Impact of coronavirus disease 2019 on medical practice in endocrine and metabolic diseases in Japan: a nationwide surveillance study conducted by the Japan Endocrine Society.

We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.

Terminal differentiation of keratinocytes was damaged in type 2 diabetic mice.

AIMS: Although skin manifestations are common in diabetic patients, its characteristics are poorly identified. This study explored the differentiation process of keratinocytes in type 2 diabetes mellitus (T2DM) in vivo. METHODS: Back skin of T2DM model KKAy/TaJcl mice (KKAy) and C57BL/6JJcl mice (control) aged 8 and 12 weeks was used. The mRNA expression of differentiation markers of keratinocytes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of each marker in situ was examined immunohistochemically. RESULTS: KKAy mice showed hyperglycemia versus control mice. The histological findings showed increased thickness and structural impairment of epidermal tissue in KKAy mice. The qRT-PCR revealed that the expression of integrin beta 1 and keratin 14 in KKAy and control mice was identical. However, the expression of involucrin at 8 weeks, keratin 10 at 12 weeks, and filaggrin and loricrin at 8 and 12 weeks was decreased in KKAy mice. Immunohistochemical findings showed that filaggrin was markedly decreased in KKAy mice, though Ki-67 remained unchanged. CONCLUSION: The terminal differentiation process was impaired in the diabetic skin, while keratinocyte proliferation was preserved. Damaged terminal differentiation of keratinocytes may contribute to impairment of the skin barrier function in diabetic dermatoses.

Simultaneous measurement of serum chemokines in autoimmune thyroid diseases: possible role of IP-10 in the inflammatory response.

Autoimmune thyroid diseases (AITDs), including Graves' diseases (GD) and Hashimoto's thyroiditis (HT), are the most common autoimmune diseases, and are mainly mediated by T cells that produce cytokines and chemokines in abnormal amounts. Few reports have described the circulating chemokines active in AITDs. Recently, we used a new multiplex immunobead assay to simultaneously measure cytokines and chemokines in small volume serum samples from patients with AITDs. We measured 23 selected serum chemokines in patients with GD (n=45) or HT (n=26), and healthy controls (n=9). GD patients were further classified as either untreated, intractable, or in remission, while HT patients were classified as either hypothyroid or euthyroid. Of the 23 serum chemokines assayed, only the serum level of IP-10 (CXCL10/interferon-γ-inducible protein 10) was elevated, depending on disease activity, in GD or HT compared with healthy controls. However, the serum level of IP-10 was also increased in both untreated GD patients and hypothyroid HT patients, suggesting that levels of this cytokine may not be affected by disease specificity. In conclusion, autoimmune inflammation in patients with AITD is closely related to the level of the serum chemokine, IP-10. Therefore, IP-10 might be a good biomarker for tissue inflammation in the thyroid, but not a useful biomarker for predicting disease specific activity, the progression of AITDs, or responsiveness to treatment because of its independence from thyroid function or disease specificity.

Circulating microRNAs in autoimmune thyroid diseases.

CONTEXT: Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are the most common autoimmune diseases. MicroRNAs (miRNAs) are small noncoding RNAs, which can play pivotal roles in immune functions and development of autoimmunity. Recently, it has been recognized that identification of circulating miRNAs can provide important and novel information regarding disease pathogenesis and clinical condition. However, the role circulating miRNAs in AITD has not yet been described. OBJECTIVE: The aim of this study was to characterize the different circulating levels of miRNA in patients with AITD. DESIGN AND METHODS: Sixty-four participants who met the criteria for HT or GD and healthy subjects were recruited. Microarrays were used to analyse the expression patterns of miRNA in serum obtained from patients with HT and GD and healthy subjects. After analysing the microarray data, four interesting miRNAs (miR-16, miR-22, miR-375 and miR-451) were selected and validated by quantitative real-time PCR. RESULTS: Several miRNAs were observed to be differently expressed in serum from patients with AITD compared with healthy subjects by microarray analysis. Further analysis consistently showed that serum levels of miR-22, miR-375 and miR-451 were increased in patients with HT. On the other hand, the serum levels of miR-16, miR-22, miR-375 and miR-451 were increased in patients with GD compared with healthy subjects. CONCLUSIONS: We revealed that different levels of serum miRNAs were associated with GD and HT, which may play a role in the pathogenesis of these diseases.

