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GI symptoms are common in acute COVID-19 patients. This study aimed to characterize the GI symptoms occurring in Japanese COVID-19 patients. This retrospective single-center cohort study included 751 hospitalized acute COVID-19 patients. The primary outcomes were the frequency and severity of GI symptoms. The secondary outcomes included the association between COVID-19 severity and GI symptoms and the timing of GI symptom onset. After exclusion, the data of 609 patients were analyzed. The median age was 62 years, and 55% were male. The median time from initial symptom onset to admission was five days. On admission, 92% of the patients had fever, 35.1% had fatigue, 75% had respiratory symptoms, and 75% had pneumonia. The sample included patients with mild (19%), moderate (59%), and severe COVID-19 (22%). A total of 218 patients (36%) had GI symptoms, of which 93% were classified as grade 1/2; 170 patients had both respiratory and GI symptoms. Diarrhea was the most frequent GI symptom, occurring in 170 patients, followed by anorexia in 73 patients and nausea/vomiting in 36 patients, and abdominal pain in 8 patients. There was no significant relationship between COVID-19 severity and GI symptoms. Among COVID-19 patients with both GI and respiratory symptoms, 48% had respiratory symptoms preceding GI symptoms, 25% had GI symptoms preceding respiratory symptoms and 27% had a simultaneous onset of respiratory and GI symptoms. Thirty-six percent of the Japanese COVID-19 patients had GI symptoms; diarrhea was the most frequent GI symptom but did not predict severe COVID-19.

At the current time of rising demand for hospital beds, it is important to triage COVID-19 patients according to the treatment needed during hospitalization. The need for oxygen therapy is an important factor determining hospital admission of these patients. Our retrospective study was designed to identify risk factors associated with the progression to oxygen requirement in COVID-19 patients. A total of 133 patients with laboratory-confirmed COVID-19 were admitted to our hospital from February 22, 2020, to August 23. After excluding asymptomatic, non-Japanese, pediatric, pregnant patients and also those who needed oxygen immediately at admission, data of the remaining 84 patients were analyzed. The patients were separated into those who required oxygen after admission and those who did not, and their characteristics were compared. Age, body mass index (BMI), lymphocyte count, C-reactive protein (CRP), lactate dehydrogenase, estimated glomerular filtration rate, glucose intolerance, hypertension, and dyslipidemia were significantly different between the two groups. Multivariate analysis identified four significant and independent risk factors of oxygen requirement, including advanced age, obesity, glucose intolerance and lymphocytopenia. Dividing the patients into subgroups according to the number of these risk factors found in each patient indicated that the need for oxygen increased with higher number of these risk factors in the same individual. Our results suggest that the presence of higher number of these risk factors in COVID-19 patients is associated with future oxygen requirement and that this index can be potentially useful in triaging COVID-19 patients staying home in the context of need for hospitalization.

Some patients with coronavirus disease 2019 (COVID-19) develop skin manifestations. There may be regional and racial differences in the frequency and type of COVID-19-associated skin manifestations. There are, however, few reports on skin manifestations in COVID-19 patients in Asia, including Japan. We retrospectively investigated the frequency, type, and clinical course of skin manifestations in Japanese patients with COVID-19. From 22 February 2020 to 16 August 2021, 738 Japanese patients (median age 59 years, 55% male) with laboratory-confirmed COVID-19 on polymerase chain reaction or antigen tests were admitted to our hospital. We mainly admitted patients with mild to moderate severity who had symptoms such as cough, fever, and oxygen demand but did not require mechanical ventilation. A total of 2.8% (21/738) of the COVID-19 patients treated at our hospital were diagnosed with viral eruptions caused by COVID-19. Of the 21 patients, 19 developed erythematous papules, and two developed urticaria. There were no cases of pernio-like lesions, known as COVID toes. The median duration from the onset of other COVID-19 symptoms to the development of skin manifestations was 9 days. This study revealed that approximately 2-3% of Japanese patients with COVID-19 developed COVID-19-associated viral eruptions, most of which were erythematous papules.

Hyperinsulinemia is often observed in obese subjects because of insulin resistance, but it may occur in nonobese subjects with unknown etiology. A 72-year-old man was admitted to our hospital for the examination of hyperinsulinemia, reactive hypoglycemia, and liver dysfunction. The patient’s body mass index was 23.7 kg/m2, but he had an elevated visceral fat area (125 cm2). His laboratory data showed mildly elevated liver enzymes, whereas plasma fasting glucose and serum insulin levels were 91 mg/dL and 52.3 μU/mL, respectively. In a 75-g oral glucose tolerance test, the serum insulin level reached the highest value of 1124 μU/mL at 180 minutes. There was no obvious etiology except for mild liver steatosis shown by liver biopsy. We suspected genetic abnormalities related to hyperinsulinemia. We performed whole-exome sequencing (WES) analyses and identified a heterozygous nonsense variant p.R924X in the insulin receptor (INSR) gene, a novel heterozygous missense variant p.V416M in the AKT1 gene, and a novel hemizygous missense variant p.R310Q in the PHKA2 gene, which is the causative gene of hepatic injury as glycogen storage disease type IX. It was speculated that the INSR gene variant, in addition to visceral fat accumulation, was the main cause of hyperinsulinemia and reactive hypoglycemia, and the remaining 2 variants were also partly responsible for hyperinsulinemia. WES analysis revealed candidate gene variants of hyperinsulinemia and hepatic-type glycogenosis. Thus, WES analysis may be a useful tool for clarifying the etiology when unexplained genetic pathophysiological conditions are suspected.

Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes.This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined.Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (β = -0.34, P = 0.0005) and age (β = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment.Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes.

We previously reported several factors that cross-sectionally correlate with treatment satisfaction in Japanese patients with type 2 diabetes visiting diabetes clinics. The aim of this study is to identify factors associated with longitudinal changes in treatment satisfaction in patients with type 2 diabetes.The study included 649 patients with type 2 diabetes treated with oral glucose-lowering agents who completed the first questionnaire in 2016. The collected data included scores from the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and other parameters regarding diabetes treatment. We analyzed 1-year longitudinal changes in DTSQ scores and investigated factors associated with these changes.Univariate linear regression analyses showed that changes in body weight, adherence to diet therapy, adherence to exercise therapy, cost burden, motivation for treatment, regularity of mealtimes, and perceived hypoglycemia correlated with changes in DTSQ scores. On the basis of multiple linear regression analyses, a decrease in hypoglycemia (β ± SE = - 0.394 ± 0.134, p = 0.0034), cost burden (β ± SE = - 0.934 ± 0.389, p = 0.017), and an increase in treatment motivation (β ± SE = 1.621 ± 0.606, p = 0.0077) correlated with DTSQ score increases, suggesting that motivation for treatment had the strongest impact on score increases. Subgroup analyses revealed that an increase in motivation for treatment most significantly correlated with a DTSQ score increase in obese and poor glycemic control groups, regardless of age.This is the first longitudinal study clarifying that an increase in motivation for treatment most strongly correlates with an increase in DTSQ score in patients with type 2 diabetes.

We herein report a 28-year-old woman with type 1 diabetes with an asymptomatic pontine lesion and diabetic amyotrophy. She had suffered from diabetes from 10 years old. Treatment in a hospital reduced the hemoglobin A1c level from 14.2% to 7.2% for approximately 2 months. She suffered from acute-onset pain and weakness of the lower limb muscles without central nervous system manifestations. Magnetic resonance imaging showed high-intensity lesions at the brainstem and lower limb muscles on T2-weighted images. These findings and symptoms gradually resolved. Rapid treatment of poor glycemic control might increase the risk of asymptomatic pontine lesions and diabetic amyotrophy.

Pancreatic islet cells have plasticity, such as the abilities to dedifferentiate and transdifferentiate. Islet cell conversion to other characteristic cell is largely determined by transcription factors, but significance of expression patterns of these transcription factors in human islet cells remained unclear. Here, we present the NKX6.1-positive ratio of glucagon-positive cells (NKX6.1+/GCG+ ratio) and the ARX-negative ratio of glucagon-positive cells (ARX−/GCG+ ratio) in 34 patients who were not administered antidiabetic agents. Both of NKX6.1+/GCG+ ratio and ARX−/GCG+ ratio negatively associated with relative beta cell area. And these ratios did not have significant correlation with other parameters including age, body mass index, hemoglobin A1c, fasting plasma glucose level or relative alpha-cell area. Our data demonstrate that these expression ratios of transcription factors in glucagon-positive cells closely correlate with the reduction of beta-cell volume in human pancreas.

Gastrin regulates gastric acid secretion, and gastrin secretion itself is regulated by the negative feedback system of gastric acidity. Autoimmune gastritis (AG) is a disease where parietal cells are destroyed, resulting in decreased acid production and an elevated serum gastrin level. We herein report 2 AG cases with marked hypergastrinemia (>5,000 pg/mL). In both cases, 24-hour gastric pH monitoring showed no time when gastric pH was

Aims/Introduction The relationship between pancreatic fatty infiltration and diabetes is widely known, whereas the causal relationship is not clear. Furthermore, it is uncertain whether pathogenesis of pancreatic fat is similar to that of liver fat. We aimed to clarify the contribution of this type of fat to glucose metabolism in type 2 diabetes patients by cross‐sectional and longitudinal analyses. Material and Methods A total of 56 patients with type 2 diabetes who had been hospitalized twice were analyzed. We evaluated the mean computed tomography values of the pancreas (P), liver (L) and spleen (S). Lower computed tomography values indicate a greater fat content. We defined indices of pancreatic or liver fat content as the differences between P or L and S. We assessed the associations among fat content for the two organs (P‐S, L‐S) and clinical parameters at the first hospitalization, and then analyzed the associations between these fat contents and changes in glycometabolic markers (the second data values minus the first). Results In the cross‐sectional study, P‐S negatively correlated with the increment of C‐peptide in the glucagon stimulation test (r = −0.71, P, In patients with type 2 diabetes, pancreatic fat was less associated with obesity‐related indicators than liver fat, but was more strongly associated with the longitudinal decrease in endogenous insulin‐secreting capacity.

