Comparative effects of fixed-dose mitiglinide/voglibose combination and glimepiride on vascular endothelial function and glycemic variability in patients with type 2 diabetes: A randomized controlled trial.

INTRODUCTION: The aim of this study was to compare the effects of mitiglinide/voglibose with those of glimepiride on glycemic variability and vascular endothelial function in patients with type 2 diabetes. MATERIALS AND METHODS: It was a multicenter, open-label, randomized, crossover study. Hospitalized patients received either mitiglinide/voglibose (three times daily administration of 10 mg mitiglinide and 0.2 mg voglibose) or glimepiride (once-daily 2 mg) in random order, each for 5 days. The reactive hyperemia index (RHI) and the mean amplitude of glycemic excursions (MAGE) were measured as co-primary endpoints using reactive hyperemia peripheral arterial tonometry and continuous glucose monitoring. RESULTS: The analysis included 30 patients (15 in each group). The RHI was 1.670 ± 0.369 during treatment with mitiglinide/voglibose and 1.716 ± 0.492 during treatment with glimepiride, with no significant difference between the two. MAGE was significantly lower in the mitiglinide/voglibose group (47.6 ± 18.5 mg/dL) than in the glimepiride group (100.6 ± 32.2 mg/dL). Although the mean blood glucose levels over the entire 24 h period were comparable between the two groups, the use of mitiglinide/voglibose was associated with a lower standard deviation of mean glucose, coefficient of variation, and mean postprandial glucose excursion compared with glimepiride. The time below range (<70 mg/dL) and the time above range (>180, >200, and 250 mg/dL) were lower in the mitiglinide/voglibose group, while the time in range (70-180 mg/dL) was higher. CONCLUSIONS: In our short-duration randomized crossover study, although not impacting vascular endothelial function, mitiglinide/voglibose demonstrated potential benefits in reducing glycemic variability, postprandial hyperglycemia, and hypoglycemia in patients with type 2 diabetes.

Possible involvement of CXCR3-CXCR6 + CD4 + T cells in Langerhans cell histiocytosis.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a condition characterized by proliferation of Langerhans cells and wide-range pathologies, ranging from single granulomatous lesions to multi-organ involvement, associated with tissue destruction. LCH pathogenesis remains obscure although association with interleukin (IL)-17A has been reported. We report here a case that illustrates the potential pathogenic role of helper T17 (Th17) cells in LCH-related bone destruction. MATERIALS AND METHODS: The patient was a 66-year-old woman. The clinical course included craniectomy and bone mass excision in X-9, diagnosis of LCH confirmed by histopathology, followed by 26-month chemotherapy. In August X, the patient was diagnosed with complete central diabetes insipidus. Symptoms improved after treatment with desmopressin. Pituitary magnetic resonance imaging showed swelling extending from the suprasellar region to the pituitary stalk, suggestive of LCH recurrence. This was followed by chemotherapy combined with mercaptopurine hydrate.  RESULTS: Subsequent peripheral blood lymphocyte analysis showed marked increase in activated Th17 cells (CXCR3-CXCR6+ CD4+ T cells). Double staining for CD4 and IL-17 by immunofluorescence of pathological tissue samples obtained during temporal bone mass excision, which confirmed the diagnosis of LCH in X-9, showed areas of combined presence of CD4-positive cells and IL-17-positive cells. Chemotherapy resulted in size reduction of the pituitary lesion and decrease in peripheral blood-activated Th17 cells. CONCLUSIONS: We found abundant peripheral blood-activated Th17 cells and high percentages of IL-17-producing cells in osteolytic bone lesions in LCH. This finding, together with the decrease in peripheral blood-activated Th17 cells following chemotherapy, suggests the potential involvement of activated Th17 cells in LCH-related osteolysis.

Real-world effectiveness of liraglutide versus dulaglutide in Japanese patients with type 2 diabetes: a retrospective study.

