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The stimulus-response coupling pathway for glucose-regulated insulin secretion has implicated a rise in cytosolic [Ca2+]i as a key factor to induce insulin exocytosis. However, it is unclear how elevated [Ca2+]i communicates with the pancreatic beta-cell's exocytotic apparatus. As Rab3A is a model protein involved in regulated exocytosis, we have focused on its role in regulating insulin exocytosis. By using a photoactivatable cross-linking synthetic peptide that mimics the effector domain of Rab3A and microsequence analysis, we found calmodulin to be a major Rab3A target effector protein in pancreatic beta-cells. Coimmunoprecipitation analysis from pancreatic islets confirmed a Rab3A-calmodulin interaction in vivo, and that it inversely correlated with insulin exocytosis. Calmodulin affected neither GTPase nor guanine nucleotide exchange activity of Rab3A. The calmodulin-Rab3A interaction was pH- and Ca2+-dependent, and it was preferential for GTP-bound Rab3A. However, Rab3A affinity for calmodulin was relatively low (Kd = 18-22 micromol/l at 10(-5) mol/l [Ca2+]) and competed by other calmodulin-binding proteins that had higher affinity (e.g., Ca2+/calmodulin-dependent protein kinase-2 [CaMK-2] [Kd = 300-400 nmol/l at 10(-5) mol/l [Ca2+]]). Moreover, the Ca2+ dependence of the calmodulin-Rab3A interaction (K0.5 = 15-18 micromol/l [Ca2+], maximal at 100 micromol/l [Ca2+]) was significantly lower compared with that of the calmodulin-CaMK-2 association (K0.5 = 40 micromol/l [Ca2+], maximal at 1 mmol/l [Ca2+]). The data suggested that a transient Rab3A-calmodulin interaction might represent a means of directing calmodulin to the cytoplasmic face of a beta-granule, where it can be subsequently transferred for activation of other beta-granule-associated calmodulin-binding proteins as local [Ca2+]i rises to promote insulin exocytosis. [ABSTRACT FROM AUTHOR]

Insulin treatment should be introduced in patients with slowly progressive type 1 diabetes (SPIDDM; definite), according to the revised diagnostic criteria of SPIDDM (2023). In contrast, SPIDDM (probable) patients are in a non-insulin-dependent state; therefore, a more flexible treatment can be considered, although sulfonylurea agents should be avoided. Insulin treatment has been shown to maintain endogenous insulin secretion capacity in SPIDDM (probable); however, this does not mean that all SPIDDM (probable) patients should use insulin from the early phase. Dipeptidyl peptidase-4 inhibitors and biguanides might be the treatment of choice for SPIDDM (probable), but no evidence exists for other hypoglycemic agents. In any case, careful monitoring of the endogenous insulin secretion capacity should be carried out, and if a decrease in insulin secretion capacity is suspected, a change in treatment should be considered to prevent progression to an insulin-dependent state., (© 2024 The Japan Diabetes Society. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: The clinical significance of age-related biomarkers in patients with diabetes has not been fully elucidated. In this study, we aimed to establish models to predict the progression of aging in patients with diabetes using biomarkers., Materials and Methods: This single-center, retrospective cohort study included 115 Japanese patients with diabetes aged ≥60 years. Age-related adverse health outcomes were defined as emergency hospitalization, any increase in the level of nursing care certification, admission to a nursing home or death. The associations of age-related biomarker levels (adiponectin, growth differentiation factor 15 [GDF15], C-X-C motif chemokine ligand 9 and apelin) and clinical indicators with age-related adverse health outcomes were evaluated. Factors that predominantly influenced the occurrence of age-related adverse health outcomes were explored using the Cox proportional hazards model., Results: The mean age of the 115 participants was 73 years, 50.6% were men, the mean body mass index and hemoglobin A1c level were 25.3 kg/m 2 and 9.79%, respectively. There were 26 age-related adverse health outcomes during the study period (median 1.93, range 0-4.65 years). In a model combining clinical indicators and biomarkers, including the Barthel Index, GDF15 and adiponectin, the occurrence of age-related adverse health outcomes was found to be significantly associated with GDF15 and Barthel Index. The group with both GDF15 and adiponectin levels higher than the median proved to be significantly higher than the group with both lower., Conclusions: The measurement of GDF15 and adiponectin levels and the Barthel Index might be useful for predicting age-related adverse health outcomes in patients with diabetes., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: The increasing incidence and prevalence of childhood overweight (OW) and obesity (OB) are major global health challenges. This study aimed to evaluate the effectiveness of a 2-year healthy lifestyle intervention program in reducing the incidence of OW and OB among schoolchildren aged 11-12 years in Vietnam., Methods: Study design: Randomized controlled trial., Participants and Interventions: In total, 733 students participated in this study. Participants were included from four schools in Hanoi based on a random cluster sampling method. Students' health outcomes were assessed at baseline and after 2 years., Main Outcomes: The primary outcomes were the incidence of OW and OB, and the secondary outcomes were the prevalence and remission of OW and OB. Generalized estimating equations (GEEs) were used to determine the outcomes and risk factors., Results: After the intervention, the prevalence of OW decreased by 9.24% in the intervention group and 3.01% in the control group. After adjustment for age and sex, the odds of overweight were 36.7% lower in the intervention group than in the control group (OR = 0.633; 95% CI: 0.434-0.925; P = 0.018). The incidence of OW was 1.31% in the intervention group compared with 5.33% in the control group. After adjustment for age and sex, the odds of incident overweight in the intervention group were 77.4% lower than in the control group (OR = 0.226; 95% CI: 0.063-0.813; P = 0.023). The proportion of patients who achieved OW remission was 41.22% in the intervention group and 28.68% in the control group. After adjustment for age and sex, the odds of OW remission of overweight were 2.219 times greater in the intervention group than in the control group (OR = 2.219; 95% CI: 1.220-4.036; P = 0.009). For most OB-related factors, there were no significant differences between the intervention and control groups., Conclusion: A multicomponent healthy lifestyle intervention was effective in reducing the incidence of OW; however, it had no significant effect on OB among children aged 11-12 years in Hanoi, Vietnam., Trial Registration: Retrospectively registered number: UMIN000014992, 20/08/2023., (© 2024. The Author(s).)