Impact of B Cell Depletion on COVID-19 in Kidney Transplant Recipients.

Kidney transplant recipients are patients at high risk for coronavirus disease 2019 (COVID-19) due to being on immunosuppressive therapy. B cell depletion therapy, including rituximab, is an important strategy for ABO-incompatible transplants. However, knowledge about the effect of B cell depletion therapy on COVID-19 is lacking. Thirty kidney transplant recipients who developed COVID-19 were included in this study. To examine the impact of B cell depletion therapy, we retrospectively investigated the relationship between the background of the patients and the clinical outcome. Of the 30 patients, 13 received B cell depletion therapy. The median time between transplant and onset of COVID-19 was 6.1 years after transplantation; however, nine cases remained markedly depleted of CD19(+) cells (<4.0%). The patients were assigned to the normal (n = 21) and depletion groups (n = 9). Progression rates in the depletion and normal groups were 55.6% and 9.5%, respectively (p = 0.014). Furthermore, the survival rate was significantly lower in the depletion group (100% in the normal group vs. 66.7% in the depletion group; p = 0.021). B cell depletion therapy may have long-term effects and increase the risk of COVID-19 in kidney transplant recipients.

Outcomes of Pancreas Transplantation for Lower-Ranked Candidates.

BACKGROUND: To perform more pancreas transplantation (PTx), our center sometimes performs pancreas transplantation for candidates ranked sixth place or lower. In this study, we analyzed the outcomes of PTx performed in our center to compare the outcomes of higher- and lower-ranked candidates. METHODS: Seventy-two cases in which PTx was performed at our center were divided into 2 groups according to the candidate's rank. Cases in which PTx was performed for candidates up to fifth place were classified into the higher rank candidate group (HRC group; n = 48), whereas PTx for candidates who were ranked sixth place or lower were classified into the lower rank candidate group (LRC group; n = 24). The outcomes of PTx were retrospectively compared. RESULTS: Although the LRC group included a greater number of older donors (age ≥60 years), a greater number of donors with deteriorated renal function, and a greater number of HLA mismatches, the 1- and 5-year patient survival rates in the HRC group were 91.6% and 91.6%, respectively, compared with 95.8% and 87.0%, respectively, in the LRC group (P = .755). In terms of both pancreas and kidney graft survival, there were no significant differences between the 2 groups. Additionally, there were no significant differences between the 2 groups regarding the glucagon stimulation test and 75 g OGTT results, insulin independence rate, HbA1c, or serum creatinine level after transplantation. CONCLUSIONS: In Japan, where there is a severe donor shortage, the performance of transplantation for lower-ranked candidates would increase the number of opportunities for patients to receive PTx.

Pancreas transplantation improves the quality of life of Japanese type 1 diabetes patients with diabetic kidney disease.

Objectives: Type 1 diabetes mellitus (T1DM) patients with diabetic kidney disease-induced kidney failure have a significantly impaired quality of life (QOL), resulting in a high level of physical, mental, and social anxiety. In this study, we evaluated the QOL of T1DM patients on the list for pancreas transplantation (PTx) at their registration, and determined whether PTx improved their QOL. Methods: There were 58 patients (men/women, 22/36; mean age, 42.8±8.0 years) with T1DM and who were registered on the waiting list for PTx. Quantitative QOL assessment was performed using the Medical Health Survey Short Form (SF-36) version 2. Changes in the QOL before and after PTx were also examined in 24 of these patients. Results: The mean value of each endpoint and the summary score of the SF-36 physical (PCS), mental (MCS), and role (RCS) components were all below the national normal level at PTx registration. No significant difference in QOL scores was observed in the intergroup comparison of 35 patients on dialysis, 13 patients without dialysis, and ten patients after kidney transplantation. The 24 patients who underwent PTx showed improvement in PCS, MCS, and most SF-36 scores. Conclusion: T1DM patients waiting for PTx had a decreased QOL, regardless of dialysis, and PTx improved their QOL.

