Matrix metallopeptidase 9 contributes to the beginning of plaque and is a potential biomarker for the early identification of atherosclerosis in asymptomatic patients with diabetes.

Aims: To determine the roles of matrix metallopeptidase-9 (MMP9) on human coronary artery smooth muscle cells (HCASMCs) in vitro, early beginning of atherosclerosis in vivo in diabetic mice, and drug naïve patients with diabetes. Methods: Active human MMP9 (act-hMMP9) was added to HCASMCs and the expressions of MCP-1, ICAM-1, and VCAM-1 were measured. Act-hMMP9 (n=16) or placebo (n=15) was administered to diabetic KK.Cg-Ay/J (KK) mice. Carotid artery inflammation and atherosclerosis measurements were made at 2 and 10 weeks after treatment. An observational study of newly diagnosed drug naïve patients with type 2 diabetes mellitus (T2DM n=234) and healthy matched controls (n=41) was performed and patients had ultrasound of carotid arteries and some had coronary computed tomography angiogram for the assessment of atherosclerosis. Serum MMP9 was measured and its correlation with carotid artery or coronary artery plaques was determined. Results: In vitro, act-hMMP9 increased gene and protein expressions of MCP-1, ICAM-1, VCAM-1, and enhanced macrophage adhesion. Exogenous act-hMMP9 increased inflammation and initiated atherosclerosis in KK mice at 2 and 10 weeks: increased vessel wall thickness, lipid accumulation, and Galectin-3+ macrophage infiltration into the carotid arteries. In newly diagnosed T2DM patients, serum MMP9 correlated with carotid artery plaque size with a possible threshold cutoff point. In addition, serum MMP9 correlated with number of mixed plaques and grade of lumen stenosis in coronary arteries of patients with drug naïve T2DM. Conclusion: MMP9 may contribute to the initiation of atherosclerosis and may be a potential biomarker for the early identification of atherosclerosis in patients with diabetes. Clinical trial registration: https://clinicaltrials.gov, identifier NCT04424706.

Time in Range Estimation in Patients with Type 2 Diabetes is Improved by Incorporating Fasting and Postprandial Glucose Levels.

INTRODUCTION: Time in range (TIR) as assessed by continuous glucose monitoring (CGM) measures an individual's glucose fluctuations within set limits in a time period and is increasingly used together with HbA1c in patients with diabetes. HbA1c indicates the average glucose concentration but provides no information on glucose fluctuation. However, before CGM becomes available for patients with type 2 diabetes (T2D) worldwide, especially in developing nations, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) are still the common biomarkers used for monitoring diabetes conditions. We investigated the importance of FPG and PPG to glucose fluctuation in patients with T2D. We used machine learning to provide a new estimate of TIR based on the HbA1c, together with FPG and PPG. METHODS: This study included 399 patients with T2D. (1) Univariate and (2) multivariate linear regression models and (3) random forest regression models were developed to predict the TIR. Subgroup analysis was performed in the newly diagnosed T2D population to explore and optimize the prediction model for patients with different disease history. RESULTS: Regression analysis suggests that FPG was strongly linked to minimum glucose, while PPG was strongly correlated with maximum glucose. After FPG and PPG were incorporated into the multivariate linear regression model, the prediction performance of TIR was improved compared with the univariate correlation between HbA1c and TIR, and the correlation coefficient (95% CI) increased from 0.62 (0.59, 0.65) to 0.73 (0.72, 0.75) (p < 0.001). The random forest model significantly outperformed the linear model (p < 0.001) in predicting TIR through FPG, PPG and HbA1c, with a stronger correlation coefficient 0.79 (0.79, 0.80). CONCLUSIONS: The results offered a comprehensive understanding of glucose fluctuations through FPG and PPG compared to HbA1c alone. Our novel TIR prediction model based on random forest regression with FPG, PPG, and HbA1c provides a better prediction performance than the univariate model with solely HbA1c. The results indicate a nonlinear relationship between TIR and glycaemic parameters. Our results suggest that machine learning may have the potential to be used in developing better models for understanding patients' disease status and providing necessary interventions for glycaemic control.

Diabetes remission in drug-naïve patients with type 2 diabetes after dorzagliatin treatment: A prospective cohort study.