Complete medical examinations are a system of preventive medicine unique to Japan. In recent years, Japanese and foreigners have been aware of complete medical examinations. However, the extent to which this concept of comprehensive medical checkup is recognized in different counties is unknown. The National Center for Global Health and Medicine (NCGM) is a facility that has been performing complete medical examinations on inbound visitors since May 2016, and more than 3,500 inbound visitors have been received to date. Based on this track record, the current study analyzed trends in foreigners' demand for medical checkups in Japan. From August 2020 to July 2023, 471 foreign residents in Japan from 22 countries were received. A certain proportion of examinees (approximately 30%) underwent examinations multiple times at a frequency of once a year. In addition, inbound medical visitors resumed starting in January 2023, and 158 inbound examinees were received. Of these, 15.2% of examinees had undergone a complete medical examination at the NCGM before the COVID-19 pandemic. This suggests that inbound medical visitors and foreign residents may regularly undergo complete medical examinations. In order to continue to meet this demand, Japanese medical facilities should enhance their system for receiving such examinees., Competing Interests: The authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

Purpose: Thyrotoxic periodic paralysis (TPP) is characterized by muscle paralysis and significant intracellular potassium movement resulting in hypokalemia. Since TPP is a rare condition, only a few studies have explicated the clinical characteristics of patients with this disease. This study aimed to elucidate the clinical characteristics of patients with TPP by comparing them with those with thyrotoxicosis without paralysis (non-TPP) and sporadic periodic paralysis (SPP)., Methods: This was a single-center retrospective cohort study. Clinical data of patients with hyperthyroidism (n = 62) or periodic paralysis (n = 92) who were emergently admitted to our hospital was extracted from the electronic medical records and analyzed., Results: All patients in the TPP group (15 males and 2 females) had Graves' disease, with 14 being newly diagnosed. The average serum potassium level on admission was 2.3±0.75 mEq/L. No significant correlation was observed among serum potassium level, amount of potassium required for normalization, and thyroid hormone levels. The TPP group showed significantly younger age, higher male ratio and body mass index (BMI), and lower serum potassium and phosphorus levels than the non-TPP group, which comprised 36 patients with Graves' disease. No significant differences were observed between the TPP and SPP (n = 11) groups in terms of age, sex, BMI, serum electrolyte levels, potassium requirement for normalization, and recovery time., Main Conclusions: Considering that most patients with TPP have undiagnosed Graves' disease, distinguishing TPP from SPP based on clinical information and course alone is difficult in emergency settings. Therefore, for early detection and launch of specific treatment of Graves' disease, screening for thyroid hormone and anti-thyroid stimulating hormone receptor antibody levels is necessary when treating patients with periodic paralysis., Competing Interests: The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright: © 2024 Yamada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims/introduction: This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state., Materials and Methods: We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques., Results: Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m 2 , F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively., Conclusions: Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor microenvironment (TME) with somatostatin receptor 2 (SSTR2) and hypoxia-induced factor-2α (HIF-2α) in PPGLs, critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored. To evaluate the association of SSTR2 and HIF-2α immunoreactivity with the TME in patients with PPGLs, we analyzed the expression of SSTR2A, HIF-2α, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. The primary outcome was to determine the association of the immune profiles with SSTR2A and HIF-2α expression. Among 45 patients with PPGLs, SSTR2A and HIF2α were positively expressed in 21 (46.7%) and 14 (31.1%) patients, respectively. The median PD-L1 immunohistochemical score (IHS) was 2.0 (interquartile range: 0-30.0). Positive correlations were observed between CD4, CD8, CD68, and CD163 levels. A negative correlation was found between the CD163/CD68 ratio (an indicator of M2 polarization) and SSTR2A expression (r = -0.385, p = 0.006). HIF-2α expression showed a positive correlation with PD-L1 IHS (r = 0.348, p = 0.013). The co-expression of PD-L1 (HIS > 10) and HIF-2α was found in seven patients (15.6%). No associations were observed between SDHB staining results and the CD163/CD68 ratio, PD-L1, or SSTR2A expression. Our data suggest the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.