Real-world data comparing the effectiveness of various glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM) are limited. We investigated the clinical effectiveness of liraglutide and dulaglutide in Japanese T2DM in a real-world setting. This retrospective study included 179 patients with T2DM who were treated with GLP-1 RA for at least 12 months (liraglutide, n = 97; dulaglutide, n = 82). We used stabilized propensity score-based inverse probability of treatment weighting (IPTW) to reduce selection bias and confounding by observed covariates. Changes in glycated hemoglobin (HbA1c) at the end of the 12-month treatment were evaluated. After adjustment by stabilized propensity score-based IPTW, no significant differences were observed in patient characteristics between the liraglutide and dulaglutide groups. HbA1c was significantly lower at 12 months in both groups (liraglutide, 8.9 to 7.4%; dulaglutide, 8.7 to 7.5%). Multivariate linear regression analysis showed no differences in the extent of changes in HbA1c at 12 months between the two agents. High baseline HbA1c, the addition of GLP-1 RA treatment modality, and in-hospital initiation of GLP-1 RA treatment were identified as significant contributing factors to HbA1c reduction. The effects of liraglutide and dulaglutide on lowering HbA1c levels at 12 months were comparable in a real-world setting.

Relationship between blood glucose variability in ambulatory glucose profile and standardized continuous glucose monitoring metrics: Subanalysis of a prospective cohort study.

AIM: To clarify the relationship between ambulatory glucose profile (AGP) indexes and standardized continuous glucose monitoring (CGM) metrics in patients with type 2 diabetes (T2D). METHODS: This is an exploratory, cross-sectional analysis of baseline data collected from a prospective, multicentre, 5-year follow-up observational study conducted and published previously by our group. The study participants were 999 outpatients with T2D who used CGM at baseline, and had no apparent history of cardiovascular disease. We investigated the relationship between average interquartile range (IQR) and time in range (TIR). We also calculated, for the first time, the cutoff values to achieve the TIR target values. RESULTS: In both the TIR more than 70% and TIR more than 90% achievement groups, the average IQR was notably small compared with the non-achievement groups. Particularly in comparison of the TIR quartiles, the average IQR became significantly smaller as the TIR became larger. The average IQR correlated negatively with TIR, and the cutoff values for TIR of more than 70% achievement and TIR of more than 90% achievement were an average IQR (>70%/>90%) of 2.13/1.85 mmol/L. CONCLUSION: Our results showed a negative correlation between TIR and the range of blood glucose variations visually represented in AGP. The results also showed that the range of blood glucose variations in AGP is associated with indices of intraday and interday blood glucose variations and also with hypoglycaemia. Our results may provide new perspectives in the assessment and application of AGP in the clinical setting.

Relationship between glycemic intraday variations evaluated in continuous glucose monitoring and HbA1c variability in type 2 diabetes: pilot study.

BACKGROUND: HbA1c variability is independent of mean HbA1c, and associated with mortality due to vascular complications. However, the significance of HbA1c variability is unknown at present. In this study, we used flash glucose monitoring (FGM) and evaluated glycemic intraday variations, and then examined the association with HbA1c variability. METHODS: We conducted a retrospective pilot study of 26 patients treated at the Outpatient department for type 2 diabetes mellitus (T2DM), and evaluated the following items associated with blood glucose levels and their changes/variations using FGM. The primary endpoint was factor(s) associated with standard deviation (SD) HbA1c over a 6-month period. To adjust for the effect of varying numbers of HbA1c measurements, we used the adjusted SD of HbA1c. RESULTS: There were significant correlations between mean HbA1c and each of glucose management indicator, maximum, percent time at glucose > 180 mg/day, mean of daily difference of blood glucose, and high blood glucose index. Adjusted SD HbA1c correlated significantly with percent time at glucose < 70 mg/dL and low blood glucose index. We estimated the regression coefficient of adjusted SD HbA1c using multivariate linear regression analysis, and noted that the presence of hypoglycemia affected Adjusted SD HbA1c (ß = 0.130, SE = 0.044, P = 0.008). Hypoglycemia was noted in 17 patients, and adjusted SD HbA1c was significantly higher (p = 0.001) in the hypoglycemic group (0.22 ± 0.12%), compared with the non-hypoglycemic group (0.08 ± 0.05%). The cut-off value of adjusted SD HbA1c was 0.109% in the hypoglycemic group. CONCLUSIONS: The results showed that HbA1c variability is associated with hypoglycemia. For patients with high HbA1c variability, we recommend evaluation for the presence of hypoglycemia and reconsideration of their treatment regimen including their glucose-lowering medications. Trial registration The study protocol and opt-out method of informed consent were approved by the ethics committees of the University of Occupational and Environmental Health (Trial registration: H27-186, Registered 25 Dec 2015).

