozin, an SGLT2 inhibitor, markedly improved glycemic control and hypoglycemic episodes were disappeared. Anti-insulin antibody was greatly improved. These results suggest that SGLT2 inhibitors provide a therapeutic option for diabetes associated with anti-insulin antibody.

SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies

Akinori Hayashi, Koji Takano, Sayuki Kawai, Masayoshi Shichiri

Abstract

Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.


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Sasaki et al. analyzed a transgenic mouse line expressing human insulin receptor after crossing the line with db/db mice. They unexpectedly found that these mice have improvements in hyperphagia and glucose tolerance without improved insulin sensitivity. Leptin receptor signaling may contribute to the discordant regulation between glucose tolerance and insulin sensitivity.

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice

Tsutomu Sasaki, Mitsutaka Kuroko, Sawako Sekine, Sho Matsui, Osamu Kikuchi, Vina Yanti Susanti, Masaki Kobayashi, Yoshinori Tanaka, Tomoyuki Yuasa, Tadahiro Kitamura

Abstract

Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.


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Fukumoto and colleagues summarized the definition and pathogenesis of rickets and osteomalacia, two metabolic disorders due to impaired mineralization of bone matrix. They also presented diagnostic criteria and flowchart for differential diagnosis, which are very useful for endocrinologists.

Pathogenesis and diagnostic criteria for rickets and osteomalacia — Proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society [Opinion]

Seiji Fukumoto, Keiichi Ozono, Toshimi Michigami, Masanori Minagawa, Ryo Okazaki, Toshitsugu Sugimoto, Yasuhiro Takeuchi, Toshio Matsumoto

Abstract

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases. We hope that these criteria and flowchart are clinically useful for the proper diagnosis and management of patients with these diseases.


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Sasaki et al. analyzed a transgenic mouse line expressing human insulin receptor after crossing the line with db/db mice. They unexpectedly found that these mice have improvements in hyperphagia and glucose tolerance without improved insulin sensitivity. Leptin receptor signaling may contribute to the discordant regulation between glucose tolerance and insulin sensitivity.

Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice

Tsutomu Sasaki, Mitsutaka Kuroko, Sawako Sekine, Sho Matsui, Osamu Kikuchi, Vina Yanti Susanti, Masaki Kobayashi, Yoshinori Tanaka, Tomoyuki Yuasa, Tadahiro Kitamura

Abstract

Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.


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Shimatsu et al. analyzed possible predictors for QOL improvement during GH replacement therapy in 83 patients with adult GH deficiency. The results show that physical, mental and social component scores were negatively correlated with the changes in fasting plasma glucose concentration (FPG). Short-term changes in FPG and IGF-I were correlated with long-term changes in QOL. These results may provide an insight into our understanding of the efficacy of GH replacement therapy for the treatment of adult GH deficiency.

Possible predictors for QOL improvement following GH replacement therapy in adult GHD

Akira Shimatsu, Noriyuki Iwamoto, Toshiaki Tanaka, Akira Teramoto, Masanori Taketsuna, Katsuichiro Ihara, Jumpei Funai, Minoru Irie, Kazuo Chihara

Abstract

In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.


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Yoshihara et al. investigated the serum levels of hCG and thyroid hormones in patients with gestational transient thyrotoxicosis (GTT) in an attempt to differentiate between active Graves' disease and GTT. Their results show that the serum hCG level is high in patients with GTT but is not a good parameter for differentiating between active Graves' disease and GTT. Instead, the FT3/FT4 ratio is a better parameter for differentiation.

Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: Is the serum hCG level useful for differentiating between active Graves' disease and GTT?

Ai Yoshihara, Jaeduk Yoshimura Noh, Koji Mukasa, Miho Suzuki, Hidemi Ohye, Masako Matsumoto, Yo Kunii, Natsuko Watanabe, Nami Suzuki, Toshiaki Kameda, Kiminori Sugino and Koichi Ito

Abstract

Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT, and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves’ disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was significantly higher than in GTT group, and was a better parameter for differentiation.