Two diabetic women (case 1, 75 years old; case 2, 49 years old) being treated with glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) showed no suppression of cortisol secretion on a dexamethasone suppression test (DST). However, its secretion was suppressed after switching from GLP-1 RAs to insulin. We also checked the cortisol secretion by a DST in five consecutive inpatients (case 3-7) being treated with GLP-1 RAs. The coefficients of R-R interval variation at rest and during deep breathing were lower in the two false-positive cases (case 1 and 2) than in the five true-negative cases (case 3-6). GLP-1 RAs can be switched to insulin in order to eliminate the slow absorption effect of dexamethasone by GLP-1 RAs if a DST is planned in diabetic patients receiving GLP-1 RAs.

A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism. Histological examination of the resected tumor with anti-CYP11B2 antibody indicated that she had a vascular endothelial cyst with primary aldosteronism (PA) due to multiple adrenocortical micronodules. This report implicates the pathological interaction between adrenal vascular cysts and PA-mediated vascular damage of the adrenal vein.

The factors predicting the progression of coronavirus disease‐2019 (COVID‐19) from mild to moderate to critical are unclear. We retrospectively evaluated risk factors for disease progression in Japanese patients with COVID‐19. Seventy‐four patients with laboratory‐confirmed COVID‐19 were hospitalized in our hospital between February 20, 2020, and June 10, 2020. We excluded asymptomatic, non‐Japanese, and pediatric patients. We divided patients into the stable group and the progression group (PG; requiring mechanical ventilation). We compared the clinical factors. We established the cutoff values (COVs) for significantly different factors via receiver operating characteristic curve analysis and identified risk factors by univariate regression. We enrolled 57 patients with COVID‐19 (median age 52 years, 56.1% male). The median time from symptom onset to admission was 8 days. Seven patients developed critical disease (PG: 12.2%), two (3.5%) of whom died; 50 had stable disease. Univariate logistic analysis identified an elevated lactate dehydrogenase (LDH) level (COV: 309 U/l), a decreased estimated glomerular filtration rate (eGFR; COV: 68 ml/min), lymphocytopenia (COV: 980/μl), and statin use as significantly associated with disease progression. However, in the Cox proportional hazards analysis, lymphocytopenia at admission was not significant. We identified three candidate risk factors for progression to critical COVID‐19 in adult Japanese patients: statin use, elevated LDH level, and decreased eGFR., Highlights To evaluate risk factors for disease progression in Japanese patients with COVID‐19, we examined seventy‐four patients with laboratory‐confirmed COVID‐19.Seven patients (12.2%) developed critical disease requiring mechanical ventilation, two (3.5%) of whom died.We identified three candidate risk factors for progression to critical COVID‐19 in adult Japanese patients: statin use elevated LDH level and decreased eGFR.

Individuals infected with the novel coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2 [SARS‐CoV‐2]) who develop coronavirus disease 2019 (COVID‐19) experience many symptoms; however, cutaneous manifestations are relatively rare. The authors encountered three patients with COVID‐19 who presented with erythema and suspected viral rash. In all cases, erythema appeared after the onset of the initial symptoms of COVID‐19. Erythema was considered to be caused by COVID‐19 and not a drug‐induced eruption because, in all cases, erythema was relieved merely by external medicine and oral antihistamines, without discontinuing the original medication. The authors’ hospital accepted 69 COVID‐19 patients between 22 February 2020 and 31 May 2020 and, of these, three (4.3%) exhibited eruptions, and all cases presented erythema. Except for seven patients who exhibited positive nasopharyngeal swab tests for SARS‐CoV‐2 RNA but no symptoms, three (4.8%) of the remaining 62 patients exhibited erythema. Although various types of eruptions have been reported in patients with COVID‐19, erythema was the only type in our patients. Erythema in the three patients exhibited many similarities to that previously reported in COVID‐19 patients, particularly in the manner it appeared and disappeared. For these reasons, these three cases were considered typical examples of erythema in patients with COVID‐19. Considering previous studies and the three cases reported here, there is a high probability that SARS‐CoV‐2 can cause erythema.

Objective This study aimed to clarify the clinical significance of the maximum body mass index (BMI) before the onset of type 2 diabetes (MBBO) for predicting pancreatic beta-cell function. Methods This was a cross-sectional observational study. Of 1304 consecutively admitted patients with type 2 diabetes, we enrolled 410 patients satisfying the criteria in this study. The correlations between the C-peptide index (CPI), which is one of the parameters that reflects beta-cell function, and various clinical parameters, including MBBO and duration of diabetes, were analyzed in multiple linear regression analyses. Results The analyses revealed that MBBO was correlated with CPI independently after adjustment for age, sex, HbA1c, and duration of diabetes. When we divided the subjects into three subgroups by MBBO (MBBO < 25 kg/m2; 25 kg/m2 ≤ MBBO < 30 kg/m2; MBBO ≥ 30 kg/m2), CPI was negatively correlated with duration of diabetes in each subgroup, while the rates of CPI based on the duration of diabetes were not different among the three MBBO subgroups. In contrast, the declining rates of CPI were higher in the BMI ≥ 25 kg/m2 group on admission than in the BMI < 25 kg/m2 group on admission. Conclusions MBBO may be an independent factor correlating with beta-cell function and may predict insulin secretion capacity at diagnosis, but it does not seem to affect the rate of decline in insulin secretion capacity after diagnosis. It is important to preserve beta-cell function by decreasing a patient’s BMI during treatment after diagnosis regardless of MBBO.

