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.

Association Between Time in Range and Postprandial Glucose Contribution Rate in Non-Insulin-Treated Type 2 Diabetes Patients: Inverse Correlation of Time in Range with Postprandial Glucose Contribution Rate.

Background: Whether time in range (TIR), a parameter derived from continuous glucose monitoring (CGM), is a marker of postprandial hyperglycemia remains to be determined. In this study, we examined the association between TIR and postprandial glucose in non-insulin-treated type 2 diabetic patients. Methods: Our cross-sectional study included 729 non-insulin-treated patients with type 2 diabetes who underwent CGM without any changes in drug therapy on admission. The 24-h CGM record was analyzed for average glucose, standard deviation, percentage coefficient of variation, time above range, TIR, time below range, area under the curve (AUC) of basal glucose, AUC of postprandial glucose, and postprandial glucose contribution rate (%). The primary endpoint was the association between TIR and the postprandial glucose contribution rate. Results: We made TIR groups divided into 10% increments for a 7-group and compared with <40% to >90%. The basal and postprandial glucose AUCs correlated negatively with TIR. The postprandial glucose contribution rate correlated with TIR. The cutoff value for TIR, where postprandial glucose contribution rate was lower than the basal glucose contribution rate, was 66.3%. Conclusions: In non-insulin-treated type 2 diabetic patients, postprandial glucose AUC was higher in the high TIR group, whereas the basal glucose AUC was higher in the low TIR group. Good glycemic control can be achieved with therapeutic interventions that target postprandial glucose and basal glucose in patients with TIR ≥66.3% and <66.3%, respectively. University Medical Information Network [UMIN] ID: UMIN0000254333.

Risk Factor Analysis for Type 2 Diabetes Patients About Hypoglycemia Using Continuous Glucose Monitoring: Results from a Prospective Observational Study.

Introduction: To determine the relationship between hypoglycemia and glucose variability in outpatients with type 2 diabetes mellitus (T2DM). Materials and Methods: The study participants were 999 outpatients with T2DM who used the FreeStyle Libre Pro for continuous glucose monitoring (FLP-CGM). Hypoglycemia was defined as glucose level of <3.0 mM, and the frequency of episodes and duration of hypoglycemia were evaluated by comparing patients who did or did not achieve time-below-range <3.0 mM (TBR<3.0) of <1% of the time. The association of TBR<3.0 and long% coefficient of variation (%CV) with medications used was examined using multivariate analysis with a proportional odds model. Results: The average TBR<3.0 was 0.33% (4.75 min). The TBR<3.0 >1% group comprised 71/999 patients. Patients of the TBR<3.0 >1% group had lower body mass index, longer disease duration, and poorer renal function. For the TBR<3.0 >1% group, the predicted cutoff values were 7.19 mM average glucose (AG), and 30.30% for %CV. When AG <7.19 mM and %CV >30.30% were considered as hypoglycemic risk factors, the frequency and duration of hypoglycemia increased as the risk factor values increased. In multivariate analysis, sulfonylurea (SU) use, insulin use, and low blood glucose index correlated significantly with increased length of TBR<3.0 and %CV, even after adjustment for concomitant diabetes medications. Conclusion: In T2DM, maintaining TBR<3.0 <1% requires to keep AG >7.2 mM and %CV <30%, in addition to comprehensive management of CGM metrics. Since SU and insulin use is associated with prolonged TBR<3.0 and increased %CV, their doses should be adjusted to avoid excessive fall in AG and raising %CV.

Enlarged glycemic variability in sulfonylurea-treated well-controlled type 2 diabetics identified using continuous glucose monitoring.

