Inflammatory Cytokine-Induced Muscle Atrophy and Weakness Can Be Ameliorated by an Inhibition of TGF-ß-Activated Kinase-1.

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-ß-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1ß. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

[A delayed diagnosis of thyroid storm in an elderly patient: A case report].

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.

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.

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.

Background: Anemia is one of the common complications of diabetes and is associated with mortality. Phase angle (PhA), ratio of extracellular water to total body water (ECW/TBW) and skeletal muscle mass index (SMI) estimated by bioelectrical impedance analysis (BIA) have been used as prognostic indicators for various chronic diseases and frailty. We aimed to clarify the clinical significance of PhA, ECW/TBW and SMI for anemia in patients with diabetes. Materials and methods: The values of PhA, ECW/TBW and SMI were estimated by a portable BIA device and blood samples were collected in 371 Japanese patients with diabetes. The relationships of PhA, ECW/TBW and SMI with hemoglobin (Hgb) and hematocrit (Hct) were statistically evaluated. Results: In simple linear regression analysis, PhA and SMI were positively correlated with Hgb and Hct levels in total subjects, male subjects and female subjects. In contrast, ECW/TBW was negatively correlated with Hgb and Hct levels regardless of sex. Multivariate regression analysis showed that both PhA and ECW/TBW but not SMI independently contributed to Hgb and Hct levels after adjustment of clinical confounding factors in both males and females. Conclusions: 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.

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.

AIMS: It is known that there are sex differences in vascular endothelial function and the development of chronic kidney diseases; however, it remains unclear whether sex differences influence the association between vascular endothelial function and renal prognosis. METHODS: To clarify the relationship between vascular endothelial function and longitudinal eGFR changes in male and female patients with cardiovascular risk factors, we retrospectively evaluated 341 patients (176 males and 165 females) with cardiovascular risk factors in whom vascular function was assessed by flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV) and in whom 24-month longitudinal eGFR values were recorded after the vascular function examinations. Associations of values of FMD and baPWV with values of eGFR slope were statistically analyzed. RESULTS: Simple regression analysis showed that the value of FMD was positively associated with eGFR slope in females (p=0.001) and non-smoking males (p=0.033) but not in smoking males. Multiple regression analysis showed that the value of FMD remains a positive contributor for eGFR slope in females (p=0.001) and non-smoking males (p=0.045) but not in smoking males. In contrast, values of baPWV had no significant association with eGFR slope regardless of sex and cigarette smoking. CONCLUSIONS: In individuals with cardiovascular risk factors, evaluation of vascular endothelial function enables prediction of renal prognosis in females and non-smoking males.

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.

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 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.

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

AIMS: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs), and thrombin-induced activation of PARs promotes the development of non-alcoholic fatty liver disease (NAFLD). Since heparin cofactor II (HCII) specifically inactivates thrombin action, we hypothesized that plasma HCII activity correlates with the severity of NAFLD. METHODS: A cross-sectional study was conducted. Plasma HCII activity and noninvasive clinical markers of hepatic fibrosis including fibrosis-4 (FIB-4) index, NAFLD fibrosis score (NFS) and aspartate aminotransferase-to-platelet ratio index (APRI) were determined in 305 Japanese patients with type 2 diabetes mellitus (T2DM). The relationships between plasma HCII activity and the clinical markers were statistically evaluated. RESULTS: 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). CONCLUSIONS: 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.

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

AIMS/INTRODUCTION: To investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD). MATERIALS AND METHODS: The subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25-30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected. RESULTS: The median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (ß = 0.340, P = 0.004) and the age at examination (ß = -0.288, P = 0.012) according to the multiple regression analysis. CONCLUSIONS: The average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination.

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 µg / dL after CRH test required replacement, and all 64 patients with the peak cortisol < 10.0 µg / dL required daily replacement. Among 8 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL 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 µg / dL ≤ the peak cortisol < 17.5 µg / dL 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 µg / dL required hydrocortisone replacement, and all patients with the peak cortisol below 10.0 µg / dL required daily replacement. Careful clinical evaluation was required to determine requirement for replacement in patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL even in combination with baseline DHEA-S. J. Med. Invest. 69 : 287-293, August, 2022.

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

AIMS/INTRODUCTION: Several research groups have reported methods for quantifying pancreatic beta cell (ß-cell) injury by measuring ß-cell-specific CpG unmethylation of the insulin gene in circulation using digital droplet PCR or next-generation sequencing. However, these methods have certain disadvantages, such as the need to consider the background signal owing to the small number of target CpG sites and the need for unique equipment. MATERIALS AND METHODS: We established a novel method for detecting four CpG unmethylations of the insulin gene using two-step amplification refractory mutation system PCR. We applied it to type 1 diabetes (T1D) patients with a wide range of disease durations and to healthy adults. RESULTS: The assay showed high linearity and could detect a single copy of unmethylated insulin DNA in experiments using methylated and unmethylated plasmid DNA. The unmethylated insulin DNA level in the type 1 diabetes group, whose ß-cell mass was considerably reduced, was similar to that of healthy adults. An inverse correlation was observed between copy number and disease duration in patients with unmethylated insulin DNA-positive type 1 diabetes. CONCLUSIONS: 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 ß-cells in human disease such as type 1 diabetes.

Plasma heparin cofactor II activity is inversely associated with albuminuria and its annual deterioration in patients with diabetes.

AIMS/INTRODUCTION: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. MATERIALS AND METHODS: Plasma HCII activity and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP), were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). RESULTS: The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate-regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log-transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL-FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log-transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). CONCLUSIONS: 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.

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. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.