Introduction: It is challenging for pregnant women with type 1 diabetes to maintain optimum glucose level to attain good neonatal outcomes. This study evaluated the efficacy of sensor-augmented insulin pump (SAP) with a predictive low-glucose suspend (PLGS) system in pregnant Japanese women with type 1 diabetes., Materials and Methods: SAP with PLGS was used in 11 of the 22 women with type 1 diabetes who delivered between 2011 and 2021 at the two medical institutions in Japan. Glucose management, insulin delivery suspension time (IST) and neonatal outcomes were retrospectively studied., Results: In SAP with PLGS cases ( n  = 11), average glycated hemoglobin levels were < 6.5% throughout the pregnancy, and the time in range (TIR, 63-140 mg/dl) was > 70% in the second and third trimesters. PLGS was safely used without inducing ketoacidosis. Positive correlation was observed between IST and TIR ( r  = 0.62, p  < 0.01). Negative correlation was observed between IST and time below range (TBR) ( r  =  - 0.40, p  = 0.02), and IST and time above range (TAR) ( r  =  - 0.45, p  = 0.01). Total daily insulin dose was adequately increased without increasing hypoglycemia. There was only one heavy-for-date HFD) infant among the 11 newborns in SAP with PLGS cases. In cases without SAP ( n  = 11), target glycemic levels were difficult to achieve and there were 5 HFD infants among the 11 newborns., Conclusion: SAP with PLGS was safely and effectively used in pregnant women with type 1 diabetes to achieve target glucose levels without increasing the risk of hypoglycemia, which may have led to good neonatal outcomes., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00716-7., Competing Interests: Conflict of interest statementAuthor Rie Kaneshima Tamura, Arata Itoh, and Hiroshi Kajio declare that they have no conflict of interest. Noriko Kodani received lecture fees from Eli lilly Japan k.k. Shu Meguro received lecture fees from Novo Nordisc, Eli lilly Japan k.k, and Sumitomo pharma Co., Ltd. Hiroshi Itoh serves as an advisory role to Meiji Co., Ltd., SBI pharmaceuticals Co., Ltd., and NIPRO CORPORATION, received lecture fees from Novartis Pharma k. k., Kowa company Ltd., DAIICHI SANKYO Ltd., Takeda pharmaceuticals Co., Ltd., and Taisho pharmaceuticals Co., Ltd., and received a grant from Sumitomo Pharma Co., Ltd., Life scan Japan K.K., Abot Japan LLC, Teijin Pharma Ltd., Mitsubishi Tanabe Pharma Corporation, and Mochida pharmaceuticals Co. Ltd., (© The Japan Diabetes Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin-dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for 'a definitive diagnosis of SPIDDM': (1) presence of anti-islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement for insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and the presence of severe endogenous insulin deficiency (fasting serum C-peptide immunoreactivity <0.6 ng/mL) at the last observed point in time. When a patient fulfills only (1) and (2), but not (3), he/she is diagnosed with 'SPIDDM (probable)' because the diabetes is non-insulin-dependent type., (© 2024 The Japan Diabetes Society (JDS). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Patients with chronic pancreatitis (CP) often have severe and intractable abdominal pain, leading to decreased quality of life (QOL), inability to work or attend school, and increased health care costs due to repeated emergency room visits and hospitalizations., Methods: We evaluated the efficacy of total pancreatectomy and islet autotransplantation (TPIAT) in terms of pain control and QOL in CP patients treated at our center in Japan. To evaluate QOL, we used the Short-Form 36 Health Survey version 2 (SF-36v2 ® Standard, Japanese), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and Quality of Life Questionnaire-Pancreatic Modification (QLQ-PAN28)., Results: Between August 2016 and June 2019, we performed this procedure in 5 patients. All patients were followed up for 12 months and all transplanted islets were still functioning at the 1-year follow-up. The major adverse events were abdominal wall hemorrhage, intestinal obstruction, intra-abdominal abscess, and abdominal pain requiring hospitalization; no case had sequelae. No major complications were due to islet transplantation. Pain scores improved postoperatively in all patients. Three QOL item dimensions role-physical ( p  = 0.03125), general health perception ( p  = 0.03125) and vitality ( p  = 0.03125) in the SF-36 were significantly improved 12 months after TPIAT. Mean values of many other QOL items improved, though not significantly., Conclusion: The QOL improvement after TPIAT for CP suggests its effectiveness in the Japanese population.