AIM: To investigate the post-treatment effect of dorzagliatin in drug-naïve patients with type 2 diabetes (T2D) regarding the achievement of stable glycaemic control and drug-free diabetes remission. MATERIALS AND METHODS: Patients who completed dorzagliatin treatment in the SEED trial and achieved stable glycaemic control were enrolled in this 52-week study without any antidiabetic medication. The primary endpoint was the diabetes remission probability at week 52 using the Kaplan-Meier method. The potential factors that contribute to stable glycaemic control and diabetes remission based on the characteristics of patients before and after treatment with dorzagliatin were analysed. A post hoc sensitivity analysis of diabetes remission probability using the American Diabetes Association (ADA) definition was conducted. RESULTS: The Kaplan-Meier remission probability was 65.2% (95% CI: 52.0%, 75.6%) at week 52. Based on the ADA definition, the remission probability was 52.0% (95% CI: 31.2%, 69.2%) at week 12. The significant improvements in the insulin secretion index ΔC30/ΔG30 (41.46 ± 77.68, P = .0238), disposition index (1.22 ± 1.65, P = .0030), and steady-state variables of HOMA2-ß (11.49 ± 14.58, P < .0001) and HOMA2-IR (-0.16 ± 0.36, P = .0130) during the SEED trial were important factors in achieving drug-free remission. A significant improvement in time in range (TIR), a measure of glucose homeostasis, in the SEED trial from 60% to more than 80% (estimated treatment difference, 23.8%; 95% CI: 7.3%, 40.2%; P = .0084) was observed. CONCLUSIONS: In drug-naïve patients with T2D, dorzagliatin treatment leads to stable glycaemic control and drug-free diabetes remission. Improvements in ß-cell function and TIR in these patients are important contributors to diabetes remission.

Effects of a Novel Glucokinase Activator, Dorzagliatin, on Glycemic Control and Glucose Fluctuation in Drug-Naïve Patients with Type 2 Diabetes Mellitus.

Aim: The prevalence rate of type 2 diabetes mellitus (T2DM) has been increasing and a large proportion of patients still do not achieve adequate or sustainable glycemic control on the basis of previous hypoglycemic treatment. In this present study, we explored whether dorzagliatin, a novel glucokinase activator (GKA), could improve glycemic control and lessen glucose fluctuation in drug-naïve patients with T2DM. Methods: A self-comparative observational study of 25 drug-naïve patients with T2DM (aged 18-75 years and HbA1c of 7.5%-11.0%) treated with dorzagliatin 75 mg twice daily for 52 weeks. Before and after dorzagliatin intervention, the serum levels of hemoglobin A1c (HbA1c), insulin, and C-peptide were measured repeatedly during fasting and after a mixed meal. The continuous glucose monitoring (CGM) device was also used to obtain 24-hour glucose profiles and assess the changes in glycemic variability parameters. Results: After 52 weeks of treatment with dorzagliatin, a numerally greater reduction in HbA1c of 1.03% from the baseline was observed in patients with T2DM, accompanied by significant improvement in insulin resistance and insulin secretion. Moreover, the standard deviation of blood glucose (SDBG) and the mean amplitude of glycemic excursion (MAGE) derived from CGM data were significantly decreased after dorzagliatin therapy. The 24-h glucose variation profile showed that study patients had obviously lower mean glucose levels during the postprandial period from the baseline to week 52, an effect also demonstrated by the significant decrease in the incremental area under glucose concentration versus time curve for 2 h (iAUC0-2 h) after meals. Conclusions: This study suggests that dorzagliatin therapy could effectively improve glycemic control and glucose fluctuation in drug-naïve patients with T2DM.

Effect of Chiglitazar and Sitagliptin on Bone Mineral Density and Body Composition in Untreated Patients with Type 2 Diabetes.

Aim: To evaluate the changes in bone mineral density (BMD) and body composition in untreated patients with type 2 diabetes mellitus (T2DM) before and after chiglitazar or sitagliptin treatment. Methods: A total of 81 patients with T2DM were randomly divided to receive chiglitazar or sitagliptin treatment for 24 weeks (54 in the chiglitazar group and 27 in the sitagliptin group). We measured the spine lumbar BMD, hip BMD, fat mass (FM), fat-free mass (FFM), percent body fat (%BF), android FM, gynoid FM and skeleton muscle mass (SMM) using dual-energy X-ray absorptiometry (DEXA) and examined serum adiponectin (ADP) levels at baseline and the end of the study. Results: There were no significant changes in the BMD of the L2-4, femoral neck, trochanter or total hip as well as in the BMC after 24 weeks of treatment with chiglitazar or sitagliptin. After chiglitazar administration, the FM, gynoid FM and gynoid to total FM ratio were higher, while the android to total FM ratio and the android to gynoid FM ratio (AOI) were significantly lower. Sitagliptin intervention did not result in statistically significant differences in total fat loss, but it did cause significant decreases in %BF and AOI as well as increases in the FFM, gynoid to total FM ratio and SMM. The ADP levels had significantly negative associations with AOI in all eligible patients. Conclusion: The chiglitazar had no deleterious effects on BMD and resulted in body fat redistribution in untreated patients with T2DM. Trial Registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02173457).