Background: The subclinical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rate in hospitalsremains unclear. To evaluate the effectiveness of our hospital's nosocomial infection control, we conducted a serological survey of anti-SARS-CoV-2 immunoglobulin G (IgG) among staff at our hospital, which is treating coronavirus disease 2019 (COVID-19) patients. Methods: The study design was cross-sectional. We measured anti-SARS-CoV-2 IgG using a laboratory-based quantitative test (Abbott immunoassay), which has a sensitivity and specificity of 100% and 99.6%, respectively. To investigate factors associated with seropositivity, we obtained additional information from participants via an anonymous questionnaire. Findings: We invited 1133 staff members in our hospital, and 925 (82%) participated. The mean age of participants was 40.0±11.8 years, and most were women (80.0%). According to job title, there were 149 medical doctors or dentists (16.0%), 489 nurses (52.9%), 140 medical technologists (14.2%), 49 healthcare providers (5.3%), and 98 administrative staff (10.5%). The overall seroprevalence for anti-SARS-CoV-2 IgG was 0.43% (4/925), which was similar to the seroprevalence of 0.54% (16/2970) in the general population in Osaka during the same period according to a government survey conducted with the same assay. Seropositive rates did not significantly differ according to job title, exposure to suspected or confirmed COVID-19 patients, or any other investigated factors. Interpretation: The subclinical SARS-CoV-2 infection rate in our hospital was similar to that in the general population under our nosocomial infection control measures. Funding: Unrestricted research funds from the Department of Gastroenterology and Department of Internal Medicine, Diabetes Center, Toyonaka Municipal Hospital. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: The present study was conducted in accordance with the principles of the Declaration of Helsinki, and approval was obtained from the Institutional Review Board of Toyonaka Municipal Hospital (No. 2020-05-08). We obtained written informed consent from participants prior to the study.

Context Low serum adiponectin (Ad) level is an important risk factor for the development of type 2 diabetes mellitus (T2DM). Objective To determine whether the changes in Ad in subjects with low baseline serum Ad levels can reduce the rate of development of T2DM. Design/Setting/Participants We performed a large-scale longitudinal study of 7052 healthy Japanese men who underwent general health checkups more than twice between April 2007 and May 2015 at the Physical Check up Center, Sumitomo Hospital. The participants were divided into quartile groups according to baseline Ad level. Subjects of the lowest baseline Ad group (≤5.2 μg/mL) were subdivided into quartile subgroups according to the percent change in Ad (%ΔAd) and into two subgroups according to endpoint Ad (>5.2 and ≤5.2 μg/mL). Main Outcome Measures The cumulative incidence rate of T2DM. Results The cumulative incidence rate of T2DM of the lowest baseline Ad group (≤5.2 μg/mL) was significantly higher than the other quartile groups. The cumulative incidence rates of T2DM were significantly lower in the largest (≥21.5%) and the second largest (9.3% to 21.4%) %ΔAd-increased subgroups compared with the %ΔAd-decreased subgroup (P < 0.001 and P = 0.005, respectively). The cumulative incidence rates of T2DM were significantly lower in the endpoint Ad >5.2 μg/mL subgroup than in the ≤5.2 μg/mL subgroup (P < 0.001). Conclusions Increases in serum Ad levels of at least ~10% or >5.2 μg/mL can potentially reduce the risk of development of T2DM in Japanese men with low baseline Ad levels who are at a high risk of developing T2DM., Increases in serum Ad levels of ∼10% or >5.2 μg/mL in Japanese men with low baseline serum Ad levels can reduce the risk of development of T2DM.

Aims/Introduction To clarify the association between perioperative variables and postoperative bleeding in pars plana vitrectomy for vitreous hemorrhage in diabetic retinopathy. Materials and Methods The present retrospective study enrolled 72 eyes of 64 patients who were admitted to Osaka University Hospital between April 2010 and March 2014, and underwent vitrectomy for vitreous hemorrhage as a result of diabetic retinopathy. Results Postoperative bleeding developed in 12 eyes. Using binomial logistic regression analysis, we found that the duration of operation was the only significant variable associated with postoperative bleeding within 12 weeks after vitrectomy. Furthermore, Poisson regression analysis identified fasting blood glucose just before vitrectomy, no treatment with antiplatelet drugs and treatment with antihypertensive drugs, as well as duration of operation, to be significantly associated with the frequency of bleeding within 52 weeks after vitrectomy. Conclusions Long duration of operation can be used to predict bleeding within both 12 and 52 weeks after vitrectomy. In addition, fasting blood glucose just before vitrectomy, no treatment with antiplatelet drugs and treatment with antihypertensive drugs might be risk factors for postoperative bleeding up to 1 year after vitrectomy.

