Comparative evaluation of clinical glycemic control markers treated with imeglimin and its effect on erythrocytes in patients with type 2 diabetes mellitus: study protocol of a single-arm, open-label, prospective, exploratory trial.

Background: Imeglimin is a novel type 2 diabetes (T2D) drug that is expected to improve mitochondrial function. In its phase 3 clinical trials in Japanese patients with T2D, the hemoglobin A1c (HbA1c) decrease following imeglimin administration was slow, reaching a plateau after 20-24 weeks of treatment. In general, the erythrocyte lifespan may be a factor when HbA1c shows an abnormal value. Therefore, this study will comparatively evaluate HbA1c and other markers of glycemic control in patients with T2D after imeglimin administration and also examine the effects of imeglimin on erythrocytes. Methods: This single-arm, open-label, prospective, exploratory study is designed to evaluate the divergence between HbA1c and glycoalbumin (GA) or 1,5-anhydroglucitol (1,5-AG) and the glycemic reduction rate in 30 patients with T2D with inadequate glycemic control when imeglimin 2,000 mg is administered for 6 months. In addition, we will examine the effect on erythrocytes, the presumed cause of this divergence. We will measure sustained glycemic variability using flash glucose monitoring and examine the relationship between changes in these indices and HbA1c. Moreover, because prolonged erythrocyte lifespan is a possible cause of falsely high HbA1c levels, erythrocyte lifespan, erythrocyte deformability, and hemoglobin concentration will be evaluated as effects of imeglimin on erythrocytes. Furthermore, if imeglimin has an ameliorative effect on erythrocyte deformability, it may improve peripheral arterial disease; thus, we will also evaluate the toe-brachial pressure index, a measure of this effect. Discussion: In this study, if imeglimin administration results in diverging rates of hypoglycemic effect between HbA1c and GA or 1,5-AG and prolongs erythrocyte lifespan, GA and 1,5-AG, rather than HbA1c, will be considered appropriate measures of the hypoglycemic effect in the early stages of imeglimin administration. If imeglimin improves erythrocyte deformability, it may also be a new treatment strategy for peripheral arterial disease, a chronic complication of T2D. Ethics and dissemination: The study protocol was scientifically and ethically reviewed and approved by the Certified Clinical Research Review Board of Toho University (approval number: THU22002). The study protocol was registered in the Japan Registry of Clinical Trials (jRCT) in December 2022 (jRCTs031220489).

Evaluation of acute toxicity of cancer-targeting albumin-based artificial metalloenzymes.

Recently, the development of abiotic metal-mediated drug delivery has been significant growth in the fields of anticancer approach and biomedical application. However, the intrinsic toxicity of abiotic metal catalysts makes in vivo use difficult. Our group developed a system of cancer-targeting albumin-based artificial metalloenyzmes (ArMs) capable of performing localized drug synthesis and selective tagging therapy in vivo for cancer therapy. The toxicity of the system at higher concentrations was investigated in vitro and in vivo in the study to demonstrate its safety for potential application in clinical trials. In cell-based experiments, the study revealed that the cytotoxicity of metal catalysts anchored within the binding cavity of the cancer-targeting ArMs could be significantly reduced compared to free-in-solution metal catalysts. Moreover, the in vivo data demonstrated that the cancer-targeting ArMs did not cause considerable damage in organs or change in the hematological parameters in a single-dose (160 mg/Kg) toxicity study in rats. Therefore, the system is safe, highlighting that it could be used in clinical trials for cancer treatment.

Correlation between Glycation-Related Biomarkers and Quality of Life in the General Japanese Population: The Iwaki Cross-Sectional Research Study.

The correlation between diabetes-related biomarkers and quality of life (QOL) remains unclear. In this cross-sectional study, we investigated the correlation between diabetes-related biomarkers and QOL in a general Japanese population who underwent health checkups as a part of the Iwaki Health Promotion Project. Male and female participants aged ≥ 20 years from Iwaki District, Hirosaki City, Aomori Prefecture who participated in the 2019 medical evaluation were recruited. QOL was evaluated using the Short Form Health Survey 36 (SF-36). Fasting blood glucose, homeostatic model assessment-estimated insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), glycoalbumin, and plasma pentosidine were also evaluated as diabetes-related markers. Of the 1065 recruited participants, 1053 completed the clinical and QOL evaluations. Multivariate regression analysis revealed that upregulated diabetes-related markers levels were correlated with decreased SF-36 scores. Blood glucose, HOMA-IR, HbA1c, glycoalbumin, and plasma pentosidine levels were correlated with general health. Moreover, plasma pentosidine levels were correlated with role physical, social functioning, and role emotional in addition to general health. These results indicated that the levels of diabetes-related biomarkers, particularly the levels of plasma pentosidine, a glycation marker, were associated with QOL in our cohort.

