Causes of In-Hospital Death and Pharmaceutical Associations with Age of Death during a 10-Year Period (2011-2020) in Individuals with and without Diabetes at a Japanese Community General Hospital.

Since diabetes and its complications have been thought to exaggerate cardiorenal disease, resulting in a short lifespan, we investigated causes of death and lifespans in individuals with and without diabetes at a Japanese community general hospital during the period from 2011 to 2020. Causes of death and age of death in individuals with and those without diabetes were compared, and associations between medications used and age of death were statistically analyzed. A total of 2326 deaths were recorded during the 10-year period. There was no significant difference between the mean ages of death in individuals with and those without diabetes. Diabetic individuals had higher rates of hepato-pancreatic cancer and cardio-renal failure as causes of death. The prescription rates of antihypertensives, antiplatelets, and statins in diabetic individuals were larger than those in non-diabetic individuals. Furthermore, the use of sulfonyl urea or glinides and insulin was independently and inversely associated with the age of death. In conclusion, individuals with diabetes were treated with comprehensive pharmaceutical interventions and had life spans comparable to those of individuals without diabetes. This study's discovery of an inverse relationship between the use of insulin secretagogues or insulin and the age of death suggests that the prevention of life-threatening hypoglycemia is crucial for individuals with diabetes.


Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.

Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.


Cross-Sectional and Longitudinal Associations between Skin Autofluorescence and Tubular Injury Defined by Urinary Excretion of Liver-Type Fatty Acid-Binding Protein in People with Type 2 Diabetes.

= 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury.


Dehydroepiandrosterone Sulfate, an Adrenal Androgen, Is Inversely Associated with Prevalence of Dynapenia in Male Individuals with Type 2 Diabetes.

Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. Although skeletal muscle disorders are often found in diabetic people, the clinical significance of DHEAS in skeletal muscle remains unclear. Therefore, we aimed to determine whether DHEAS is associated with the development of skeletal muscle disorders in individuals with type 2 diabetes (T2D). A cross-sectional study was conducted in 361 individuals with T2D. Serum DHEAS levels, skeletal muscle mass index (SMI), handgrip strength (HS), and gait speed (GS) were measured in the participants. Pre-sarcopenia, sarcopenia, and dynapenia were defined according to the definitions of the AWGS 2019 criteria. DHEAS level was positively associated with HS but not with SMI or GS after adjustment of confounding factors. Multiple logistic regression analyses in total subjects showed that DHEAS level had an inverse association with the prevalence of dynapenia but not with the prevalence of pre-sarcopenia or sarcopenia. Furthermore, a significant association between DHEAS level and dynapenia was found in males but not in females. ROC curve analysis indicated that cutoff values of serum DHEAS for risk of dynapenia in males was 92.0 μg/dL. Therefore, in male individuals with T2D who have low serum levels of DHEAS, adequate exercise might be needed to prevent dynapenia.


Vascular Endothelial Function Is Associated with eGFR Slope in Female and Non-Smoking Male Individuals with Cardiovascular Risk Factors: A Pilot Study on the Predictive Value of FMD for Renal Prognosis.

In individuals with cardiovascular risk factors, evaluation of vascular endothelial function enables prediction of renal prognosis in females and non-smoking males.

Journal of Atherosclerosis and Thrombosis


Phase angle and extracellular water-to-total body water ratio estimated by bioelectrical impedance analysis are associated with levels of hemoglobin and hematocrit in patients with diabetes.

PhA and ECW/TBW but not SMI were associated with levels of Hgb and Hct in patients with diabetes. Therefore, aberrant values of PhA and ECW/TBW suggest a risk of anemia in diabetic patients.


Plasma Heparin Cofactor II Activity Is Inversely Associated with Hepatic Fibrosis of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus.

Plasma HCII activity was inversely associated with clinical hepatic fibrosis indices including FIB-4 index, NFS and APRI and with the prevalence of advanced hepatic fibrosis in patients with T2DM. The results suggest that HCII can serve as a novel biomarker for assessment of hepatic fibrosis of NAFLD in patients with T2DM.