Various oral glucose-lowering agents are available in Japan. Although the objective characteristics of these drugs are well described, little is known about treatment satisfaction by patients using these agents. The aim of this study was to assess treatment satisfaction of diabetic patients visiting diabetes clinics using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and to determine the association of the DTSQ scores with various factors including oral glucose-lowering agents. The study subjects were 754 outpatients who had been treated with one or more oral glucose-lowering agents, but not insulin or glucagon-like peptide-1 receptor agonist. The collected data included the response to DTSQ as completed by the patients, various parameters pertaining diabetes treatment including adherence, motivation, life style, social support, complications and cost burden from the patients and attending physicians. The associations among satisfaction scores and various parameters were analyzed by multiple linear regression analysis. In all subjects, use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) were positively, and irregular diet time were negatively associated with satisfaction scores significantly as well as some factors which had been previously reported to be associated. Subgroup analysis showed that adherence to diet and use of SGLT2i were positively in obese (body mass index ≥25 kg/m2), and HbA1c and irregular work time were negatively in non-obese (

The subclinical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rate in hospitals during the pandemic remains unclear. To evaluate the effectiveness of our hospital's current nosocomial infection control measures, we conducted a serological survey of anti-SARS-CoV-2 antibodies (immunoglobulin [Ig] G) among the staff of our hospital, which is treating coronavirus disease 2019 (COVID-19) patients.The study design was cross-sectional. We measured anti-SARS-CoV-2 IgG in the participants using a laboratory-based quantitative test (Abbott immunoassay), which has a sensitivity and specificity of 100% and 99.6%, respectively. To investigate the factors associated with seropositivity, we also obtained some information from the participants with an anonymous questionnaire. We invited 1133 staff members in our hospital, and 925 (82%) participated. The mean age of the participants was 40.0 ±â€Š11.8 years, and most were women (80.0%). According to job title, there were 149 medical doctors or dentists (16.0%), 489 nurses (52.9%), 140 medical technologists (14.2%), 49 healthcare providers (5.3%), and 98 administrative staff (10.5%). The overall prevalence of seropositivity for anti-SARS-CoV-2 IgG was 0.43% (4/925), which was similar to the control seroprevalence of 0.54% (16/2970) in the general population in Osaka during the same period according to a government survey conducted with the same assay. Seropositive rates did not significantly differ according to job title, exposure to suspected or confirmed COVID-19 patients, or any other investigated factors.The subclinical SARS-CoV-2 infection rate in our hospital was not higher than that in the general population under our nosocomial infection control measures.

Context: Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects. Purpose: The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations. Methods: We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11). Conclusions: To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia., In nonobese healthy subjects, the prevalence of hyperinsulinemia without apparent diabetes is 0.4%. The prevalence of insulin receptor gene mutations in 11 subjects with hyperinsulinemia is 18.2%.

Aims/Introduction The present study was carried out to generate induced pluripotent stem cells (iPSCs) from patients with fulminant type 1 diabetes, and evaluate the cytokine-induced apoptotic reactions of β-like insulin-producing cells differentiated from the iPSCs. Materials and Methods iPSCs were generated from fibroblasts of patients with fulminant type 1 diabetes by inducing six reprogramming factors. Insulin-producing cells were differentiated from the iPSCs in vitro. The proportion of cleaved caspase-3-positive or terminal deoxynucleotidyl transferase 2′-deoxyuridine, 5′-triphosphate nick end labeling-positive cells among insulin (INS)-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines was evaluated under treatment with tumor necrosis factor-α, interleukin-1β and interferon-γ. Ribonucleic acid sequencing was carried out to compare gene expressions in INS-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines. Results Two iPSC clones were established from each of three patients with fulminant type 1 diabetes. The differentiation of insulin-producing cells from fulminant type 1 diabetes iPSC was confirmed by immunofluorescence analysis and KCl-induced C-peptide secretion. After treatment with pro-inflammatory cytokines, these INS-positive cells showed higher expression of cleaved caspase-3 than those derived from control human iPSCs. Altered expression levels of several apoptosis-related genes were observed in INS-positive cells derived from the fulminant type 1 diabetes iPSCs by ribonucleic acid sequencing. Conclusions We generated iPSCs from patients with fulminant type 1 diabetes and differentiated them into insulin-producing cells. This in vitro disease model can be used to elucidate the disease mechanisms of fulminant type 1 diabetes.

Context:Fulminant type 1 diabetes mellitus (T1DM) is thought to be partly caused by virus infection.Objective:This study investigated the mechanism of β cell destruction in fulminant T1DM after drug-induced hypersensitivity syndrome (DIHS).Methods:We determined the localization of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV) and the expression of interferon regulatory factor 3 (IRF3) and viral receptors of Z-DNA binding protein 1 (ZBP1) and retinoic acid-inducible gene I (RIG-I), together with inflammatory cells, by immunohistochemistry of the autopsy pancreas of a patient with fulminant T1DM with DIHS and in seven subjects with normal glucose tolerance who underwent pancreatectomy.Results:HCMV-positive cells were detected in islets and exocrine areas in the patient with fulminant T1DM. Greater numbers of macrophages and CD4+ and CD8+ T lymphocytes had infiltrated into HCMV-positive islets than into HCMV-negative islets, and 52.6% of HCMV-positive cells were also positive for IRF3. α Cells expressed IRF3, ZBP1, or RIG-I. No HCMV-positive cells were detected in the control subjects. HHV-6−positive, but not EBV-positive, cells were present in the patient and the control subjects.Conclusions:These findings indicate that the immunoresponse caused by HCMV infection was associated with β cell injury.