Aims/introduction: Research on the incidence and underlying mechanisms of rapid renal function decline in patients with type 2 diabetes mellitus with preserved renal function and normoalbuminuria is limited. This study aimed to investigate the involvement of hemoglobin level as a risk factor for rapid decliners among patients with type 2 diabetes with preserved renal function and normoalbuminuria., Materials and Methods: This was a retrospective observational study of 242 patients with type 2 diabetes with a baseline estimated glomerular filtration rate of ≥60 mL/min/1.73 m 2 and normoalbuminuria (<30 mg/gCr), followed up for >1 year. The annual rate of estimated glomerular filtration rate decline during the follow-up period was calculated using least square regression analysis; rapid decliners defined at ≥3.3%/year. Risk factors associated with rapid decliners were identified using a logistic regression analysis of variables previously identified as risk factors of rapid decliners., Results: The median follow-up period was 6.7 years, and 34 patients showed rapid decliners. On multivariate analysis, lower baseline hemoglobin level was a risk factor of rapid decliners (odds ratio 0.69, 95% confidence interval 0.47-0.99; P = 0.045). Furthermore, the baseline hemoglobin levels were correlated positively with iron and ferritin levels, implying that an impaired iron metabolism might cause lower hemoglobin levels in rapid decliners., Conclusions: In patients with type 2 diabetes with preserved renal function and normoalbuminuria, lower hemoglobin levels were a risk factor for rapid decliners, where disturbed iron metabolism might precede the development of diabetic kidney disease., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Type 2 diabetes is associated with an increased risk of developing cardiovascular events. Previous studies have reported that advanced glycation end products (AGEs) were related to cardiovascular events in type 2 diabetes. However, data on associations between long-term AGEs and cardiovascular events in type 2 diabetes are lacking. This study aimed to determine whether a long-time shift in the levels of serum AGEs is associated with cardiovascular events in patients with poorly controlled type 2 diabetes., Methods: Two-time serum methyl-glyoxal-hydroimidazoline (MG-H1) levels were measured in 138 patients with type 2 diabetes whose mean glycated hemoglobin level was 10.1%. We categorized patients whose serum MG-H1 levels were < 2.8 µg/mL at both times as the continuous low MG-H1 group. The primary endpoints of this study were combined cardiovascular events, which were defined as heart disease, peripheral arterial disease, stroke, and all-cause death. Hazard ratios (HRs) for combined cardiovascular events with 95% confidence intervals (CIs) were calculated using the Cox proportional hazard models to compare the outcomes between the continuous low MG-H1 group and others., Results: The continuous low MG-H1 group was associated with a significantly lower risk than others in combined cardiovascular events after adjusting for possible confounders (HR: 0.50; 95% CI, 0.28-0.87; P = 0.02). Furthermore, the same relationship was observed in patients without a history of cardiovascular events., Conclusions: Continuous low serum MG-H1 levels are associated with a low frequency of diabetes-related complications in patients with poorly controlled type 2 diabetes., (© 2023. The Author(s).)