Basal Insulin Reduces Glucose Variability and Hypoglycaemia Compared to Premixed Insulin in Type 2 Diabetes Patients: A Study Based on Continuous Glucose Monitoring Systems.

Aims: To examine the glycaemic variability and safety of basal and premixed insulin by using continuous glucose monitoring (CGM) systems. Methods: 393 patients with type 2 diabetes mellitus (T2DM) treated with basal or premixed insulin for more than 3 months were enrolled. Patients were classified into a basal insulin group or premixed insulin group according to their insulin regimens. CGMs were used for 72 h with their previous hypoglycaemic regimen unchanged. The following glycaemic parameters were calculated for each 24 h using CGM data. Results: Despite similar HbA1c and fasting C-peptide concentrations, glycaemic variability (GV), including the mean amplitude of glycaemic excursion (MAGE), standard deviation (SD) and coefficient of variation (CV), and the time below range (TBR) were significantly lower in the basal insulin group than these in the premixed insulin group. Night-time hypoglycaemia was lower in the basal insulin group than that in the premixed insulin group (p<0.01). Among participants with haemoglobin A1c (HbA1c) < 7%, the GV and TBR were higher in the premixed insulin group than that in the basal insulin group. Conclusion: Compared with basal insulin, the patients who use premixed insulin had higher GV, smaller TIR and an increased incidence of hypoglycaemia. For patients who use premixed insulin and with HbA1c < 7%, more attention needs to be given to hypoglycaemic events and asymptomatic hypoglycaemia. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03566472.

Comparative Evaluation of Chiglitazar and Sitagliptin on the Levels of Retinol-Binding Protein 4 and Its Correlation With Insulin Resistance in Patients With Type 2 Diabetes.

Aims: We evaluated the efficacy and significant changes in the levels of retinol-binding protein 4 (RBP-4) and insulin resistance in patients with type 2 diabetes mellitus (T2DM) treated with chiglitazar versus sitagliptin. Methods: Eighty-one T2DM patients with haemoglobin A1c (HbA1c) level of 7.5%-10.0% were selected. Based on the study criteria, patients were randomly assigned to receive chiglitazar (32 mg), chiglitazar (48 mg), or sitagliptin (100 mg) orally for 24 weeks. Sociodemographic and anthropometric characteristics, lipid profiles, glucose profiles, and serum RBP-4 levels were determined at baseline and at the end of the therapy. Results: After treatment for 24 weeks, significant changes in fasting blood glucose (FBG), fasting insulin (Fins), 2 h-blood glucose (2h-BG), the score values of insulin resistance/insulin secretion/ß cell function (HOMA-IR, HOMA-IS, and HOMA-ß), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), and RBP-4 levels were detected in patients with chiglitazar administration and sitagliptin administration. Changes in RBP-4 levels were positively correlated with changes in HOMA-IR and 2 h-BG in linear regression. Conclusions: Chiglitazar showed a greater improvement in parameters of diabetes than sitagliptin, and changes in serum RBP-4 levels were associated with changes in insulin-sensitizing parameters. Clinical Trial Registration: ClinicalTrials.gov, CT.gov identifier: NCT02173457.

Real-Time Flash Glucose Monitoring Had Better Effects on Daily Glycemic Control Compared With Retrospective Flash Glucose Monitoring in Patients With Type 2 Diabetes on Premix Insulin Therapy.

Background and Aims: To compare the effects of real-time and retrospective flash glucose monitoring (FGM) on daily glycemic control and lifestyle in patients with type 2 diabetes on premix insulin therapy. Methods and Results: A total of 172 patients using premix insulin, with HbA1c ≥ 7.0% (56 mmol/mol), or the time below the target (TBR) ≥ 4%, or the coefficient of variation (CV) ≥36% during the screening period, were randomly assigned to retrospective FGM (n = 89) or real-time FGM group (n = 83). Another two retrospective or real-time 14-day FGMs were performed respectively, 1 month apart. Both groups received educations and medication adjustment after each FGM. Time in range (3.9~10.0 mmol/l, TIR) increased significantly after 3 months in the real-time FGM group (6.5%) compared with the retrospective FGM group (-1.1%) (p = 0.014). HbA1c decreased in both groups (both p < 0.01). Real-time FGMs increased daily exercise time compared with the retrospective group (p = 0.002). Conclusions: Real-time FGM with visible blood glucose improves daily glycemic control and diabetes self-care behaviors better than retrospective FGM in patients with type 2 diabetes on premix insulin therapy. Clinical Trial Registration: https://clinicaltrials.gov/NCT04847219.