Multiple regression analysis including confounding factors showed that plasma HCII activity independently contributed to decreases in FIB-4 index (p<0.001), NFS (p<0.001) and APRI (p=0.004). In addition, logistic regression analysis for the prevalence of advanced hepatic fibrosis defined by the cutoff points of the clinical scores showed that plasma HCII activity was the sole and common negative factor for prevalence of advanced hepatic fibrosis (FIB-4 index: p=0.002, NFS: p=0.026 and APRI: p=0.012).


Novel method utilizing bisulfite conversion with dual amplification-refractory mutation system polymerase chain reaction to detect circulating pancreatic β-cell cfDNA.

We developed a novel method for detecting unmethylated insulin DNA in circulation that can be performed using a conventional real-time PCR system. This method would be useful for analyzing dynamic profiles of β-cells in human disease such as type 1 diabetes.


Effectiveness of a Diabetes Oral Nursing Program Including a Modified Diabetes Oral Health Assessment Tool for Nurses (M-DiOHAT©): A 12-Month Follow-Up Intervention Study

This study aimed to evaluate the effectiveness of a diabetes oral nursing intervention program for individuals with diabetes. Fifty-six participants with diabetes underwent a diabetes oral nursing intervention program. The program's effect was evaluated through questionnaires and small interviews. The modified diabetes oral health assessment tool (M-DiOHAT©) was used to assess and educate four factors;oral conditions, behaviors, perceptions and knowledge about diabetes and periodontal disease, and health information-sharing, among participants at baseline, 3, 6, and 12 months later. Primary outcomes included changes in the M-DiOHAT© total scores. Secondary outcomes included scores on the motivation stage of changes in oral health behaviors' scales, dental visits, number of present teeth, hemoglobin A1c (HbA1c), and participants' comments. The M-DiOHAT© total score and the motivation stage score significantly improved with the narrative comment of "being motivated to practice oral health behaviors" between the baseline and 12 months later. Eight participants visited the dentist, whereas no differences were observed in the number of present teeth or HbA1c. This program improved participants' M-DiOHAT© total score, motivation stage score, and dental visits. These results suggest the program improved oral health perceptions and behaviors among individuals with diabetes. J. Med. Invest. 69 : 86-96, February, 2022.

The Journal of Medical Investigation : JMI


Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index.


Identification of an endoplasmic reticulum proteostasis modulator that enhances insulin production in pancreatic β cells.

Perturbation of endoplasmic reticulum (ER) proteostasis is associated with impairment of cellular function in diverse diseases, especially the function of pancreatic β cells in type 2 diabetes. Restoration of ER proteostasis by small molecules shows therapeutic promise for type 2 diabetes. Here, using cell-based screening, we report identification of a chemical chaperone-like small molecule, KM04794, that alleviates ER stress. KM04794 prevented protein aggregation and cell death caused by ER stressors and a mutant insulin protein. We also found that this compound increased intracellular and secreted insulin levels in pancreatic β cells. Chemical biology and biochemical approaches revealed that the compound accumulated in the ER and interacted directly with the ER molecular chaperone BiP. Our data show that this corrector of ER proteostasis can enhance insulin storage and pancreatic β cell function.


An attempt to create a treatment algorithm of central adrenal insufficiency using CRH test, DHEA-S and clinical evaluation.