Aim/introduction: To investigate the differences in the clinical significance and glutamic acid decarboxylase autoantibody (GADA) affinity between RIA (RIA-GADA) and ELISA (ELISA-GADA) in patients with type 1 diabetes., Methods: A total of 415 patients with type 1 diabetes were enrolled, including 199 acute-onset type 1 diabetes, 168 slowly progressive type 1 diabetes (SPIDDM), and 48 fulminant type 1 diabetes. GADA affinity was measured by a competitive binding experiment using unlabeled recombinant human GAD65 protein, and the diagnostic performance of both assays and the relationship between GADA affinity and the decline of fasting C-peptide (F-CPR) were examined., Results: While the ELISA-GADA displayed a higher sensitivity than the RIA method in diagnosing type 1 diabetes in acute-onset patients, about 40% of SPIDDM patients with low-titer RIA-GADA were determined as negative by the ELISA method. Patients with type 1 diabetes with RIA-GADA alone had an older age of onset, less diabetic ketoacidosis, a higher BMI, and a higher F-CPR compared with patients positive for both RIA-GADA and ELISA-GADA. Additionally, 36% of RIA-GADA-positive patients had low-affinity GADA (<10 10  L/mol), which was significantly higher than in the ELISA-GADA-positive patients (4%, P < 0.0001). Furthermore, over a 3 year monitoring period, F-CPR levels decreased in ELISA-GADA-positive SPIDDM, whereas it was maintained in patients with RIA-GADA alone, regardless of GADA affinity., Conclusions: These results suggest that bivalent ELISA for GADA is superior to the RIA method in diagnosing type 1 diabetes. Moreover, the diagnostic superiority of the ELISA-GADA made possible the concurrent identification of SPIDDM patients at high-risk of early progression, and allowed for more accurate clinical diagnosis and management., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: To assess the association of undiagnosed diabetes mellitus and its acute-to-chronic glycemic ratio with clinical outcome in patients hospitalized with coronavirus disease 2019 (COVID-19) using a large-scale nationwide registry in Japan., Materials and Methods: Overall, 4,747 patients were included between July 2021 and January 2022. We evaluated blood glucose and glycated hemoglobin levels at admission, and calculated the acute-to-chronic glycemic ratio for each non-diabetes mellitus, undiagnosed diabetes mellitus and pre-existing diabetes mellitus group. The primary composite outcome comprised in-hospital mortality, invasive mechanical ventilation, extracorporeal membrane oxygenation support, intensive care unit admission and transfer to a more advanced medical facility., Results: Compared with the non-diabetes mellitus group, the undiagnosed diabetes mellitus group was significantly associated with a worse COVID-19 outcome (odds ratio 2.18, 95% confidence interval 1.50-3.18). In patients with undiagnosed diabetes mellitus, the 3rd tertile of the acute-to-chronic glycemic ratio was linked with a worse COVID-19 outcome compared with the 1st tertile (odds ratio 3.33, 95% confidence interval 1.43-7.77), whereas glycated hemoglobin levels were not; among patients with pre-existing diabetes mellitus, glycated hemoglobin levels were linked with a worse outcome., Conclusions: Among patients with undiagnosed diabetes mellitus with COVID-19, the magnitude of elevation of blood glucose from chronic to acute levels is associated with worse outcomes., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Summary: A 47-year-old man was diagnosed with a left adrenal incidentaloma at 40 years of age. The tumor had irregular margins and grew from 18 mm to 30 mm in maximum diameter over 7 years. On computed tomography scan, the mass appeared to localize within the tip of the lateral limb of the left adrenal gland, and between the left adrenal gland and the posterior wall of the stomach. The plasma corticotropin and cortisol concentrations and the 24-h urine fractionated metanephrine levels were normal. 123I-metaiodobenzylguanidine scintigraphy showed tumor avidity consistent with a hormonally inactive pheochromocytoma. A laparoscopic left adrenalectomy was performed; however, no tumor was present in the resected specimen. Abdominal computed tomography postoperatively showed that the tumor remained intact and appeared to connect to the posterior wall of the stomach. A laparotomy was performed and the tumor was removed. The tumor was localized to the intraperitoneal space and isolated from the posterior wall of the stomach. The pathological diagnosis was a gastrointestinal stromal tumor. Clinicians need to be aware of the limitations of diagnostic imaging studies in diagnosing non-functioning adrenal incidentalomas, which require a pathological analysis for the final diagnosis. Moreover, clinicians need to provide patients with sufficient informed consent when deciding on treatment strategies., Learning Points: Anatomic structures and tumors that develop in neighboring tissues to the adrenal glands may be confused with primary adrenal tumors. 123I- metaiodobenzylguanidine (MIBG) scintigraphy is specific for diagnosing pheochromocytomas and paragangliomas; however, it has been reported that 123I-MIBG may accumulate in neuroendocrine tumors as well as other tumors. Clinicians should recognize the limitations of imaging studies and the uncertainty of an imaging-based preoperative diagnosis.

Aims/introduction: This study aimed to investigate the clinical significance and antigen specificity of autoantibodies to insulinoma-associated antigen-2 (IA-2A) by radioimmunoassay (RIA; IA-2A-RIA) and enzyme-linked immunosorbent assay (ELISA; IA-2A-ELISA) in Japanese patients with type 1 diabetes., Materials and Methods: A total of 338 type 1 diabetic patients were enrolled, including 38 fulminant type 1 diabetes, 168 acute-onset type 1 diabetes and 137 slowly-progressive type 1 diabetes (SPIDDM). The concordance, correlation of autoantibody titer, and the relationship between IA-2A and progression to the insulin-deficient state were examined. Also, competitive assay was used to examine the antigen specificity., Results: The prevalence of IA-2A-ELISA was 4-5% lower than that of IA-2A-RIA in both the acute-onset type 1 diabetes and SPIDDM, but the diagnostic sensitivities of both subtypes, when measured in combination with glutamic acid decarboxylase autoantibody, were comparable. The diagnosis of type 1 diabetes using either the RIA or ELISA methods showed substantial agreement with the exponential correlation of autoantibody titers detected by RIA and ELISA. Among the SPIDDM patients, the fasting C-peptide for IA-2A-positive cases by ELISA, but not the RIA method, was significantly lower than in the negative cases (P < 0.05). Furthermore, IA-2A-ELISA proved superior to the RIA method in predicting the progression to insulin deficiency in SPIDDM. Competitive analysis showed that even sera with discrepant results by RIA and ELISA have IA-2-specific autoantibodies., Conclusion: These results suggest that IA-2A-ELISA is a reliable marker not only for the diagnosis of type 1 diabetes, but also for the prediction of future insulin dependency; that is, detection of IA-2A-ELISA helps identify a subtype of SPIDDM patients who would likely progress onto insulin-deficient state., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

