Moon-like Facies by Glucocorticoid Is Associated With the Development of Diabetes and Body Image Disturbance.

Context: Moon-like facies (MLF) are a typical side effect of glucocorticoid (GC) therapy; however, its predisposing factors, relationship with GC-induced complications, and effects on body image are not well understood. Objective: This study aimed to determine the predisposing factors for MLF during GC therapy; its association with GC-induced diabetes, hypertension, and dyslipidemia; and its effects on body image. Methods: This prospective observational study spanned 24 weeks and targeted patients who received GC therapy at the University of Yamanashi Hospital from June 2020 to August 2022. The MLF was defined based on the following 3 factors: (1) an increase in facial measurement lengths, (2) subjective facial changes by patients' self-assessment using a visual analog scale; (3) objective and qualitative facial changes assessed by physicians. We examined the predisposing factors for MLF and the association of MLF with GC-induced diabetes, hypertension, dyslipidemia, and body image. Results: The cumulative incidence rate of MLF at 24 weeks was 37.6%. Predisposing factors for MLF were an initial oral prednisolone dosage of ≥ 30 mg/day [odds ratio (OR) 63.91, 95% confidence interval (CI) 5.82-701.81] and female (OR 6.66, 95% CI 1.35-32.79). MLF showed a significant association with the onset of GC-induced diabetes (OR 6.58, 95% CI 1.25-34.74). MLF was also an independent factor contributing to body image disturbance (ß = -18.94, P = .01). Conclusion: MLF contributes to body image disturbance and is associated with the development of GC-induced diabetes; therefore, it is clinically important as a physical manifestation of GC therapy.

Membrane protease prostasin promotes insulin secretion by regulating the epidermal growth factor receptor pathway.

Prostasin (PRSS8) is a serine protease that metabolizes and moderates the effect of specific substrates. Epidermal growth factor receptor (EGFR), which modulates insulin secretion and pancreatic ß-cell proliferation, is regulated via proteolytic shedding by PRSS8. We first detected PRSS8 expression in ß-cells of pancreatic islets of mice. To better understand the molecular processes involved in PRSS8-associated insulin secretion, pancreatic ß-cell-specific PRSS8 knockout (ßKO) and PRSS8-overexpressing (ßTG) male mice were generated. We found that glucose intolerance and reduction in glucose-stimulated insulin secretion developed in ßKO mice compared with the control subjects. A higher response to glucose was noted in islets retrieved from ßTG mice. Erlotinib, a specific blocker of EGFR, blocks EGF- and glucose-stimulated secretion of insulin among MIN6 cells, and glucose improves EGF release from ß-cells. After silencing PRSS8 in MIN6 cells, glucose-stimulated insulin secretion decreased, and EGFR signaling was impaired. Conversely, overexpression of PRSS8 in MIN6 cells induced higher concentrations of both basal and glucose-stimulated insulin secretion and increased phospho-EGFR concentrations. Furthermore, short-term exposure to glucose improved the concentration of endogenous PRSS8 in MIN6 cells through inhibition of intracellular degradation. These findings suggest that PRSS8 is involved in glucose-dependent physiological regulation of insulin secretion via the EGF-EGFR signaling pathway in pancreatic ß-cells.

Gaucher Disease Types I and III Responded Well to Substrate Reduction Therapy Using Eliglustat.

Gaucher disease (GD) causes the accumulation of glucocerebrosides in various organs, resulting in hepatosplenomegaly, anemia, decreased platelet counts, and bone disorders. Glucosylsphingosine accumulates in the brain and causes central nervous system (CNS) disorders. GD can be classified into types I (without CNS disorders), II, and III. Substrate reduction therapy (SRT) is an oral therapy that improves patients' quality of life; however, its effect on type III GD is unknown. We administered SRT to GD types I and III patients and found it effective. Malignancy is a late complication of GD, but this is the first report of Barrett adenocarcinoma.

Antidiabetic effects of hydroxychloroquine in two Japanese patients with systemic lupus erythematosus.

Hydroxychloroquine (HCQ), an antimalarial drug, is recommended for all patients with systemic lupus erythematosus (SLE), and is widely used around the world. HCQ has various beneficial effects, including antidiabetic effects but was unavailable in Japan until gaining approval for SLE treatment in 2015. We present herein the cases of two Japanese women with SLE and diabetes mellitus (DM) who were treated using HCQ and achieved reductions in glycosylated hemoglobin (HbA1c). A 48 year-old Japanese woman with SLE and DM (patient 1) received oral HCQ at 200 mg/day for the treatment of lupus nephritis. HbA1c levels decreased from 7.2-6.2% after 14 months of HCQ without any loss of body weight or alterations in doses of glucocorticoid or hypoglycemic agents. A 64 year-old Japanese woman with SLE and DM (patient 2) received oral HCQ at 200 mg and 400 mg on alternate days for the treatment of erythema. She also received intensive insulin therapy. HCQ drastically reduced both HbA1c levels, from 10.3 to 7.5%, and the insulin doses required without altering the doses of glucocorticoid or hypoglycemic agents, although body weight increased slightly. No episodes of hypoglycemia were seen in either patient. HCQ can achieve antidiabetic effects in Japanese SLE patients.