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Maejima et al. reported a case of DEND syndrome caused by a mutation in the Kir6.2 subunit of the ATP-sensitive potassium channel. The patient was responsive to sulfonylurea and, interestingly, was associated with water intake disorder. This raises a possibility that the ATP-sensitive potassium channel in the brain is involved in the regulation of water intake and/or osmoregulation.

Water intake disorder in a DEND syndrome afflicted patient with R50P mutation

Yuko Maejima, Shinji Hasegawa, Shoichiro Horita, Kensuke Kumamoto, Juris Galbanovskis, Seiichi Takenoshita, Kenju Shimomura

Abstract

In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K+ (KATP) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 µl aliquot of 340 µM KATP channel opener diazoxide or 100 µM KATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the KATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered KATP channel activity.


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Kim et al. demonstrate by using ghrelin knockout mice that ghrelin is required for neurogenesis in hippocampus induced by dietary restriction.

Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice

Kim Y, Kim SH, Kim CY, Sato T, Kojima M, Park SJ.

Abstract

Neurogenesis occurs in the adult hippocampus and is enhanced by dietary restriction (DR), and neurogenesis enhancement is paralleled by circulating ghrelin level enhancement. We have previously reported that ghrelin modulates adult neurogenesis in the hippocampus. In order to investigate the possible role of ghrelin in DR-induced hippocampal neurogenesis in adult mice, ghrelin knockout (GKO) mice and wild-type (WT) mice were maintained for 3 months on DR or ad libitum (AL) diets. Protein levels of ghrelin in the stomach and the hippocampus were increased by DR in WT mice. One day after BrdU administration, the number of BrdU-labeled cells in the hippocampal dentate gyrus was decreased in GKO mice maintained on the AL diet. DR failed to alter the proliferation of progenitor cells in both WT and GKO mice. Four weeks after BrdU injection, the number of surviving cells in the dentate gyrus was decreased in AL-fed GKO mice. DR increased survival of newborn cells in WT mice, but not in GKO mice. Levels of brain-derived neurotrophic factor protein in the hippocampus were similar between WT and GKO mice, and were increased by DR both in WT and GKO mice. These results suggest that elevated levels of ghrelin during DR may have an important role in the enhancement of neurogenesis induced by DR.


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Leonova et al. investigated the effects of long-term TSH suppression therapy and Calcium-D3 supplementation on bone mineral density in 124 young female patients treated for differentiated thyroid cancer at a mean age of 14 years and followed up for an average of 10 years. No effects of L-T4 and radioiodine therapies on bone mineral density was found. In addition, bone mineral density was significantly higher in patients receiving Calium-D3 medication. They conclude that long-term TSH suppression does not affect bone mineral density in women treated for differentiated thyroid cancer at young age.

Bone mineral density in treated at a young age for differentiated thyroid cancer after Chernobyl female patients on TSH-suppressive therapy receiving or not Calcium-D3 supplementation

Leonova TA, Drozd VM, Saenko VA, Mine M, Biko J, Rogoinovitch TI, Takamura N, Reiners C, Yamashita S.

Abstract

Long-term management of patients with differentiated thyroid cancer (DTC) commonly includes TSH-suppressive therapy with L-T4 and, in case of postsurgical hypoparathyroidism, Calcium-D3 supplementation, both of which may affect skeletal health. Experience with female patients treated for DTC at a young age and who were then receiving long-term therapy with L-T4 and Calcium-D3 medication is very limited to date. This cross-sectional study set out to investigate effects of Calcium-D3 supplementation and TSH-suppressive therapy on bone mineral density (BMD) in 124 young female patients treated for DTC at a mean age of 14 years and followed-up for an average of 10 years. BMD was found to be significantly higher in patients receiving Calcium-D3 medication than in patients not taking supplements. The level of ionized calcium was the strongest factor determining lumbar spine BMD in patients not receiving Calcium-D3 supplementation. Pregnancy ending in childbirth and HDL-cholesterol were associated with a weak adverse effect on spine and femoral BMD. No evidence of adverse effects of L-T4 and of radioiodine therapies on BMD was found. We conclude that Calcium-D3 medication has a beneficial effect on BMD, and that TSH-suppressive therapy does not affect BMD in women treated for DTC at young age, at least after 10 years of follow-up.