In patients with severe coronavirus disease 2019 (COVID-19) with diabetes, glycemic control is essential for a better outcome, however, we face difficulty controlling hyperglycemia induced by high-dose glucocorticoids. We report five cases of severe COVID-19 patients with diabetes, whose glycemic control was managed using an intermittently scanned continuous glucose monitoring (isCGM) system during methylprednisolone therapy. Patients using isCGM showed significantly lower average blood glucose levels and significantly higher total daily insulin dose during the methylprednisolone therapy, compared to patients under regular blood glucose monitoring. The use of isCGM enables remote glucose monitoring, and this can reduce the risks of healthcare workers who have frequent contact with the patients. Thus, we suggest that using isCGM should be considered in hospitalized patients with diabetes under the COVID-19 pandemic to achieve better glycemic control and to minimize the possible risks of healthcare workers., Competing Interests: The authors have no conflicts of interest to disclose., (2022, National Center for Global Health and Medicine.)

Background: Helicobacter pylori (HP) is a causative factor for several gastrointestinal diseases. A HP seropositive antibody titer (i.e., ≥10 U/mL), a threshold indicating an HP infection, is known to be associated with changes in lipid metabolism. There is evidence that HP infection can be found in some individuals with HP antibody titer of between 3 and 9.9 U/mL (termed as "negative-high titer"). However, it is unknown about the relationship between HP negative-high titer and lipid metabolism. The present study aimed to quantify the association between HP negative-high antibody titer and lipid profiles., Materials and Methods: We surveyed 2,478 people who underwent a Ningen Dock examination and had serological HP antibody data, from May 2016 to December 2020 at National Center for Global Health and Medicine, Tokyo, Japan. Multiple regression models were used to quantify the association between HP antibody titer and serum lipid levels., Results: The adjusted odds ratio (95% confidence interval [CI]) for dyslipidemia in HP negative-high and positive titer was 1.24 (0.96, 1.79) and 1.36 (1.10, 1.68), respectively, compared with HP negative-low titer; p trend =0.005. The adjusted mean (95% CI) of high-density lipoprotein cholesterol (HDL-C) in HP negative-low, negative-high, and positive titer was 58.78 (57.86-59.71), 55.30 (53.70-56.91), and 53.76 (52.90-54.63) mg/dL, respectively; p trend <0.001. Higher HP antibody titers were also associated with higher ratio of low-density lipoprotein cholesterol (LDL-C) to HDL-C, but not triglycerides, or total cholesterols., Conclusion: The present cross-sectional study suggests that a HP negative-high antibody titer may be associated with dyslipidemia, HDL-C, and LDL-C to HDL-C ratio among Japanese Ningen Dock's participants., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Jun Lu et al.)

Aim: To cross-sectionally and longitudinally investigate the association between tumor markers (Cancer embryonic antigen (CEA) Carbohydrate antigen 19-9 (CA19-9)) and malignancies in type 2 diabetes patients without evidence of malignancy., Materials and Methods: The study included 707 patients admitted for the treatment of diabetes from 1 August 2010 to 1 September 2018. Serum CEA and CA19-9 levels were measured for screening of malignancies at admission. Abdominal ultrasonography, computed tomography, and endoscopy were performed for close examination. The percentage of patients diagnosed with malignancy was calculated, and among those without malignancy, the incidence of malignancies was examined after discharge., Results: A total of 26 patients (3.7%) were newly diagnosed with malignancy during hospitalization. The optimal cut-off value of CEA and CA19-9 by receiver operating characteristic analysis was 5.0 ng/mL and 75 U/mL, and their positive predictive values (PPV) were 8.7% and 22.5%, respectively. The addition of CA19-9 to age, smoking status, body mass index, and glycated hemoglobin significantly improved classification performance for malignancy using net reclassification improvement (0.682, 95% CI 0.256-1.107) and integrated discrimination improvement (0.150, 95% CI 0.007-0.294). Among 681 patients without malignancies during hospitalization, 30 patients (4.4%) developed malignancies during an average follow-up of 3.9 years. CA19-9 (hazard ratio: 1.005, 95% CI: 1.003-1.008) was associated with the development of malignancies., Conclusions: PPV of serum CEA and CA19-9 for detecting malignancy was high in type 2 diabetes patients with poor glycemic control. Measuring CA19-9 was found to be valuable to cross-sectionally and longitudinally detect malignancies., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00594-x., Competing Interests: Conflict of interestMT, RB, TF, NI-S, NK, MO, AT, KU, and HK declare that they have no conflict of interest., (© The Japan Diabetes Society 2022.)