The aim of this study was to determine the efficacy of insulin degludec (IDeg) relative to insulin glargine (IGlar) or insulin detemir (IDet) in glycemic control, as evaluated by continuous glucose monitoring (CGM) in insulin-deficient patients with type 1 diabetes.We studied 28 outpatients treated with IGlar or IDet (IGlar/IDet). Basal insulin was switched to IDeg when glycemic control was considered unstable, as judged by the dawn phenomenon or nocturnal hypoglycemia. Whole-day CGM data were also divided into daytime and nighttime data.The dawn phenomenon or nocturnal hypoglycemia under IGlar/IDet treatment was observed in all patients. Among 26 patients who completed the study, there were no significant differences in parameters representing glycemic variability, hyperglycemia, mean glycemic control, and HbA1c or insulin therapy-related quality of life at the night score. Measures of hypoglycemia [whole-day %Low and area under the curve (AUC) below 70] were significantly lower under IDeg treatment than under IGlar/IDet treatment (%Low, 9.6 ± 11.5 vs. 14.7 ± 14.9%,Patients with unstable glycemic control under IGlar/IDet treatment did not improve glycemic control upon switching to IDeg, but the frequency and the degree of hypoglycemia was reduced in insulin-deficient outpatients with type 1 diabetes, especially in those suffering from severe hypoglycemia.

The aim of this study was to determine the effective waist circumference (WC) reduction rate in avoiding the development of type 2 diabetes mellitus (T2DM) in

Aims: Glucagon plays pivotal roles in systemic glucose homeostasis mainly by promoting hepatic glucose output. Using a sandwich enzyme-linked immunosorbent assay (ELISA), we evaluated fasting plasma glucagon levels in hospitalized patients with type 1 or type 2 diabetes, and assessed the relationships between glucagon levels and various clinical parameters. Methods: We enrolled adult Japanese diabetes patients admitted to Osaka University Medical Hospital for glycemic control between July 2017 and May 2018 in this study. After patients had fasted for 12 h, blood samples were obtained and plasma glucagon levels were measured using a sandwich ELISA. Results: Total 107 patients participated in the study. The mean fasting plasma glucagon level of patients with acute onset type 1 diabetes was significantly lower than that of patients with type 2 diabetes (p < 0.05). Plasma glucagon levels were not significantly correlated with plasma glucose levels in patients with type 1 diabetes or in patients with type 2 diabetes. Multiple regression analysis indicated that fasting glucagon levels were independently and significantly correlated with fasting serum C-peptide levels in patients with type 2 diabetes. Conclusions: Our results suggest that insulin and glucagon secretion are balanced in the fasting state in patients with type 2 diabetes.

Type 1 diabetes is a disease characterized by destruction of the β-cells in the pancreatic islets. The inhibitory receptor programmed cell death-1 (PD-1) and its ligands, programmed cell death ligand-1 (PD-L1) and PD-L2, have been shown to play an important role in regulating T-cell activation and peripheral tolerance. Inhibitors targeting PD-1 or PD-L1 are especially advantageous in the treatment of cancer. There are several reports where type 1 diabetes developed after administration of anti–PD-1 antibody (1). However, there is no report containing an immunohistochemical study of the pancreas. At the age of 55 years, a male patient underwent left radical nephrectomy for kidney cancer. At age 60, he was diagnosed with type 2 diabetes. Under the administration of vildagliptin, his hemoglobin A1c was maintained at ∼6% (41 mmol/mol). He was diagnosed with gallbladder metastasis of renal carcinoma at age 61 and underwent a cholecystectomy. Thereafter, he was diagnosed with renal carcinoma pancreatic metastasis, which increased in size, whereupon anti–CTLA4 antibody (ipilimumab) and anti–PD-1 antibody (nivolumab) combination therapy was started. Ipilimumab and nivolumab were administered four times over 2 months and nine times over 5 months, respectively. At age 63, 5 months after the start of administration, he developed diabetic ketoacidosis, his serum C-peptide was 1.8 ng/mL at that time, and insulin treatment was started. Anti–glutamic acid decarboxylase, anti–IA-2, and anti-IAA antibodies were negative, and his HLA haplotype was DRB1\*11:01-DQB1\*03:01 and DRB1\*09:01-DQB1\*03:03 . Two weeks after hospitalization, his serum C-peptide was

An impaired awareness of hypoglycemia is a serious problem in diabetic patients, which can lead to life-threatening severe hypoglycemia. Recurrent hypoglycemia attenuates the function of the central, mainly hypothalamic, nervous system and it causes an impaired awareness of hypoglycemia. Vitamin B12 deficiency is also associated with the dysfunction of central nervous system. We report a 72-year-old type 1 diabetic patient with vitamin B12 deficiency whose impaired awareness of hypoglycemia improved after 4 weeks of vitamin B12 administration with an increased counter-hormone secretion in response to hypoglycemia. We should recognize vitamin B12 deficiency as one of the causes of an impaired awareness of hypoglycemia in diabetic patients.