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Kiyota et al. identified an antigen with molecular weight of 51 KDa in pituitary extract recognized by sera from patients with isolated ACTH deficiency. By LC-MS/MS analysis, they identified the 51 KDa protein to be Rab GDI. Rab GDI may be a candidate of autoantigen involved in the pathogenesis of isolated ACTH deficiency.

Identification of the novel autoantigen candidate Rab GDP dissociation inhibitor alpha in isolated adrenocorticotropin deficiency

Kiyota A, Iwata S, Sugimura Y, Takeuchi S, Takagi H, Iwata N, Nakashima K, Suzuki H,
Nishioka T, Kato T, Enomoto A, Arima H, Kaibuchi K, Oiso Y.

Abstract

Isolated adrenocorticotropin deficiency (IAD) is characterized by low or absent adrenocorticotropic hormone (ACTH) production. IAD is presumed to be caused in part by an autoimmune mechanism, and several lines of evidence have suggested the presence of anti-pituitary antibodies in IAD. However, the exact autoantigens remain unknown. The present study was designed to identify the autoantigen(s) in IAD using chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Rat anterior pituitary lysate was subjected to SDS-PAGE, and immunoblotting was performed using the sera from two patients with IAD and from a healthy subject. The bands detected by the patient serum samples, but not by the healthy subject sample, were excised, in-gel digested using trypsin, and subjected to LC-MS/MS analysis. On immunoblots, a 51-kDa band in the insoluble pellet was detected by the sera from the IAD patients but not from the healthy subject. Mass spectrometric analysis revealed the 51-kDa band contained Rab guanine nucleotide dissociation inhibitor (GDI) alpha. Consistent with the mass spectrometric analysis, a recombinant full-length human Rab GDI alpha was recognized by the two IAD patient samples but not by the healthy subject sample using immunoblotting. In total, anti-Rab GDI alpha antibodies were detected in serum samples from three of five patients with IAD (60%) but were absent in 5 healthy subjects. In addition, Rab GDI alpha was expressed in the anterior pituitary. In conclusion, it appears that Rab GDI alpha is a candidate autoantigen involved in IAD, and that anti-Rab GDI alpha antibodies are present predominantly in patients with IAD.


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Kawate et al. demonstrate that patients with subclinical Cushing's syndrome, especially those with bilateral lesions, have a risk of extra-adrenal malignancy. Screening of malignancies may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors

Hisaya Kawate, Michiko Kohno, Yayoi Matsuda, Yuko Akehi, Makito Tanabe, Toshihiro
Horiuchi, Keizo Ohnaka, Masatoshi Nomura, Toshihiko Yanase, Ryoichi Takayanagi

Abstract

Subclinical Cushing's syndrome (SCS) is characterized by subtle autonomous cortisol secretion from adrenal tumors without specific signs and symptoms of hypercortisolism. Patients with SCS have a high prevalence of "lifestyle-related diseases," such as hypertension, diabetes mellitus, dyslipidemia, and osteoporosis. Long-term follow-up of SCS patients is reportedly indispensable for establishing indications for surgical treatment of SCS. We performed a follow-up survey of 27 patients with SCS (median: 5.3 years) and compared those who had undergone surgical treatment (n=15) with those who had not (n=12). The mean diameter of tumors was 31 mm; 16 (59%) patients had unilateral lesions and 11 (41%) carried bilateral ones. In 67% and 60% of the treatment group, respectively, hypertension and diabetes mellitus improved. We also noticed that eight of 11 (73%) SCS patients with bilateral adrenal tumors had extra-adrenal malignancies in various tissues. Interestingly, among nine SCS patients who had malignancies, eight showed bilateral adrenal uptake in 131I-aldosterol scintigraphy. The results imply that surgical treatment can reduce cardiovascular risks in SCS patients. Screening for malignancy may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

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