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.

Association between gut microbiota composition and glycoalbumin level during pregnancy in Japanese women: Pilot study from Chiba Study of Mother and Child Health.

AIMS/INTRODUCTION: Gut microbiota have various effects on human health. Some previous reports have shown that gut microbiota change during pregnancy and affect metabolism, but others have shown that microbiota do not change. Here, we examined the gut microbiota and glycoalbumin levels of 45 healthy Japanese women during pregnancy. MATERIALS AND METHODS: We carried out 16S rRNA gene sequencing analyses of maternal stool samples and compared the gut microbiota composition of samples from women in early and late pregnancy. We also examined the association between gut microbiota and maternal characteristics, including glycoalbumin. RESULTS: Microbiota composition in early and late pregnancy did not differ, according to principal coordinate analysis of weighted and unweighted UniFrac distances. Shannon indices were not different between early and late pregnancy. The proportion of one phylum, TM7, significantly decreased in late pregnancy compared with early pregnancy, but the proportions of other major phyla did not change. The Shannon index of late pregnancy was negatively associated with pregestational body mass index and positively correlated with glycoalbumin level, with adjustment of covariates. CONCLUSIONS: We concluded that Japanese women did not show obvious differences in gut microbiota during pregnancy, except for TM7, and that the diversity of gut microbiota might affect maternal metabolism. As this study had limited statistical power, further large-scale studies are required.

Effect of Lactobacillus casei strain Shirota-fermented milk on metabolic abnormalities in obese prediabetic Japanese men: a randomised, double-blind, placebo-controlled trial.

An obesity-related prediabetic state is characterised by metabolic abnormalities such as post-glucose load hyperglycaemia and dyslipidaemia and consequently increases the risk for type 2 diabetes and cardiovascular disease. This study aimed to investigate the effects of Lactobacillus casei strain Shirota (LcS) on metabolic abnormalities in obese prediabetic subjects in a randomised, double-blind, placebo-controlled trial. Herein, 100 obese subjects (body mass index ≥25), who had moderate post-load hyperglycaemia (1-hr post-load plasma glucose (PG) levels ≥180 mg/dl during the oral glucose tolerance test), consumed LcS-fermented milk or placebo milk daily for 8 weeks. The post-load PG and fasting blood markers were evaluated. Although post-load PG levels were not significantly different between the groups, 1-hr post-load PG, glycoalbumin, and HbA1c levels decreased at 8 weeks compared with the baseline levels only in the LcS group (p=0.036, p=0.002, and p=0.006, respectively). The reduction in glycoalbumin levels was statistically significantly greater in the LcS group than in the placebo group (p=0.030). Stratified analyses revealed significantly improved 1-hr post-load PG and glycoalbumin levels in the LcS group compared with the placebo group among subjects with severe glucose intolerance (2-hr post-load PG levels higher than the median at baseline; p=0.036 and p=0.034, respectively). In terms of lipidic outcomes, total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels were significantly lower in the LcS group than in the placebo group (p=0.023, p=0.022, and p=0.008, respectively). These findings suggest that LcS may favourably affect metabolic abnormalities in obese prediabetic subjects, though the effects on glycaemic control may be limited.

Sequential Double "Clicks" toward Structurally Well-Defined Heterogeneous N-Glycoclusters: The Importance of Cluster Heterogeneity on Pattern Recognition In Vivo.

Structurally well-defined heterogeneous N-glycoclusters are prepared on albumin via a double click procedure. The number of glycan molecules present, in addition to the spatial arrangement of glycans in the heterogeneous glycoclusters, plays an important role in the in vivo kinetics and organ-selective accumulation through glycan pattern recognition mechanisms.

In†Vivo Gold Complex Catalysis within Live Mice.

Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin-AuIII complex was designed and developed that enables organ-specific, localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5- and TAMRA-linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.

Re-evaluation of glycated hemoglobin and glycated albumin with continuous glucose monitoring system as markers of glycemia in patients with liver cirrhosis.

