Manabu Narisawa

Metabolic Reprogramming Commits Differentiation of Human CD27 + IgD + B Cells to Plasmablasts or CD27 − IgD − Cells

B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-α markedly induced the differentiation of CD27+IgD+ unswitched memory B cells into CD27hiCD38hi plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27−IgD− memory B cells with high cytokine production, but such differentiation was suppressed by IFN-α. AMP-activated protein kinase activation enhanced the differentiation to CD27−IgD− B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19+ B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-α amplifies mTORC1-glycolysis pathways) or CD27−IgD− memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE.

Factors influencing inter-day glycemic variability in diabetic outpatients receiving insulin therapy.

The aim of the present study was to determine the actual state of inter‐day glycemic variability and identify the factors that affect glycemic variability in diabetic outpatients on insulin therapy.

Prednisolone Dosing Regimen for Treatment of Subacute Thyroiditis.

The rate of recurrence of subacute thyroiditis (SAT) during prednisolone (PSL) therapy is approximately 10 to 20%. However, there is little or no information on the time period to relapse following administration of a tapered dose of PSL and the factors associated with such relapse. The aim of this study was to determine the correlation between SAT recurrence and PSL tapering regimen used in the treatment of SAT. This study was a medical record-based retrospective study and involved 26 patients (3 men, 23 women) who received PSL therapy for SAT. The primary endpoint was the association between recurrence and number of days required to taper daily PSL dose to 5 mg. The secondary endpoint was the relationship between recurrence and several variables including age, clinical score, free thyroxine, inflammatory reaction, thyroglobulin, total treatment time, total dose of PSL and presence or absence of creeping thyroiditis. The SAT recurrence rate was 15.3%. There was no significant difference in the initial PSL dose between the non-recurrence and recurrence groups (27.5 mg vs 24.5 mg, P = 0.302). However, for the primary endpoint, significant differences were found between the two groups in time required for tapering PSL to 5 mg/day (non-recurrence: 44.3 ± 15.3 days, recurrence: 19.0 ± 11.9 days, P = 0.012). None of the clinical variables evaluated correlated significantly with SAT relapse. In conclusion, to prevent recurrence of SAT, consideration should be given to the period required for PSL tapering to 5 mg/day.

Comparative analysis of the effects of alogliptin and vildagliptin on glucose metabolism in type 2 diabetes mellitus

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Clinical Features of Patients with Basedow's Disease and High Serum IgG4 Levels

Objective IgG4-related disease is a recently characterized condition presenting with high blood IgG4 levels, swelling of organs, and hypertrophic lesions. This disease is associated with thyroid disease, Hashimotos disease, and Riedels thyroiditis. However, there is little information on the association between IgG4-related disease and Basedows disease. We herein defined the clinical features of patients with Basedows disease and high IgG4 levels. Methods We compared two groups of patients with Basedows disease (n=72) who had either normal IgG4 levels (<135 mg/dL; n=67) or high IgG4 levels (≥135 mg/dL; n=5 [6.9%], mean IgG4: 206±116 mg/dL, IgG4/IgG ratio: 10.6%±3.3%). Patients Seventy-two newly diagnosed, untreated patients with Basedows disease. Results Compared to the normal IgG4 group, patients in the high IgG4 group were predominantly male and showed a significantly higher thyroid low-echo score (1.8±0.4 vs. 1.2±0.5) and eosinophil count (363±354/mm2 vs. 136±122/mm2). Five patients had high IgG4 levels: one had a pancreatic lesion, and four had thyroid lesions. Conclusion Patients with Basedows disease and high IgG4 levels may represent a new subtype of Basedows disease. Further studies with larger sample sizes are needed.

Association Between Diabetic Microangiopathies and Glycemic Variability Assessed by Continuous Glucose Monitoring

The aim of this retrospective study was to elucidate the association between glucose profile using the continuous glucose monitoring system (CGMS) and microvascular complications in patients with type 2 diabetes mellitus (T2DM). The subjects were 160 inpatients with T2DM. The mean blood glucose (MBG) level, percentage of time in a 24-hour period spent with blood glucose level higher than 180 mg/dl (time at >180 mg/dl), standard deviation (SD), and mean amplitude of glycemic excursions (MAGE) were measured continuously over 48 hours using the CGMS. The primary outcome was the association between microvascular complications and glycemic variability. The secondary outcome was the association between microangiopathies and MBG. The SD and MAGE were not associated with presence of microangiopathies or number of complications. There were also no associations between abnormal vibratory sensation in the bilateral lower extremities, coefficient of variation of the R-R interval (CVRR), retinopathy stage, nephropathy stage, or microalbuminuria. MBG was associated, however, with retinopathy, retinopathy stage, and number of complications. Time at >180 mg/dl correlated with abnormal vibratory sensation in the bilateral lower extremities and presence or stage of retinopathy. MBG and time at >180 mg/dl were not associated with presence or stage of nephropathy. Our findings suggest that broad glycemic variability was not associated with microvascular complications, the number of which increased in patients with a high mean glucose level and long time spent with hyperglycemia. It is important, therefore, to reduce the mean glucose level and time spent with hyperglycemia to prevent future microangiopathies.

Twenty-four-hour variations in blood glucose level in Japanese type 2 diabetes patients based on continuous glucose monitoring

High fluctuations in blood glucose are associated with various complications. The correlation between glycated hemoglobin (HbA1c) level and fluctuations in blood glucose level has not been studied in Japanese patients with type 2 diabetes. In the present study, blood glucose profile stratified by HbA1c level was evaluated by continuous glucose monitoring (CGM) in Japanese type 2 diabetes patients.