Abnormality of carbohydrate metabolism is often observed in myotonic dystrophy. Hyperinsulinemia and impaired glucose metabolism in the skeletal muscle have also been reported in myotonic dystrophy 1 (DM1); thus, insulin resistance could be the primary pathophysiology leading to glucose intolerance in DM1. One of the molecular mechanisms of insulin resistance is an aberrant expression of the low-signaling IR-A in the muscle resulting from abnormal splicing caused by altered RNA binding due to the CUG expansion in the DMPK gene. It is also suggested that DMPK itself affects insulin action, and reduced DMPK causes insulin resistance. Fasting hyperinsulinemia and hypersecretion of insulin on glucose loading are observed in DM1 patients from early period before the onset of diabetes, and these may be risk of developing diabetes. Myotonic dystrophy patients have some factors for deterioration of glucose intolerance other than genetic-based insulin resistance: reduced lean body mass, relatively increased body fat, and low physical activity with progression of myopathy. Concerning treatment, it is reasonable to use insulin-sensitizing drugs such as pioglitazone and metformin. However, most of patients, especially with long duration of diabetes, need to use other medicines including insulin for keeping adequate glycemic control. In clinical practice, the goals of glycemic control should be determined individually in light of the patient’s important comorbidities. Since myotonic dystrophy is one of the important comorbidities, further studies will be needed to answer how we determine the goals of glycemic control and how we should treat in safe the individuals with progressed myopathy.

Insulinoma and insulin or insulin receptor (IR) autoantibodies are the main causes of hyperinsulinemic hypoglycemia in adults, but the exact cause in other cases remains obscure. This study is to determine the genetic basis of hyperinsulinemic hypoglycemia in two cases without the above abnormalities. Sequence analysis of IR gene in two patients with adult-onset hyperinsulinemic hypoglycemia and their relatives were performed, and the mutant gene observed in one case was analyzed. Both cases had normal levels of fasting plasma glucose (FPG), fasting hyperinsulinemia, low insulin sensitivity, and hypoglycemia with excessive insulin secretion during oral glucose tolerance test (OGTT). Both reported adult-onset postprandial hypoglycemic symptoms. In one patient, a missense mutation (Arg256Cys) was detected in both alleles of the IR gene, and his parents had the same mutation in only one allele but no hypoglycemia. The other had a novel nonsense mutation (Trp1273X) followed by a mutation (Gln1274Lys) in one allele, and his 9-year old son had the same mutation in one allele, together with hyperinsulinemic hypoglycemia during OGTT. Overexpression experiments of the mutant gene found in Case 1 in mammalian cells showed abnormal processing of the IR protein and demonstrated reduced function of Akt/Erk phosphorylation by insulin in the cells. In two cases of hyperinsulinemic hypoglycemia in adults, we found novel mutations in IR gene considered to be linked to hypoglycemia. We propose a disease entity of adult-onset hyperinsulinemic hypoglycemia syndrome associated with mutations in IR gene.

Objective The purpose of this study was to determine the differences in emotional distress among three groups of inpatients with type 1, obese type 2, and non-obese type 2 diabetes during hospitalization. Methods The 42 participating inpatients were divided into three groups: type 1 diabetes (n=11), obese type 2 diabetes [body mass index (BMI) ≥25 kg/m(2); n=24], and non-obese type 2 diabetes (BMI