Dulaglutide improves glucocorticoid-induced hyperglycemia in inpatient care and reduces dose and injection frequency of insulin.

BACKGROUND: Glucocorticoid (GC)-induced hyperglycemia is characterized by elevated postprandial blood glucose, which commonly requires multiple insulin injections. We investigated whether a long-acting glucagon-like peptide-1 receptor agonist, dulaglutide (Dula), safely improved GC-induced hyperglycemia in inpatients, to reduce insulin injection frequency. METHODS: The data of hospitalized patients with GC-induced hyperglycemia treated with Dula (Dula group, n = 38) or without (non-Dula group, n = 38) were retrospectively evaluated. Baseline data were collected at the beginning of GC treatment. The primary outcome in this study was glycemic control, which was compared between the groups using the six-point blood glucose (before and 2 h after each meal) profiles at discharge. The daily injection frequency of injectable drugs at discharge were also compared between groups. RESULTS: No specific trend of underlying diseases was observed between the non-Dula and Dula groups. The proportion of patients previously administered with GC pulse therapy was comparable between the two groups. No significant differences were observed between groups, in the starting maintenance GC dose, GC dose at pretreatment of Dula and discharge, and cumulative GC dose during the observation. Six-point blood glucose levels at pretreatment and discharge were comparable between the two groups. However, daily injection frequency of injectable drugs and insulin dose were significantly lower in the Dula group than that in the non-Dula group. No differences were observed in the number of hypoglycemic events, the elevation of serum pancreatic enzyme levels, or gastrointestinal adverse events. CONCLUSION: These findings suggest that Dula could provide glycemic control while reducing the insulin dose and injection frequency in inpatients with GC-induced hyperglycemia. The occurrence of adverse events such as gastrointestinal symptoms and hypoglycemia did not increase in the Dula-treated patients compared to those not treated, suggesting its safety.

Calcitonin levels by ECLIA correlate well with RIA values in higher range but are affected by sex, TgAb, and renal function in lower range.

Calcitonin (CT) is a marker for both initial diagnosis and monitoring of patients with residual or recurrent medullary thyroid carcinoma (MTC). In Japan, serum CT had been measured by radioimmunoassay (RIA) until recently. Electrochemiluminescence immunoassay (ECLIA) became commercially available in 2014, and this technique is now the only method used to examine CT concentration. The purposes of this study were to investigate the correlations between the CT concentration measured with ECLIA (ECLIA-CT) and RIA (RIA-CT) and to explore the clinical characteristics of patients with elevated ECLIA-CT. CT concentrations of 348 sera samples from 334 patients with various thyroid disorders including nine MTC were measured using both assays. The correlation analysis revealed an excellent correlation between ECLIA-CT and RIA-CT among the cases with CT level >150 pg/mL by both assays (rs = 0.991, p < 0.001). However, 63% of all samples exhibited undetectable ECLIA-CT, while their RIA-CTs were measured between 15 and 152 pg/mL. The ECLIA-CTs in all patients who underwent total thyroidectomy for non-MTC showed low concentrations. High ECLIA-CT was observed in patients with MTC or pancreas neuroendocrine tumor. ECLIA-CT was also increased in 14 other male patients with non-MTC, including four with renal failure. Multivariate logistic regression analysis showed that male sex, negative TgAb, and lower estimated glomerular filtration rate were independent factors to predict detectable ECLIA-CT (≥0.500 pg/mL). These results indicate that ECLIA-CT correlates well with RIA-CT in higher range and is affected by sex, TgAb, and renal function.

Acute Kidney Injury with Hemolysis after Glycerin Enema-induced Rectal Injury in a Patient with Type 2 Diabetes.

A 66-year-old man with type 2 diabetes was admitted for glycemic control and weight loss. The rectal mucosa was unfortunately injured during glycerin enema administration in preparation for colonoscopy, after which dark red urine and renal dysfunction were observed. Considering the clinical diagnosis of glycerol-induced hemolysis and acute kidney injury, intravenous hydration and haptoglobin administration were started, which successfully treated the dark red urine and renal dysfunction. This case highlights the importance of appropriate glycerin enema administration and emphasizes the need to recognize glycerol-induced hemolysis and acute kidney injury as complications of glycerin enemas. This case also provides insight into glycerol-induced hemolysis and acute kidney injury as complications of glycerin enemas.

Follicle-stimulating Hormone-secreting Pituitary Adenoma Accompanied by Painful Thyroiditis.

A 30-year-old woman with multiple ovarian cysts presented with high serum estradiol levels. She had a pituitary adenoma, but the follicle-stimulating hormone (FSH) concentration was within the normal range. The patient complained of neck pain and palpitations during the disease course, and laboratory results revealed thyrotoxicosis and a systemic inflammatory response with negative findings for anti-thyroid stimulating hormone (TSH) receptor antibody and positive findings for anti-thyroglobulin and anti-thyroid peroxidase antibodies. Prednisolone improved the symptoms and the thyroid function and was discontinued after two months. A histological examination of the pituitary tumor confirmed it to be FSH-producing pituitary adenoma, with subsequent normalization of the serum estradiol concentration.