Aim: To investigate (1) the association of lifestyle changes and living and working conditions with glycemic control and (2) whether treatment was intensified appropriately in patients with diabetes under the first COVID-19 state of emergency in Japan., Materials and Methods: A total of 321 participants were included. Participants completed a questionnaire regarding lifestyle changes, including diet, physical activity, and living and working conditions during the COVID-19 pandemic. The change in hemoglobin A1c (HbA1c) levels was estimated before (June 1, 2019 to August 31, 2019) and during (June 1, 2020 to August 31, 2020) the pandemic. Factors associated with changes in HbA1c levels were examined by multiple linear regression analysis. The proportion of patients who received treatment intensification for diabetes was compared between before and during the pandemic., Results: There was no significant change in HbA1c levels before the pandemic and during the pandemic (7.13 ± 0.98% vs 7.18 ± 1.01%, P = 0.186). Teleworking (estimate 0.206, P = 0.004) and living with a dog (estimate -0.149, P = 0.038) were significantly associated with changes in HbA1c levels after adjusting for covariates. There was no significant difference in the proportion of patients who received treatment intensification for diabetes during the pandemic and before the pandemic in either the elderly or non-elderly patients., Conclusions: Overall glycemic control did not worsen during the pandemic. Nonetheless, environmental factors, including telework, were found to influence glycemic control in patients with diabetes. Further studies are needed to clarify whether the COVID-19 pandemic could affect treatment intensification for diabetes., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: Diabetes is associated with poor clinical outcomes of coronavirus disease 2019 (COVID-19). However, the impact of newly diagnosed diabetes on prognosis has not been clarified. The objective of this study was to show the features and outcome of COVID-19 patients with newly diagnosed diabetes in Japan., Materials and Methods: We retrospectively analyzed 62 patients with diabetes hospitalized for COVID-19 between 1 April and 18 August 2021 at the National Center for Global Health and Medicine in Tokyo, Japan. We evaluated the worst severity of COVID-19 and plasma blood glucose levels in patients with newly diagnosed diabetes or pre-existing diabetes., Results: This study included 62 confirmed COVID-19 patients with diabetes, including 19 (30.6%) patients with newly diagnosed diabetes and 43 (69.4%) patients with pre-existing diabetes. Patients with newly diagnosed diabetes significantly progressed to a critical condition more frequently during hospitalization than patients with pre-existing diabetes (52.6% vs 20.9%, P = 0.018). In addition, patients with newly diagnosed diabetes had significantly higher average plasma blood glucose levels for the first 3 days after admission than those with pre-existing diabetes., Conclusions: Our study suggests that the proportion of COVID-19 patients who are newly diagnosed with diabetes is high, and they have an increased risk of developing severe disease than those with pre-existing diabetes. It might be advisable that at the point of COVID-19 diagnosis, blood glucose and glycated hemoglobin levels be assessed in all patients., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

A 79-year-old woman with type 2 diabetes receiving insulin was rushed to our hospital due to severe hypoglycemia. Glucose was administered, and the consciousness disturbance was promptly improved. A few hours later, conjugate deviation of the eyes to the right and left hemiplegia occurred at a normal glucose level. Cerebral magnetic resonance imaging (MRI) showed hyperintensities of the right posterior limb of the internal capsule and the medial thalamus on diffusion-weighted imaging sequences. However, the changes observed using MRI disappeared completely on the third day, and her symptoms subsequently improved. This may have been a case of glucose reperfusion injury.