Evaluation of the Efficacy and Effects of Common Hepatic Artery Reconstruction in Pancreas Transplantation: A Randomized Controlled Trial.

Maintenance of postoperative graft flow is important in pancreas transplantation. In Japan, reconstruction of the common hepatic artery is performed primarily to increase perfusion in the pancreatic head. We investigated the effects of common hepatic artery reconstruction on patient and graft survival and endocrine functions. Twenty-nine cases of pancreas transplantation were registered in the clinical trial. Of the 29 cases, four were excluded because of the risk of ischemia without reconstruction or complicated reconstruction due to a narrow artery. A total of 25 cases were randomized into two groups: 13 in the non-reconstructed group and 12 in the reconstructed group. The 1-year patient survival and graft survival rates of the non-reconstructed and reconstructed groups were 92.3% and 83.3%, and 91.7% and 82.5%, respectively. The incidence of complications in the two groups was comparable, with 38.5% (5/13 cases) in the non-reconstructed group and 33.3% (4/12 cases) in the reconstructed group. The results of the glucagon stimulation test and oral glucose tolerance test at 1 month and 1 year post-transplantation were comparable. Common hepatic artery reconstruction is not essential unless there is risk of ischemia. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry under UMIN000027213.

An Examination of Donor Factors That Impact the Results of the Glucagon Stimulation Test as an Assessment of the Pancreatic Graft Endocrine Function.

OBJECTIVES: Delta C-peptide derived by the glucagon stimulation test is a reliable value for the evaluation of the pancreatic endocrine function after pancreas transplantation. We examined the associations between delta C-peptide as pancreatic graft endocrine function and donor background factors. METHODS: Sixty-five cases of pancreatic transplantation from brain-dead donors, which were performed in our facility, were enrolled in this study. Enrolled recipients underwent a glucagon stimulation test within 1 to 3 months after transplantation to evaluate the pancreatic graft endocrine function with delta C-peptide to compare donor background factors. RESULTS: The following factors were associated with significant deterioration of the delta C-peptide: age of 50 years or greater, death from cerebrovascular accident, hemoglobin A1c level of 5.6% or greater, creatinine level of 1.0 mg/dL or greater, C-reactive protein level of 25 mg/dL or greater, and sodium level of 150 mmol/L or greater. In addition, increased numbers of these donor factors indicated significantly greater deterioration of the posttransplant pancreatic endocrine function ( P < 0.001). CONCLUSIONS: To secure insulin independence after pancreas transplantation, which means maintaining a delta C-peptide level of 1.0 ng/mL or greater on a glucagon stimulation test, the utilization of donors, who possesses more than equal to 3 of the donor factors identified in this study, should be carefully considered.

Changes in Serum Immunoglobulin G4 Levels in Patients with Newly Diagnosed Graves' Disease.

OBJECTIVE: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ. We investigated the association between IgG4-RD and the main characteristics of Graves' disease (GD) at the time of diagnosis. Additionally, we evaluated whether serum IgG4 levels change during treatment. DESIGN AND PATIENTS: Twenty-eight patients with newly diagnosed GD were enrolled into this longitudinal follow-up study. Serum IgG4 levels and thyroid function were measured in all the participants at the time of diagnosis. Further, the serum IgG4 levels of nine of 28 patients with untreated GD were measured after the achievement of euthyroid state (through the use of methimazole). RESULTS: Two (7.1%) of 28 patients with untreated GD had elevated serum IgG4 levels of >135 mg/dL. There was no significant difference in the average IgG4 levels before and after the achievement of euthyroid state (66.2±74.0 mg/dL vs. 50.5±47.3 mg/dL). In two patients, the elevated serum IgG4 levels returned to normal after treatment. However, one patient had an elevated serum IgG4 level of 136.6 mg/dL after treatment. CONCLUSIONS: This study showed that serum IgG4 levels varied with treatment in patients with GD, independent of thyroid function, suggesting that IgG4 might be indirectly related to GD.