Objective : To examine diagnostic performance of corticotropin-releasing hormone (CRH) test combined with baseline dehydroepiandrosterone sulfate (DHEA-S) in patients with a suspect of central adrenal insufficiency. Methods : Patients (n=215) requiring daily or intermittent hydrocortisone replacement, or no replacement were retrospectively checked with their peak cortisol after CRH test and baseline DHEA-S. Results : None of 106 patients with the peak cortisol · 17.5 g /L after CRH test required replacement, and all 64 patients with the peak cortisol < 10.0 g /L required daily replacement. Among 8 patients with 10.0 g /L the peak cortisol < 17.5 g /L and baseline DHEA-S below the reference range, 6 patients required daily replacement and 1 patient was under intermittent replacement. Among 37 patients with 10.0 g /L the peak cortisol < 17.5 g /L and baseline DHEA-S within the reference range, 10 and 6 patients were under intermittent and daily replacement, respectively. Conclusions : No patients with the peak cortisol · 17.5 g /L required hydrocortisone replacement, and all patients with the peak cortisol below 10.0 g /L required daily replacement. Careful clinical evaluation was required to determine requirement for replacement in patients with 10.0 g /L the peak cortisol < 17.5 g /L even in combination with baseline DHEA-S. J. Med. Invest. 69 : 287-293, August, 2022.


循環血中遊離 DNA を用いた膵β細胞傷害の新規検出法の確立

循環血中遊離 DNA を用いた膵β細胞傷害の新規検出法の確立

In people with type1 diabetes(T1D), biomarkers that can sensitively and quantitatively evaluate injury of pancreatic beta cell are required in order to predict the onset of the disease at an early stage and to provide interventions to prevent the progression of the disease. We developed a new method for quantifying pancreatic beta cell-derived insulin DNA in circulation that combines bisulfite conversion and Amplification Refractory Mutation System(ARMS)PCR, which can be performed using a conventional real-time PCR system. We applied this method to T1D patients and healthy adults, both could be detected in about 30% of cases. The results in healthy adults indicate that this method may have sensitivity to detect the turnover of pancreatic beta cells at physiological conditions. In post-onset T1D patients, there were many negatives because the amount of residual pancreatic beta cells was extremely small. However, in some cases with a short duration of the disease, pancreatic beta cell-derived insulin DNA was detected in negative correlation between the duration of the disease, that suggested the residual pancreatic beta cells continue to be slowly destroyed. It was demonstrated that the time course of pathophysiology in T1D could be understood using this method.


繰り返す脆弱性骨折を契機に発見されたクッシング症候群の一例

繰り返す脆弱性骨折を契機に発見されたクッシング症候群の一例

A 38-year-old woman had suffered from an avulsion fracture of the left cuboid bone, a rib fracture, a fatigue fracture of the left second metatarsal bone and a pubic fracture within the last 4 years. She also realized that her face was getting rounded and became aware of edema on extremities. She had repeated fragile fractures before menopause and was referred to our department on suspicion of secondary osteoporosis. The patients showed physical signs of moon face, central obesity, and abdominal violaceous striae. Cushing's syndrome was suspected, therefore confirmatory studies were performed. Circadian variation of cortisol : serum cortisol19．3μg/dL(at7:00), 21．4μg/dL(at23:00), urinary free cortisol :247．4μg/24h, ACTH :2．5pg/mL. Low-dose(1mg) dexamethasone did not suppress cortisol level(18．9μg/dL). Based on these findings, we diagnosed as Cushing's syndrome and glucocorticoid excess seemed to be the cause of secondary osteoporosis. Abdominal CT identified a 2．7 cm tumor in the left adrenal gland, and in-phase T1‐weighted MRI showed decreased signal compared to out-phase, suggesting an adrenocortical adenoma. She underwent laparoscopic left adrenalectomy. Postoperative fasting serum cortisol decreased to2．2 μg/dL, and glucocorticoid replacement therapy was started. It is necessary to find out any secondary causes for premenopausal women with fragility fractures. It is well known that endocrine disorders including Cushing's syndrome are the most frequent associated diseases in patients with premenopausal osteoporosis. Cushing's syndrome should be considered as a causative disease in premenopausal women with osteoporosis.