The estimated number of people with type 2 diabetes worldwide was approximately 415 million people in 2015, and that number should reach more than 642 million in 2040 (IDF Diabetes Atlas, 7th edition), thus prevention of type 2 diabetes is a major challenge for public health professionals throughout the world. In Japan, approximately 7.8 million Japanese were estimated to have type 2 diabetes in 1990, and the number gradually increased to reach more than 22.1 million in 2007. Subsequently, however, the number decreased though by a small margin, and was estimated to be approximately 20.5 million in 2012 according to the Ministry of Health, Labor and Welfare. The apparent break in the rise of the prevalence of diabetes in Japan is probably related to the tokutei kenshin, formally called tokutei kenko shinsa; that is, annual medical check‐up, which was legislated in 20081, 2, 3. The tokutei kenshin is an annual medical examination in Japan that was established with a special focus on metabolic syndrome, namely visceral fat syndrome. Under this system, when the results of clinical examination and laboratory tests show that the examinee has or is at high risk of metabolic syndrome, s/he receives assistance in reviewing her/his lifestyle for improvement (specific health guidance), which is called tokutei hoken shido. The purpose of this educational program is lifestyle intervention that can lead to prevention of potential lifestyle‐related diseases, such as diabetes, hypertension, dyslipidemia and cardiovascular diseases. Type 2 diabetes results from both genetic predisposition and environmental risk factors, such as obesity, visceral fat accumulation and physical inactivity. Therefore, lifestyle interventions, especially those designed to reduce bodyweight, are thought to be effective in preventing or delaying the onset of the disease. In fact, several large‐scale intervention trials in the USA and Europe have concluded that lifestyle interventions designed to reduce bodyweight prevent or delay the onset of type 2 diabetes in subjects with impaired glucose tolerance (IGT). However, most of the participants in the aforementioned studies were obese, and especially in the Diabetes Prevention Program4, the mean body mass index (BMI) of the participants was more than 30 kg/m2 at baseline, which makes them very different from the Japanese population. One Japanese study5 that analyzed the correlation between weight reduction and change in glycemic control in men suggested that bodyweight reduction is an effective strategy for prevention of type 2 diabetes in men with visceral fat accumulation. The study showed that in Japanese men with glycated hemoglobin (HbA1c) levels of 5.6–6.4%, who are considered prediabetics, reduction in bodyweight within 1 year correlated positively with the change in HbA1c in men with visceral fat accumulation, but not in those without visceral fat accumulation, irrespective of BMI (whether BMI was ≥25 kg/m2 or not). This suggests that weight reduction could be effective in preventing diabetes, especially in individuals with visceral fat accumulation, and that assessment of visceral fat, rather than BMI, seems more important in identifying those individuals that would benefit most from lifestyle intervention. In this context, the tokutei hoken shido, which focuses on metabolic syndrome (visceral fat syndrome), is reasonable and should be effective in preventing diabetes. Then, to what extent should bodyweight be reduced to prevent the development of type 2 diabetes? In the Diabetes Prevention Program in USA, a randomized clinical trial designed to prevent the development of diabetes in patients with IGT4, the incidence of type 2 diabetes was reduced by 58% after 2.8 years with an average weight reduction of 5.6 kg (loss of approximately 6% of bodyweight) in the intensive lifestyle intervention group compared with the placebo group, with an average weight loss of 0.1 kg. In the same study, loss of more than 5–7% of bodyweight reduced the risk of type 2 diabetes by more than 90%. Similarly, a Japanese observational study6 showed that in Japanese men with visceral fat accumulation and HbA1c level of 5.6–6.4%, a weight loss of ≥4.3% significantly reduced the risk of diabetes by approximately 80% compared with the bodyweight gain group (mean weight gain, 2.8%) during the 3‐year study period, whereas weight loss of

Aim/introduction The patients with type 1 diabetes are classified into three subtypes: acute-onset, fulminant, and slowly progressive in Japan. Acute-onset type 1 diabetes would be equivalent to type 1A diabetes, the typical type 1 diabetes in Western countries. The insulin secretion capacity in Japanese subjects with long-standing type 1A diabetes is unclear. The aim of this study is to clarify the course of endogenous insulin secretion during long-term follow-up and factors associated with residual insulin secretion in patients with acute-onset type 1 diabetes (autoimmune). Materials and Methods We retrospectively investigated endogenous insulin secretion capacity in 71 patients who fulfilled the diagnostic criteria for acute-onset type 1 diabetes (autoimmune) in Japan. To assess the residual insulin secretion capacity, we evaluated randomly measured C-peptide levels and results of glucagon stimulation test in 71 patients. Results In the first year of disease, the child- and adolescent-onset patients had significantly more in residual insulin secretion than the adult-onset patients (34 patients in total). C-peptide levels declined more rapidly in patients whose onset were younger than 18 years old have than in patients whose onset were older than 19 years old. Endogenous insulin secretion capacity stimulated by glucagon was completely lost in almost all patients at more than 15 years after onset (61 patients in total). Conclusions Most patients with acute-onset type 1 diabetes (autoimmune) completely lose their endogenous insulin secretion capacity during the disease duration in Japan. Age of onset may affect the course of insulin secretion. This article is protected by copyright. All rights reserved.

We present a case of a novel PAX6 heterozygous mutation with aniridia and insulin‐dependent diabetes mellitus.To the best of our knowledge, this is the first case of its mutation with a complete loss of insulin secretory capacity. We believe that our letter will add new knowledge to diabetes mellitus associated with PAX6 mutations and might help us to understand the role of PAX6 in beta‐cell development.

Aims/Introduction To establish the validity of the plasma glucose disappearance rate (KITT), derived from an insulin-tolerance test (ITT), for evaluating the insulin sensitivity of patients with type 2 diabetes after insulin therapy. Materials and Methods In the first arm of the study, 19 patients with poorly controlled diabetes were treated with insulin and underwent an ITT and a euglycemic clamp test (clamp-IR). The relationship between the insulin resistance index, as assessed by both the clamp-IR and KITT tests, was examined. In the second arm of the study, the relationships between KITT values and various clinical parameters were investigated in 135 patients with poorly controlled diabetes, after achieving glycemic control with insulin. Results In study 1, a close correlation between KITT and the average glucose infusion rate during the last 30 min of the standard clamp-IR test (M-value) was noted (P