Time in range (TIR) is an index of glycemic control obtained from continuous glucose monitoring (CGM). The aim was to compare the glycemic variability of treatment with sulfonylureas (SUs) in type 2 diabetes mellitus (T2DM) with well-controlled glucose level (TIR > 70%). The study subjects were 123 patients selected T2DM who underwent CGM more than 24 h on admission without changing treatment. The primary endpoint was the difference in glycemic variability, while the secondary endpoint was the difference in time below range < 54 mg/dL; TBR < 54, between the SU (n = 63) and non-SU (n = 60) groups. The standard deviation, percentage coefficient of variation (%CV), and maximum glucose level were higher in the SU group than in the non-SU group, and TBR < 54 was longer in the high-dose SU patients. SU treatment was identified as a significant factor that affected %CV (ß: 2.678, p = 0.034). High-dose SU use contributed to prolonged TBR < 54 (ß: 0.487, p = 0.028). Our study identified enlarged glycemic variability in sulfonylurea-treated well-controlled T2DM patients and high-dose SU use was associated with TBR < 54. The results highlight the need for careful adjustment of the SU dose, irrespective of glycated hemoglobin level or TIR value.

Correlations Between Glycemic Parameters Obtained from Continuous Glucose Monitoring and Hemoglobin A1c and Glycoalbumin Levels in Type 2 Diabetes Mellitus.

It is difficult to detect glycemic excursions using CGM in daily clinical practice. We retrospectively analyzed CGM data in type T2DM to define the correlations between HbA1c and GA levels at admission and the parameters representing glycemic excursions measured by CGM, including the mean amplitude of glycemic excursions (MAGE) and standard deviation (SD). The MAGE correlated significantly with GA and HbA1c, but not with the GA/HbA1c ratio. The SD correlated significantly with GA, HbA1c, and GA/HbA1c. Multivariate analysis identified the GA value to be the most reflective of MAGE. Patients were divided into 2 groups using a MAGE cutoff value of 75 mg/dl, which reflects stable diabetes. There was a significant difference in GA, but not HbA1c, between the groups with low and high mean amplitudes of glycemic excursions. Receiver operating characteristic curve analysis indicated that the cutoff for GA for identifying patients with MAGE of ≤75 mg/dl was 18.1%. Our study identified GA to be the most reflective of glycemic excursions in patients with T2DM. GA can be a useful index of glycemic excursions and treatment optimization to prevent arteriosclerosis.

Tumour necrosis factor alpha promotes secretion of 14-3-3η by inducing necroptosis in macrophages.

BACKGROUND: 14-3-3η is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3η and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study. METHODS: The source of 14-3-3η was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4+ cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-α. Extracellular 14-3-3η protein levels were examined by western blotting. RESULTS: Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3η protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-α, but not interleukin (IL) 6/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-α-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3η were detected in the culture supernatants of macrophages stimulated with diamide and TNF-α, but not IL-6/sIL-6R. CONCLUSIONS: Macrophages that highly express 14-3-3η undergo TNF-α-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3η into the extracellular space. The current study provides a novel mechanism for 14-3-3η level increase in the RA synovial fluid.

Hypoglycemia in blood glucose level in type 2 diabetic Japanese patients by continuous glucose monitoring.

BACKGROUND: Hypoglycemia is associated with cardiovascular diseases, increased risk of death. Therefore, it is important to avoid hypoglycemia. The aim of this study was to characterize hypoglycemia according to glycated hemoglobin (HbA1c) level and determine the contributing factors in type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM). METHODS: T2DM patients (n = 293) receiving inpatient care were divided into five groups according to HbA1c level on admission (Group 1: ≥ 6 to < 7%, Group 2: ≥ 7 to < 8%, Group 3: ≥ 8 to < 9%, Group 4: ≥ 9 to < 10%, and Group 5: ≥ 10%). The frequency of hypoglycemia and factors associated with hypoglycemia were analyzed. RESULTS: Hypoglycemia occurred in 15 patients (5.1%), including 4 (8%), 4 (6%), and 7 (10%) patients of Groups 1, 2, and 3, respectively, but in none of groups 4 and 5. Patients with hypoglycemia of Groups 1 had low insulin secretion and were high among insulin users, those of Groups 2 had low homeostasis model assessment of insulin resistance (HOMA-IR). Those of Group 2 and 3 had significantly lower mean blood glucose levels, those of Group 3 only had significantly lower maximum blood glucose level and percentage of AUC > 180 mg/dL. In any of the HbA1c groups, variations in blood glucose level were significantly larger in patients with hypoglycemia than without. CONCLUSIONS: Hypoglycemia occurred in patients with a wide range of HbA1c on admission (range 6-9%), suggesting that prediction of hypoglycemia based on HbA1c alone is inappropriate. Among patients with low HbA1c, strict control sometimes induce hypoglycemia. Among patients with high HbA1c, the possibility of hypoglycemia should be considered if there is a marked discrepancy between HbA1c and randomly measured blood glucose level. Larger variations in blood glucose level induce hypoglycemia in any of the HbA1c groups. The treatment to reduce variations in blood glucose level is important to prevent hypoglycemia.