TIA様症状を契機に診断されたインスリノーマの1例

TIA様症状を契機に診断されたインスリノーマの1例

We report the case of a67-year-old woman who had symptoms suggestive of a transient ischemic attack(TIA), such as lightheadedness and transient visual changes before meals for 4 months. She experienced altered consciousness before lunch and was taken to the emergency room2weeks ago. She had repeated hypoglycemia with a blood glucose level of 31 mg/dL. Insulin secretion was not suppressed, with an immunoreactive insulin level of 14．0 μU/mL and connecting peptide immunoreactivity of 1．83 ng/mL for occasional blood glucose levels of 49 mg/dL. Dynamic CT revealed a 17‐mm mass enhanced during the arterial phase in the pancreatic uncinate process, suggestive of a pancreatic neuroendocrine tumor. A selective arterial secretagogue(calcium)injection test revealed the localization of insulinoma in the head of the pancreas. Therefore, pancreatoduodenectomy was performed. Hyperglycemia occurred after the surgery, and it was judged that the insulinoma was resected. This case showed TIA-like symptoms without signs of sympathetic overdrive associated with hypoglycemia. Thus, the diagnosis was delayed. Insulinoma may present with symptoms of neuroglycopenia but not autonomic activity due to hypoglycemia. Insulinoma should be distinguished in patients with unknown neurological symptoms since neuroglycopenia caused by insulinoma is diverse.


歩行不能だったが，多職種の高度な連携と患者特性に配慮したケアにより自宅生活可能となった高度肥満症の一例

A 48-year-old man who weighed 216 kg was significantly overweight with a body mass index (BMI)of 75．6kg/m2, and was unable to walk due to disuse syndrome. Because of the psychological and social problems in the background, a psychological examination was performed and the staff took time to build a trusting relationship with the patient, taking into account his characteristics. With diet and rehabilitation, he was able to lose weight to 124kg and BMI 43．9kg/m2 over 600 days, and was able to walk with assistive devices and defecate by himself. The patient was discharged from our hospital after a series of multidisciplinary meetings with medical, nursing, welfare, and governmental agencies to create an environment for home recuperation. The reasons for the improvement to enable him to be discharged from the hospital were due to the multi-disciplinary meetings among the staff inside and outside the hospital, information sharing and advanced coordination, and smooth communication with the patient by taking into account his characteristics from a psychological standpoint.


Plasma Heparin Cofactor II Activity Is Inversely Associated with Albuminuria and Its Annual Deterioration in Patients with Diabetes.

The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria.


Delayed diagnosis of thyroid storm in an elderly patient: A case report

診断に時間を要した高齢者の甲状腺クリーゼの1例

A 70-year-old woman was hospitalized for diarrhea, vomiting, loss of appetite, fatigue, and dyspnea on exertion for the past 3 weeks and treated with intravenous fluid for dehydration. She was receiving prednisolone for polymyositis. She did not have a history of thyroid disease. On day 4 of hospitalization, the patient was diagnosed with congestive heart failure and tachycardiac atrial fibrillation, and treatment with a diuretic agent was initiated. On day 7 of hospitalization, a clinical laboratory evaluation revealed that the level of free thyroxine was 9.95 ng/dL, free triiodothyronine was >30 pg/mL, and thyroid-stimulating hormone was <0.01 μU/mL, and the patient was initially diagnosed with thyrotoxicosis because of Graves' disease. She showed restlessness and had a fever of 39 °C, tachycardia of ≥140 beats/min, pulmonary edema, and frequent diarrhea, all of which were consistent with the symptoms of thyroid storm. Her general condition gradually improved with comprehensive treatment of thyroid storm comprising thiamazole, potassium iodide, hydrocortisone, and landiolol. A reassessment revealed that the patient had already had thyrotoxicosis and thyroid storm on admission. Thyroid storm is a potentially fatal disease that must be urgently addressed; however, its symptoms are difficult to distinguish from those caused by other diseases. Furthermore, elderly individuals may not exhibit typical symptoms of thyroid storm, so the diagnosis is difficult. In this case, the diagnosis was delayed because of the absence of typical symptoms of thyroid storm and the influence of a pre-existing medical condition and medication.

