Featured Article (Before Volume 68)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.