The role of cellular autoimmunity in the pathogenesis of fulminant type 1 diabetes (FT1D) remains largely unknown. In this study, we performed an integrated assay using peripheral blood mononuclear cells to determine the islet antigen-specific CD8 + T cell responses in FT1D and compare the responses among acute-onset T1D (AT1D) and slowly progressive T1D (SP1D). IGRP- and ZnT8-specific IL-6, G-CSF, and TNF-α responses were significantly upregulated in patients with FT1D, while IGRP- and ZnT8-specific IP-10 responses were significantly upregulated in patients with AT1D than in non-diabetics (ND). Furthermore, the frequencies of IGRP-specific type 1 CD8 + cytotoxic T (Tc1) cells were significantly higher in the FT1D group than in the ND, SP1D, and AT1D groups. Additionally, IGRP-specific Tc1 cells were more abundant in the FT1D with HLA-A2 group than in the FT1D without A2 group. In conclusion, our study suggests that IGRP-specific CD8 + T cells significantly contribute to the pathogenesis of FT1D., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients., Competing Interests: Conflict of interestDaisuke Chujo received honorarium for lectures from Eli Lilly and Company; research funding from Novo Nordisk Pharma Ltd., and Sanofi K.K.; Akihisa Imagawa received honorarium for lectures from Astellas Pharma Inc.; clinical commissioned/joint research grant from Astra Zeneca, Soiken Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck KGaA, and Parexel International Inc.; research grant from Shionogi Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company, and Ono Pharmaceutical Co., Ltd.; Norio Abiru received honorarium for lectures from Novo Nordisk Pharma Ltd., Astellas Pharma Inc., and Eli Lilly and Company; research funding from Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb, Taisho Pharmaceutical Co., Ltd., and Astellas Pharma Inc.; Takuya Awata received honorarium for lectures from Astellas Pharma Inc.; Hiroshi Ikegami received honorarium for lectures from Astellas Pharma Inc., Eli Lilly and Company, MSD K.K., Novo Nordisk Pharma Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., and Terumo Corporation; donations from Abbott Japan Co., Ltd., LifeScan Japan K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company. Akira Shimada received honorarium for lectures from Novo Nordisk Pharma Ltd., Eli Lilly and Company, and Sanofi K.K.; Other authors have no conflict of interest to declare., (© The Japan Diabetes Society 2021.)

Objective: To assess whether vision-threatening retinopathy developed after 4 years in patients with type 2 diabetes with good glycemic control during follow-up., Patients and Methods: Using data from the Action to Control Cardiovascular Risk in Diabetes and Action to Control Cardiovascular Risk in Diabetes Follow-on studies (conducted from January 1, 2001, to October 14, 2014), we investigated the incidence of vision-threatening retinopathy after 4 years in patients with type 2 diabetes with good or poor glycemic control. Patients with proliferative diabetic retinopathy at baseline were excluded. Vision-threatening retinopathy was defined as severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, laser photocoagulation, or vitrectomy. Good and poor glycemic control was defined as mean glycated hemoglobin level less than 7% and 7% or greater during follow-up, respectively., Results: This study included 2285 patients. Among patients with no retinopathy at baseline, the 4-year incidence of vision-threatening retinopathy was 0% (0 of 386) and 0.8% (6 of 721) in those with good and poor glycemic control, respectively (P=.54). Similarly, severe retinopathy was not observed at 8 years in patients who did not have retinopathy at 4 years. Among patients with mild to moderate nonproliferative diabetic retinopathy at baseline, the 4-year incidence of vision-threatening retinopathy was significantly higher in those with poor glycemic control than in those with good glycemic control (9.7% [77 of 790] vs 4.4% [13 of 297]; P=.004). Additionally, the remission rate of diabetic retinopathy was low in patients with a long duration of diabetes. Four-year incidences of vision-threatening retinopathy were higher in patients with retinopathy at baseline who had poorer glycemic control and longer durations of diabetes., Conclusion: It may be safe to extend screening intervals for diabetic retinopathy to 4 years or longer in patients with type 2 diabetes with no retinopathy., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background Resistant hypertension is a salt-retaining condition possibly attributable to inappropriate aldosterone secretion. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin-angiotensin system blocker (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53-0.91; P =0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83-1.20; P =0.97). There was a significant interaction between spironolactone use and resistant hypertension ( P =0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only. Conclusions Spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.

Context: Type 1 diabetes (T1D) is classified into 3 subtypes: acute-onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The differences in the type of cellular autoimmunity within each subtype remain largely undetermined., Objective: To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D., Participants: Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND)., Methods: We performed an integrated assay to determine cellular immune responses and T-cell repertoires specific for islet antigens. This assay included an ex vivo assay involving a 48-hour stimulation of peripheral blood mononuclear cells with antigen peptides and an expansion assay involving intracytoplasmic cytokine analysis., Results: The results of the ex vivo assay indicated that glutamic acid decarboxylase 65 (GAD65)-specific interleukin-6 and interferon-inducible protein-10 (IP-10) responses and preproinsulin (PPI)-specific IP-10 responses were significantly upregulated in AT1D compared with those of ND. Furthermore, GAD65- and PPI-specific granulocyte colony-stimulating factor responses were significantly upregulated in FT1D. Expansion assay revealed that GAD65- and PPI-specific CD4+ T cells were skewed toward a type 1 helper T (Th1)- cell phenotype in AT1D, whereas GAD65-specific Th2 cells were prevalent in SP1D. GAD65-specific Th1 cells were more abundant in SP1D with human leukocyte antigen-DR9 than in SP1D without DR9. FT1D displayed significantly less type 1 regulatory T (Tr1) cells specific for all 4 antigens than ND., Conclusions: The phenotypes of islet antigen-specific CD4+ T cells differed among the three T1D subtypes. These distinct T-cell phenotypes may be associated with the manner of progressive β-cell destruction., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)