The Outcomes of Pancreatic Transplantation from Pediatric Donors-A Single Institution Experience.

OBJECTIVES: The aim of this study was to compare the outcomes of pancreatic transplantation from pediatric donors younger than 15 years of age to the outcomes of pancreatic transplantation from adult donors. METHODS: Sixty patients underwent pancreatic transplantation in our facility from August 2012 to June 2019. These patients were divided into two groups according to the age of the donor: Cases in which the donor was younger than 15 years of age were classified into the PD group (n = 7), while those in which the donor was older than 15 years of age were classified into the AD group (n = 53). The outcomes of pancreas transplantation were retrospectively compared between the two groups. RESULTS: Pancreatic graft survival did not differ between the PD and AD groups. Furthermore, there were no differences in the HbA1c and serum creatinine levels at three months, with good values maintained in both groups. The results of oral glucose tolerance tests (OGTTs) revealed that the blood glucose concentration did not differ between the two groups. However, the serum insulin concentration at 30 min after 75 g glucose loading was significantly higher in the PD group. CONCLUSION: The outcomes of pancreatic transplantation from pediatric donors may be comparable to those of pancreatic transplantation from adult donors and the insulin secretion ability after transplantation may be better.

Low-carbohydrate diet by staple change attenuates postprandial GIP and CPR levels in type 2 diabetes patients.

AIMS: The aim of this study is to investigate the effects of a low-carbohydrate staple food (i.e., low-carbohydrate bread) on glucose and lipid metabolism and pancreatic and enteroendocrine hormone secretion in comparison with meals containing normal-carbohydrate bread, without consideration of the carbohydrate content of the side dishes. METHODS: T2DM patients (n = 41) were provided meals containing low-carbohydrate bread (LB) together with side dishes or normal-carbohydrate bread (NB) together with side dishes every other day as a breakfast. Blood glucose levels were evaluated by using a continuous glucose monitoring system; blood samples were collected before and 1 and 2 h after the breakfast. RESULTS: Postprandial blood glucose levels, plasma insulin, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma triglyceride were significantly lower and plasma glucagon levels were significantly higher in LB compared with those in NB. Plasma glucagon-like peptide-1 (GLP-1) levels did not differ in the LB and NB groups. CONCLUSIONS: These results indicate that changing only the carbohydrate content of the staple food has benefits on glucose and lipid metabolism in T2DM patients concomitant with the decrease of insulin and GIP secretion, which ameliorate body weight gain and insulin resistance.

Prediction of Insulin Secretion Ability With Microcirculation Evaluated by Contrast-enhanced Ultrasonography in Pancreas Transplantation.