Liver cirrhosis (LC) is frequently accompanied by glucose intolerance. The present study was designed to determine whether glycated hemoglobin A1c (HbA1c) and glycated albumin (GA) were predictive markers of glycemia, as determined by a continuous glucose monitoring system (CGMS), in patients with LC. A total of 30 patients with LC, including 3, 19, 5, 2 and 1 with LC due to hepatitis B virus, hepatitis C virus, non-alcoholic steatohepatitis, alcohol and unknown causes, respectively, were assessed by CGMS. The average, maximum and minimum blood glucose (BG) levels were measured by CGMS, and correlated with HbA1c and GA. The average, maximum and minimum BG in these individuals were 142±38.7, 209.3±65.7 and 85.1±25.4 mg/dl, respectively. HbA1c was significantly correlated with average BG (r=0.447, P=0.015) and maximum BG (r=0.523, P=0.004). In addition, GA was significantly correlated with average BG (r=0.687, P<0.001) and maximum BG (r=0.648, P<0.001). Neither HbA1c nor GA was significantly correlated with minimum BG. Correlation analysis yielded formulas by which HbA1c and GA were predictive of average BG in individuals with LC: Average BG=19.2 × HbA1c (%) + 36.5 and average BG=6.6 × GA (%) + 13.0, respectively. In conclusion, HbA1c and GA showed significant correlations with average and maximum BG, as determined by CGMS. The derived formulas allow for estimates of average BG based on HbA1c and GA, and may contribute to the control of glycemia in patients with LC.

Influence of Varying Dietary Protein Levels on Glycation of Albumin, Tryptophan and Valine in the Plasma of Chickens.

Glycation is a chemical reaction in which reducing sugars bind non-enzymatically to compounds containing amino groups. Avian species like chickens are hyperglycemic animals and have high body temperature compared to mammalian species, which enables avian species to accelerate the glycation of proteins and amino acids with glucose. Although varying dietary crude protein (CP) levels alter plasma concentrations of proteins and amino acids, the influence of varying CP levels on the glycation of plasma proteins and amino acids has not been studied so far. In the present study, therefore, glycation of albumin, tryptophan and valine in the plasma of chickens fed diets with varying CP levels (0, 10, 20, 40 and 60%) was examined. At the end of the experimental period, blood samples were collected and plasma concentrations of glycoalbumin, glycated tryptophan (tryptophan-Amadori product and (1R, 3S) - 1 - (D - gluco - 1, 2, 3, 4, 5 - pentahydroxypentyl) - 1, 2, 3, 4 - tetrahydro - ß - carboline - 3 - carboxylic acid (PHP-THßC)), and valine-Amadori product were measured. Although plasma albumin concentration was reduced along with the decrease in dietary CP levels from 20% to 0%, glycoalbumin in the plasma was increased under such dietary conditions. Similar increase in the ratios of tryptophan-Amadori product to tryptophan and valine-Amadori product to valine in the plasma of chickens fed a protein-free diet was observed. These results suggest that dietary protein deficiency might enhance the non-enzymatic glycation of plasma proteins and amino acids in chickens.

Detection of hemoglobin variant HbS on the basis of discrepant HbA1c values in different measurement methods.

Glycated hemoglobin (HbA1c) is commonly used to assess long-term glycemic control in patients with diabetes mellitus. Numerous conditions, including hemoglobinopathies, can alter HbA1c measurements and cause misleading results. More than 20 methods for determining HbA1c are commercially available to clinical laboratories. Herein, we report a diabetic patient in whom the HbS variant was detected on the basis of discrepant Hb1Ac levels estimated using immunonephelometry or high-performance liquid chromatography (HPLC). The patient, a 48-year-old African man with a 10-year history of type 2 diabetes, was referred to our hospital with an HbA1c level estimated at 13.3 % by immunonephelometry and 7.6 % by HPLC, whereas the glycoalbumin level was 47.5 %. These discrepancies prompted us to carry out genetic sequence analysis in which we identified an A â†’ T transversion in codon 6 of the patient's HBB gene, corresponding to a predicted E6V substitution (ßCD6) characteristic of HbS. Our results indicate that redundant measurements of HbA1c using diverse methods may be useful when the presence of abnormal Hb is suspected.

The apolipoprotein B concentration in gingival crevicular fluid increases in patients with diabetes mellitus.

OBJECTIVE: Oral health conditions have a significant relationship with diabetes mellitus (DM) as well as dyslipidemia. In this study, we investigated the levels of apolipoprotein B (apoB) and oxidized low-density lipoprotein (oxLDL) in the gingival crevicular fluid (GCF) from patients with DM. METHODS: GCF and blood samples from 18 DM patients and 18 healthy subjects were examined. GCF was collected with paper points without inflicting any harm. The apoB and oxLDL levels were measured by sandwich ELISA assays. RESULTS: The number of teeth with a deep probing pocket depth and the number of teeth with bleeding on probing, two typical periodontal parameters, correlated with the DM parameters, such as hemoglobin A1c. The GCF volume and the concentrations of protein, apoB and oxLDL in GCF were significantly higher in the DM patients than in the healthy subjects. In particular, the apoB concentration in GCF was increased 6-fold in the DM patients. The GCF apoB concentration correlated well with the DM parameters in plasma. CONCLUSION: GCF could be a clinical source for examining not only the oral status of patients, but also certain systemic conditions.