甲状腺クリーゼは致死的かつ緊急疾患であるが，他疾患に起因する症状と区別がつきにくいことや，高齢者では典型的クリーゼ症状を呈さない場合があり，診断は容易ではない．今回，消化器症状で発症し，心房細動と心不全の加療中に，甲状腺クリーゼと未治療バセドウ病の診断に至った症例を経験したので報告する．症例は70歳の女性．甲状腺疾患の既往はなく，多発筋炎でプレドニゾロン服用中であった．X月中頃より下痢・嘔吐が出現し，徐々に増悪し，労作時呼吸困難も出現した．X+1月8日に嘔気と倦怠感のため消化器内科に入院し，脱水に対して補液を行った．さらに消化器症状，発熱，呼吸困難の症状が悪化し，入院4日目にうっ血性心不全，頻脈性心房細動の診断で循環器内科において利尿薬を中心とした治療が開始された．入院7日目にFT4 9.95 ng/dL，FT3 >30 pg/mL，TSH <0.01 μU/mLとTSH抑制を伴う甲状腺ホルモン過剰が判明し，内分泌代謝内科へ紹介された．TRAb 22.6 IU/Lと上昇がありバセドウ病と診断するとともに，不穏，39℃の発熱，140回/分以上の頻脈，肺水腫，頻回な下痢を認め，確実な甲状腺クリーゼの状態であった．チアマゾール，ヨウ化カリウム，ヒドロコルチゾン，ランジオロールなどによる甲状腺クリーゼの包括的治療を行い，後遺症を残すことなく救命できた．甲状腺ホルモンの低下とともに，心不全診断時に認めた左室壁の局所運動異常と心電図のST-T変化は改善し，たこつぼ型心筋症も合併していたと考えられた．後の検査で入院時から甲状腺中毒症が存在し，すでに甲状腺クリーゼの状態であったことが判明した．本症例は，入院時に高熱や多動などの意識障害を呈さず，倦怠感が目立ち，基礎疾患や服用薬の影響など診断を困難にする要因が重なり，甲状腺クリーゼの診断までに時間を要したと考えられた．


Congenital Hypogonadotropic Hypogonadism with Early-Onset Coronary Artery Disease.

The patient with congenital hypogonadotropic hypogonadism (HH) shows low serum levels of androgen, which is a group of sex hormones including testosterone, caused by the decreased gonadotropin release in the hypothalamus. Recent reports showed androgens exert protective effects against insulin resistance or atherosclerotic diseases, such as diabetes mellitus or coronary artery disease. However, whether the juvenile hypogonadism affects the diabetes or cardiovascular disease is unclear. We report a case of a middle-aged man with congenital HH who had severe coronary artery disease complicated with metabolic disorders. J. Med. Invest. 68 : 189-191, February, 2021.

The Journal of Medical Investigation : JMI


A case of severe obesity who had been unable to walk but became able to live at home thanks to a high level of coordination and patient-specific care by a multidisciplinary team

多職種連携と患者特性に配慮したケアを行った高度肥満症の一例


腹壁遠心性脂肪萎縮症の1例

腹壁遠心性脂肪萎縮症の1例


糖尿病患者の口腔保健行動アセスメントツールを用いた看護支援プログラムの評価

糖尿病患者の口腔保健行動アセスメントツールを用いた看護支援プログラムの評価

Journal of the The Japan Diabetes Society


Modified diabetes oral health assessment tool (M-DiOHAT©) for nurses and their association with efficacy beliefs and outcome expectancies in patients with diabetes

JNI : The Journal of Nursing Investigation


Circulating Apolipoprotein L1 is associated with insulin resistance-induced abnormal lipid metabolism.