Glycemic Profiling in Patients with Drug-Naïve Type 2 Diabetes by Continuous Glucose Monitoring.

The purpose of this study was to determine the glycemic profiles of drug-naïve type 2 diabetes patients according to hemoglobin A1c (HbA1c) level using continuous glucose monitoring. We aimed to clarify factors associated with HbA1c and average blood glucose level. Patients were divided into three groups according to their HbA1c level (< 7.0% n=23, 7.0% ≤ HbA1c < 8.0% n=17 and ≥ 8.0% n=31), and the factors associated with HbA1c and average glucose of each group were evaluated. Pre-meal glucose levels were the highest before lunch, and the 2 hour postprandial blood glucose level was the lowest after lunch. The pre-meal and postprandial blood glucose levels increased after each meal with increases in HbA1c. Average glucose level was the most significant determinant of HbA1c, whereas pre-meal glucose level at dinner was the most significant determinant of average glucose level, and the range of increase in glucose from pre-meal at dinner was the most significant determinant of standard deviation (SD) of 24 hour glucose levels. HbA1c subgroup analysis indicated that pre-meal glucose level at lunch significantly correlated with average glucose level in the HbA1c < 8.0% group, while pre-meal glucose level at dinner significantly correlated with average glucose level in the HbA1c ≥ 8.0% group. The range of increase in glucose from pre-meal in the morning significantly correlated with SD of 24 hour glucose levels in the HbA1c < 8.0% group, and the postprandial peak glucose level at lunch significantly correlated with SD of 24 hour glucose levels in the HbA1c ≥ 8.0% group. The results suggest that improvement of the average glucose level is necessary to improve the HbA1c levels. For patients with HbA1c < 7.0%, it is important to improve blood glucose level after breakfast and before lunch to decrease the average glucose level. For patients with 7.0% ≤ HbA1c < 8.0%, it is important to improve blood glucose level before lunch and after dinner to decrease the average glucose level. For patients with HbA1c ≥ 8.0%, it is important to improve blood glucose levels after lunch and before dinner to decrease the average glucose level.

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.

Relation Between Hypoglycemia and Glycemic Variability in Type 2 Diabetes Patients with Insulin Therapy: A Study Based on Continuous Glucose Monitoring.

BACKGROUND: To determine the factors associated with hypoglycemia in patients with type 2 diabetes mellitus (T2DM) on insulin therapy. METHODS: This retrospective study included 62 inpatients with T2DM on insulin therapy who underwent 5-day continuous glucose monitoring (CGM). We analyzed the relation between hypoglycemia (defined as blood glucose below 70 mg/dL, as determined by the CGM) and time spent in hypoglycemia with fasting blood glucose, mean blood glucose (MBG), standard deviation (SD), coefficient of variation, minimum blood glucose level, maximum blood glucose level, and the percent time spent with blood glucose levels of >180 mg/dL. RESULTS: Twelve patients (19.4%) developed hypoglycemia, and most were maintained on mix insulin therapy alone. In the hypoglycemic group, MBG was lower and SD was higher, than in the non-hypoglycemic group, although HbA1c was not different. Multivariate logistic regression analysis identified MBG and SD as factors related to hypoglycemia. Receiver operating characteristic curve analysis showed that the optimal MBG and SD cutoff values for prediction of hypoglycemia were 150.9 and 41.1 mg/dL, respectively. When subjects were divided into four groups according to these values, time at blood glucose <70 mg/dL was longest, and total insulin dosage highest, in the MBG-low/SD-high group. CONCLUSIONS: MBG and SD of glucose levels were identified as significant and independent determinants of hypoglycemia in T2DM on insulin therapy. It is important to use the least insulin dose, with the target of minimizing glycemic variability, to achieve good glycemic control without hypoglycemia.