OBJECTIVES: Contrast-enhanced ultrasonography can evaluate microcirculation. Thus, we used contrast-enhanced ultrasonography in evaluating pancreas graft perfusion and examined the relationship between graft circulation and function. METHODS: Contrast-enhanced ultrasonography was performed in 17 cases within 24 hours and at 1, 3, 5, 7, 14, 21, and 28 days after transplantation (Tx). The time between the time to peak intensity in the parenchyma and that in the vein was defined as delta-Tp(P-V). Graft function was evaluated with oral glucose tolerance test (OGTT) at 1 and 3 months after Tx, and glucagon stimulation test at 1 month after Tx. RESULTS: Differences in delta-Tp(P-V) between individual cases were more significant early after Tx, and delta-Tp(P-V) within 24 hours (delta-Tp[P-V]24h) was used in the subsequent analysis. Delta-Tp(P-V)24 hours showed a negative correlation with C-peptide increment in the glucagon stimulation test and the area under the curve of insulin level in oral glucose tolerance test. The cases were divided into the following 2 groups: the standard group (delta-Tp[P-V]24h ≤6.10 seconds) and the delayed group (>6.10 seconds). The area under the curve of insulin level increased significantly from 1 to 3 months after Tx in the standard group only. CONCLUSIONS: These results suggest that delta-Tp(P-V)24 hours affects insulin secretion after Tx. Contrast-enhanced ultrasonography is useful in predicting endocrine function of the graft.

Circulating MicroRNAs in Graves' Disease in Relation to Clinical Activity.

BACKGROUND: Understanding the roles of circulating microRNAs (miRNAs) can provide important and novel information regarding disease pathogenesis and a patient's clinical condition. Circulating miRNAs, such as exosomal miRNA, may regulate various bioactivities related to intercellular communication. However, the circulation of miRNAs in Graves' disease (GD) in relation to disease activity has never been elucidated. This study aimed to identify circulating miRNAs in GD in relation to disease activity and whether their exosomes play a role in the pathogenesis of GD. METHODS: Circulating miRNAs were measured in serum obtained from seven intractable GD patients, seven GD patients in remission, and seven healthy controls using the miScript miRNA PCR Array. Altered miRNAs selected from array data were validated in 65 subjects. To investigate exosome biology, peripheral blood mononuclear cells (PBMCs) were incubated with exosomes isolated from the subjects' sera. mRNAs were quantified for cytokines using quantitative real-time polymerase chain reaction. RESULTS: Circulating miR-23b-5p and miR-92a-39 were increased in GD patients in remission compared with intractable GD patients (p < 0.05). On the other hand, let-7g-3p and miR-339-5p were decreased in GD patients in remission compared with intractable GD patients (p < 0.05). Exosomes from intractable GD patients stimulated mRNA expression for IL-1ß and TNF-α compared with GD patients in remission or healthy controls. CONCLUSIONS: This study demonstrates that different levels of circulating miRNAs are associated with intractable GD. Moreover, serum exosomes of patients with intractable GD may activate immune cells, which may play an important role in GD pathogenesis.

Nutritional status of calcium and other bone-related nutrients in Japanese type 2 diabetes patients.

OBJECTIVES: Traditional Japanese food appears to be healthy but contains a small amount of milk products. Type 2 diabetes (T2DM) patients commonly reduce their energy intake to control their blood glucose levels. However, nutritional guidance for diabetes does not emphasize calcium (Ca) consumption. The aim of this study is to estimate the nutritional status of Ca and other nutrients, which affect bone and Ca metabolism, in T2DM patients. METHODS: This observational study was conducted with Japanese T2DM patients (n = 96; M/F = 50/46; age: 61.6 ± 10.1 years). We estimated nutrient intake using a simple food frequency questionnaire. RESULTS: Median total energy intake was 1750 kcal/day (1440-1970). Their median daily intake of Ca, vitamin D, and vitamin K was 451 mg (336-560), 10.2 µg (8.5-12), and 206 µg (84-261), respectively. Only 17.7% of the study subjects were found to take more than 600 mg/day of Ca. Protein and salt intake was 78 (64-90) and 10.6 (9.3-12.2) g/day, respectively. Male subjects had more salt, less Ca and vitamin K than female. Daily Ca intake was positively associated with total energy, protein, and lipid intake but not with carbohydrates. Vitamin D intake correlated only with protein intake. CONCLUSIONS: The daily Ca intake of Japanese T2DM patients appears to be insufficient and could depend on protein and lipid intake. Additionally, these patients should have specific recommendations to ensure sufficient intake of Ca with protein and lipid during energy restriction.