The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities.

In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1ß levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.

Sensitive detection of hemodynamic failure during orthostatic stress in patients with diabetic polyneuropathy using a mini laser Doppler blood flowmeter.

Autonomic dysfunction in diabetes is serious but often underestimated. The purpose of this study was to evaluate hemodynamics within the important initial phase just after standing, which cannot be evaluated by conventional instruments for orthostatic hypotension. Earlobe blood flow (EBF), which indirectly reflects the blood pressure response on standing, was evaluated using a mini laser Doppler flowmeter during standing from the sitting position in 58 healthy controls and 56 diabetic patients categorized as without (11), mild (27), and advanced diabetic polyneuropathy (18). The response area of the EBF waveform within 30 seconds after standing was calculated. An increased response area indicates poor recovery of EBF. Response area increased significantly with the degree of neuropathy (P < .001 for linear trend). Orthostatic hypotension was detected in two patients in the mild neuropathy group. The present approach may be sensitive and practical for detecting autonomic dysfunction not detected with the conventional orthostatic test.

Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM).

AIMS: Whether the titer of glutamic acid decarboxylase antibodies (GADAs), especially a low titer, is a marker of progression of beta cell dysfunction in patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) is unclear. MATERIALS AND METHODS: Patients were subdivided as follows: patients with high GADA titers [≥10 U/ml (≥180 WHO U/ml): high GADA] (group 1, n = 37); those with low GADA titers [<10 U/ml (<180 WHO U/ml): low GADA] (group 2, n = 33); those without GADA and with islet cell antibodies (ICA) (group 3, n = 8); those without both GADA and ICA and with insulinoma-associated antigen 2 antibodies (IA-2A) (group 4, n = 6). We also allocated 198 type 2 diabetic patients without any GADA, ICA or IA-2A as group 5. Serum C-peptide responses to annual oral glucose tolerance tests (OGTTs) were followed up for a mean of 107 months from entry. RESULTS: The proportion of patients progressing to an insulin-dependent state in groups 1, 2, 3 and 4 was significantly higher than in group 5. C-peptide responses in OGTTs of patients in groups 1 and 2 were decreased at a significantly higher rate than in group 5. Multivariate Cox proportional hazard analysis revealed that factors including high GADA, low GADA, onset age <45 years, duration of diabetes <24 months, body mass index (BMI) <22.0 kg/m2, low degree of preserved beta cell function and ICA were independent risk factors for progression to an insulin-dependent state. CONCLUSIONS: SPIDDM patients with low GADA titers have a significantly higher risk of progression to an insulin-dependent state than type 2 diabetic patients, suggesting that the presence of GADA, irrespective of the titer, is a hallmark of beta cell failure. Other risk factors for further progression to an insulin-dependent state in SPIDDM patients were ICA, onset age, duration of diabetes, BMI and residual beta cell function.

Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG) protein in fulminant type 1 diabetes.

BACKGROUND: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear. PROCEDURES: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.

Absorption of radionuclides from the Fukushima nuclear accident by a novel algal strain.

Large quantities of radionuclides have leaked from the Fukushima Daiichi Nuclear Power Plant into the surrounding environment. Effective prevention of health hazards resulting from radiation exposure will require the development of efficient and economical methods for decontaminating radioactive wastewater and aquatic ecosystems. Here we describe the accumulation of water-soluble radionuclides released by nuclear reactors by a novel strain of alga. The newly discovered green microalgae, Parachlorella sp. binos (Binos) has a thick alginate-containing extracellular matrix and abundant chloroplasts. When this strain was cultured with radioiodine, a light-dependent uptake of radioiodine was observed. In dark conditions, radioiodine uptake was induced by addition of hydrogen superoxide. High-resolution secondary ion mass spectrometry (SIMS) showed a localization of accumulated iodine in the cytosol. This alga also exhibited highly efficient incorporation of the radioactive isotopes strontium and cesium in a light-independent manner. SIMS analysis showed that strontium was distributed in the extracellular matrix of Binos. Finally we also showed the ability of this strain to accumulate radioactive nuclides from water and soil samples collected from a heavily contaminated area in Fukushima. Our results demonstrate that Binos could be applied to the decontamination of iodine, strontium and cesium radioisotopes, which are most commonly encountered after nuclear reactor accidents.

RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes.

OBJECTIVE: The contribution of innate immunity responsible for aggressive ß-cell destruction in human fulminant type 1 diabetes is unclear. RESEARCH DESIGN AND METHODS: Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes. RESULTS: RIG-I was strongly expressed in ß-cells in all three pancreata infected with enterovirus. Melanoma differentiation-associated gene-5 was hyperexpressed in islet cells, including ß- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-ß were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid-receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in ß-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes. CONCLUSIONS: These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive ß-cell toxicity in fulminant type 1 diabetes.