A Case of Acromegaly in which a Pituitary Gland Tumor was Reduced Significantly by Administering Octreotide Long Acting Release (LAR) and Could Be Removed Surgically.

A 54-year-old woman was admitted to our hospital for detailed examination of acromegaly because she noticed bilateral hand and finger swelling at the age of 43 and plantar thickening, facial changes and unclear articulation at the age of 49. She had prominent brow ridges, mandibular protrusion, and enlargement of the hands, feet, nasal wings, lips and tongue. Her growth hormone (GH) level was 39.8 ng/ml, insulin-like growth factor-1 (IGF-1) level was 717 ng/ml, GH level was not suppressed (22.9 ng/ml) during a 75-g oral glucose tolerance test (OGTT). Radiography showed cauliflower-like enlargement of the distal phalanx of the fingers, thickening/enlargement of the plantar soft tissues, and increased antero-posterior diameter of the sella turcica. Magnetic resonance imaging showed a mass (21×17 mm) growing towards the right suprasellar region and invading the cavernous sinus. She was diagnosed with acromegaly based on the characteristic physical findings, GH excess, high IGF-1, lack of GH suppression during the 75-g OGTT, and the presence of a pituitary tumor. She was started on octreotide long acting release (Oct-LAR) 20 mg/4w for tumor shrinkage. After three doses, her GH and IGF-1 levels decreased to 2.19 ng/ml (1.69 during the 75-g OGTT) and 205 ng/ml, respectively, meeting cure criteria for acromegaly. In this case, a decrease in GH and IGF-1 levels, tumor shrinkage, and resolution of cavernous sinus invasion allowed the patient to undergo surgery with curative intent (the first-line treatment for acromegaly) without postoperative complications. Thus, preoperative Oct-LAR administration has the potential to improve treatment outcomes of acromegaly.

Hybrid immobilization of galactosyl lactose and cellobiose on a gold substrate to modulate biological responses.

Bioactive O-ß-d-galactopyranosyl-(1→4)-O-ß-d-galactopyranosyl-(1→4)-d-glucopyranose (4'-galactosyl lactose) was site-selectively modified at a reducing end with thiosemicarbazide (TSC). As-synthesized 4'-galactosyl lactose-TSC was immobilized on a gold substrate with cellobiose-TSC as a spacer through spontaneous self-assembly chemisorption via SAu bonding. Quartz crystal microbalance analysis suggested the successful formation of self-assembled monolayers (SAMs) of 4'-galactosyl lactose-TSC and/or cellobiose-TSC. Galactose-binding lectin exhibited the highest affinity for hybrid SAMs with an equimolar ratio of the two oligosaccharide-TSCs, while glucose-binding lectin showed decreasing adsorption with a decrease in cellobiose-TSC ratios. Human hepatocellular carcinoma cells, which recognize galactose residues, efficiently adhered to the hybrid SAMs. Higher enzymatic deethoxylation of ethoxyresorufin via cytochrome P450 appeared on hybrid SAMs. These results suggested that clustering of the bioactive sugars was involved in the cellular responses, possibly via biological carbohydrate-protein interactions. This approach to designing carbohydrate-based scaffolds should provide a basis for the functional development of glyco-decorated biointerfaces for cell culture applications.