Circulating ApolipoproteinL1 (ApoL1) is a component of pre-β-high-density lipoprotein (HDL), however little is known about the relationship of ApoL1 with cardiometabolic factors. Considering previous studies reporting the correlation of ApoL1 to triglyceride, we have hypothesized that ApoL1 associates with insulin-related metabolism. The current study examined their associations in 126 non-diabetic subjects and 36 patients with type 2 diabetes (T2DM). Non-diabetic subjects demonstrated triglyceride (standardized coefficients [s.c.] = 0.204, p < 0.05), body mass index (s.c. =0.232, p < 0.05) and HDL cholesterol (s.c. = -0.203, p < 0.05) as independent determinant of ApoL1 levels, and the significant elevation of ApoL1 in metabolic syndrome. Lipoprotein fractionation analysis revealed the predominant distribution of ApoL1 in large HDL fraction, and the significant increase of ApoL1 in large LDL fraction in high ApoL1 samples with insulin resistance. In T2DM, ApoL1 was higher in T2DM with metabolic syndrome, however ApoL1 was lower with β cell dysfunction. Insulin significantly promotes ApoL1 synthesis and secretion in HepG2 cells. In conclusion, circulating ApoL1 may be associated with abnormal HDL metabolism in insulin resistant status. This may suggest a regulation of insulin signal on the ApoL1 level, leading to offer a novel insight to the ApoL1 biology.


A case of isolated ACTH deficiency that required 6 months for the diagnosis from onset.

症状発現から診断までに半年を要したACTH単独欠損症の一例

A 53-year-old man noticed anorexia, nausea, and arthralgia of the upper limbs in April, 201X. Since these symptoms persisted, he visited general hospital and clinic and was examined for blood chemistry, ECG, echocardiography and so on. However, he did not get a definitive diagnosis and was followed up with drip infusion of saline. The symptoms did not subside and fatigue and syncope with hypotension developed. Furthermore, he also suffered weight loss of 10 kg in few months and was referred to our hospital for more detailed examinations in October, 201X. Upon the initial examination, all his symptoms matched those of adrenal insufficiency and notable decreases of both plasma ACTH and serum cortisol level were observed. Prompt glucocorticoid supplementation improved his symptoms and the abnormal laboratory data immediately. He was diagnosed adrenal insufficiency due to isolated ACTH deficiency from the results of CRH loading test and insulin tolerance test. Since most of the symptoms and laboratory findings are non-specific, diagnosis of adrenal insufficiency is often delayed. However, adrenal insufficiency could worsen when the patient is under stress (e.g. infection) and often be life-threatening. Glucocorticoid replacement therapy should be initiated as soon as the diagnosis is confirmed. Furthermore, educating patients and his families plays a very important role in the management of chronic adrenal insufficiency, in particular to the prevention of adrenal crisis.


Persistent Activation of Calcium-Sensing Receptor Suppresses Bone Turnover, Increases Microcracks, and Decreases Bone Strength.

Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.


Association of accumulated advanced glycation end-products with a high prevalence of sarcopenia and dynapenia in patients with type 2 diabetes.

Advanced glycation end-products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so-called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. We recruited 166 patients with type 2 diabetes aged 30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m ; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes.


Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-α and ATRA.


Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma.


Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.

Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.


Effective impairment of myeloma cells and their progenitors by hyperthermia.

Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated "side population" fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs.


Predictors for the Treatment Effect of Sodium Glucose Co-transporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus.

Predictors for the effect of sodium glucose co-transporter 2 (SGLT2) inhibitors at lowering hemoglobin A1c (HbA1c) levels in type 2 diabetes mellitus patients remain unclear. We therefore aimed to elucidate these predictors in type 2 diabetes patients after 3 months of SGLT2 treatment. A total of 302 consecutive type 2 diabetes patients who had been treated with SGLT2 inhibitors as monotherapy or add-on therapy to existing antidiabetic treatments were enrolled retrospectively. After excluding 27 patients whose HbA1c levels could not be evaluated 3 months after treatment, the glucose-lowering effects of SGLT2 inhibitors were assessed in 275 patients by measuring HbA1c levels before and 3 months after treatment. The predictors for changes in HbA1c levels after 3 months of treatment were evaluated. SGLT2 inhibitor treatment for 3 months decreased HbA1c levels from 7.8 ± 1.2% to 7.4 ± 1.0% (p < 0.0001). A multiple regression analysis showed that the independent determinants for SGLT2 inhibitor treatment effect included decreased HbA1c levels after 1 month of treatment, high baseline HbA1c levels, and a high estimated glomerular filtration rate (eGFR). We show that type 2 diabetes patients who received the greatest glucose-lowering effect with SGLT2 inhibitor treatment were those with preserved renal function (high baseline eGFR) and high baseline HbA1c levels. Moreover, SGLT2 inhibitor treatment efficacy could be predicted by the patients' initial response to treatment.


TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor -activated kinase-1 (TAK1), and thus activated NF-B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-B activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.


Remarkable Shrinkage of a Growth Hormone (GH)-secreting Macroadenoma Induced by Somatostatin Analogue Administration: A Case Report and Literature Review.

Acromegaly is caused by excessive growth hormone secretion, usually from pituitary adenomas. Somoatostatin analogues are widely used as primary or adjunctive therapy in the management of acromegaly. In this report, we present a case with remarkable shrinkage of a tumor after relatively short-term octreotide long-acting release (LAR) administration. During the 30-month follow-up after starting octreotide LAR, there was no recurrence of acromegaly with remarkable shrinkage of the tumor on pituitary magnetic resonance imaging. A literature review of the predictors for tumor shrinkage after the administration of somatostatin analogues in patients with acromegaly is also discussed in relation to this case.


The Role of Heparin Cofactor in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice.

The present studies provide evidence to support the idea that HC plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HC production may serve as novel therapeutic tools for the treatment of type 2 diabetes.

Journal of Atherosclerosis and Thrombosis


Suppression of the Hypothalamic-pituitary-adrenal Axis by Maximum Androgen Blockade in a Patient with Prostate Cancer.

A 78-year-old Japanese man showed suppression of the hypothalamic-pituitary-adrenal axis during maximum androgen blockade (MAB) therapy including chlormadinone acetate (CMA) for prostate cancer. After stopping the MAB therapy, both the basal ACTH level and the response to CRH recovered. While no reports have indicated that CMA suppresses the hypothalamic-pituitary-adrenal axis in patients with prostate cancer, CMA has been shown to inhibit this axis in animals. These observations suggest that we must monitor the hypothalamic-pituitary-adrenal axis in patients treated with CMA, especially under stressful conditions.


A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.

Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.


Serum carboxy-terminal telopeptide of type I collagen levels are associated with carotid atherosclerosis in patients with cardiovascular risk factors.

Carboxy-terminal telopeptide of type I collagen (ICTP) is generated through matrix metalloproteinase (MMP)-dependent type I collagen digestion, and has been widely utilized as a biomarker for bone turnover. The fact that atherosclerotic lesions are rich in both type I collagen and MMP-producing macrophages led to the hypothesis that serum ICTP concentrations may serve as a non-invasive clinical biomarker for atherosclerosis. Therefore, the association of serum ICTP concentrations with the maximum intima-media thickness (IMT) of carotid arteries, a surrogate index of systemic atherosclerosis, or brachial-ankle pulse wave velocity (baPWV) in patients with atherosclerotic risk factors was evaluated. A total of 52 male and 65 female (mean age: 62.8 yrs) patients without renal failure, malignancies or bone diseases known to affect serum ICTP concentrations were recruited. Patients with max IMTs ≥1.1 mm showed significantly higher serum ICTP concentrations compared with patients with max IMTs <1.1 mm (3.33 ± 0.97 vs 2.82 ± 0.65 ng/mL, p<0.05). Serum ICTP concentration was also positively correlated with max IMT (p<0.001) or baPWV values (p<0.05). Multivariate analyses also revealed that serum ICTP concentrations were correlated with max IMT (p<0.001; 95% CI 0.200 to 0.454). These results suggest that serum ICTP concentrations can be used as a non-invasive biomarker for systemic atherosclerosis.


The eukaryotic translation initiation factor 2 (eIF2) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2 protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2 phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine.-Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle-specific eukaryotic translation initiation factor 2 phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.