Relationship between interstitial glucose variability in ambulatory glucose profile and standardized continuous glucose monitoring metrics; a pilot study.

BACKGROUND: Treatment indexes using continuous glucose monitoring (CGM) have become standardized internationally, and the use of ambulatory glucose profile (AGP) is currently recommended. However, the relationship between AGP indexes and standardized CGM metrics has not been investigated. Using flash glucose monitoring (FGM), this retrospective study served to evaluate the association of the inter-quartile range (IQR) of AGP with standardized CGM metrics. METHODS: The study subjects were 30 patients with type 2 diabetes mellitus (T2DM) and 23 non-diabetic patients (control group). We evaluated average IQR (AIQR) and standardized CGM metrics. The primary endpoint was the relationship between AIQR and Time in range (TIR) in a 24-h period. RESULTS: In the T2DM group, the AIQR was notably high and correlated negatively with TIR, and positively with Time above range, average interstitial glucose level, standard deviation of interstitial glucose, coefficient of variation of interstitial glucose, and mean of daily difference in blood glucose (MODD). For the T2DM group, the AIQR was notably lower in patients who achieved TIR > 70%, compared to those who did not. The AIQR cutoff value, as determined by ROC analysis, was 28.3 mg/dl for those who achieved TIR > 70%. No association was detected between the presence of hypoglycemia and AIQR. CONCLUSIONS: Our study is the first to provide the AIQR cutoff value for achieving the TIR target value. The range of interstitial glucose variability in AGP was associated with indexes of intra- and interday variations and hyperglycemia. Our results provide new perspectives in the yet-to-be established methods for evaluation of AGP in practical clinical settings.

Response of thyrotropin-secreting pituitary tumors to preoperative lanreotide therapy. Report of two cases.

Case 1 was a 51-year-old man diagnosed with thyrotropin (TSH)-secreting pituitary tumor. The octreotide loading test showed suppression of TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. Three months after treatment initiation, tumor shrinkage was observed, and pituitary tumor resection was performed through transsphenoidal surgery. Case 2 was a 47-year-old woman in whom the octreotide loading test showed suppressed TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. After six months of treatment, tumor reduction was observed, and transsphenoidal surgery was performed. In both cases, lanreotide administration before TSH-secreting pituitary tumor resection achieved normalization of thyroid function and tumor shrinkage. Treatment with lanreotide seems effective in patients who show TSH secretion suppression in the octreotide loading test.

Addition of canagliflozin to insulin improves glycaemic control and reduces insulin dose in patients with type 2 diabetes mellitus: A randomized controlled trial.

The aim of this study was to evaluate the efficacy of canagliflozin in reducing the required insulin dose and the risk of hypoglycaemia in type 2 diabetes (T2D). This study was conducted in patients with T2D treated with insulin. They were randomly assigned to the control (n = 17) and canagliflozin (n = 17, plus 100 mg/day canagliflozin) groups. In both groups, a defined insulin dose adjustment protocol was applied to achieve the same level of glycaemic control. The change from baseline in daily insulin dose was significantly smaller in the canagliflozin group (3.9 units/day) than in the control group (13.4 units/day; P = 0.040). Low blood glucose index and predicted % of blood glucose (BG) <70 mg/dL, which are hypoglycaemia-related variables, worsened significantly in the control group but both remained unchanged in the canagliflozin group. The standard deviation for night-time BG levels improved significantly only in the canagliflozin group. Supplementation of insulin therapy with 100 mg canagliflozin in patients with T2D reduced the required insulin dose and hypoglycaemic risk and flattened night-time glycaemic fluctuations while maintaining the same level of glycaemic control.