Thymosin beta-4 improves endothelial function and reparative potency of diabetic endothelial cells differentiated from patient induced pluripotent stem cells.

BACKGROUND: Prior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin ß-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction. METHODS AND RESULTS: Using dia-hiPSC-ECs as models of endothelial dysfunction, we determined the effect of Tb-4 on cell proliferation, senescence, cyto-protection, protein expression of intercellular adhesion molecule-1 (ICAM-1), secretion of endothelin-1 and MMP-1, mitochondrial membrane potential, and cyto-protection in vitro and angiogenic potential for treatment of ischemic limb disease in a mouse model of type 2 diabetes mellitus (T2DM) in vivo. We found that 600 ng/mL Tb4 significantly up-regulated AKT activity and Bcl-XL protein expression, enhanced dia-hiPSC-EC viability and proliferation, limited senescence, reduced endothelin-1 and MMP-1 secretion, and improved reparative potency of dia-hiPSC-ECs for treatment of ischemic limb disease in mice with T2DM. However, Tb4 had no effect on improving mitochondrial membrane potential and glycine homeostasis and reducing intercellular adhesion molecule-1 protein expression in dia-hiPSC-ECs. CONCLUSIONS: Tb-4 improves endothelial dysfunction through enhancing hiPSC-EC viability, reducing senescence and endothelin-1 production, and improves angiogenic potency in diabetes.

Effect of chiglitazar and sitagliptin on glucose variations, insulin resistance and inflammatory-related biomarkers in untreated patients with type 2 diabetes.

AIMS: To evaluate glycemic variations, changes in insulin resistance and oxidative stress after chiglitazar or sitagliptin treatment in untreated patients with type 2 diabetes mellitus (T2DM). METHODS: Based on the study inclusion and exclusion criteria, 81 patients with T2DM were randomly divided to receive chiglitazar or sitagliptin treatment for 24 weeks. Continuous glucose monitoring (CGM) systems were conducted for 72 h in eligible patients. We analyzed the following glycemic variation parameters derived from the CGM data and measured the serum levels of hemoglobin A1c (HbA1c), fasting blood glucose (FBG), 2-h postprandial blood glucose (2-h PBG), fasting insulin (Fins) and inflammatory-related indicators at baseline and the end of the study. RESULTS: After treatment for 24 weeks, our data showed a similar reduction in HbA1c between chiglitazar and sitagliptin. The 24-h mean blood glucose (MBG), standard deviation (SD) and mean amplitude of glycemic excursion (MAGE) were significantly decreased, and the time in range (TIR) was increased after chiglitazar and sitagliptin therapy. Chiglitazar administration led to significant improvement in insulin resistance/insulin secretion (HOMA-IR, HOMA-IS), interleukin-6 (IL-6), prostaglandin F2α (PGF-2α), 17-hydroxyprogesterone (17-OHP) and adiponectin (ADP) score values compared with sitagliptin administration. CONCLUSIONS: Chiglitazar therapy effectively reduced glucose variation and showed a larger improvement in insulin resistance and inflammatory parameters than sitagliptin.

Evaluating Glycemic Control During Basalin or Lantus Administration in Adults With Controlled Type 2 Diabetes Mellitus Using Continuous Glucose Monitoring.

Aim: This study aims at evaluating glycemic control during Basalin or Lantus administration in adults with controlled type 2 diabetes mellitus using continuous glucose monitoring system (CGM). Methods: 47 patients with well-controlled T2DM using both Basalin and oral hypoglycemic drugs were recruited. CGM were applied from day 1 to day 3 with the unchanged dose of Basalin and then removed from day 4. A washout was performed with Lantus at the same dose as Basalin from day 4 to day 10. Then patients were continued to install the CGM under Lantus administration from day 11 to day 13. Variables of CGM, such as the area under the curve (AUC) for both hyperglycemia and hypoglycemia, 24h mean blood glucose (24h MBG), 24h standard deviation of blood glucose (24h SDBG), 24h mean amplitude of glycemic excursion (24h MAGE), PT (percentage of time), and time in range (TIR), were calculated and compared between Basalin group and Lantus group. Results: The group of Lantus showed lower 24h MBG (p<0.01), 24h MAGE (p<0.05), and lower 24h SDBG (p<0.01) than the Basalin group. Lantus-treated patients had a lower PT and AUC when the cut-off point for blood glucose was 10 mmol/L (p<0.05) and 13.9 mmol/L (p<0.05), respectively. In this study, no patient developed symptomatic hypoglycemia, few hypoglycemia was observed and there was no difference of hypoglycemia between the two groups. Conclusion: In patients with well-controlled T2DM who were treated with insulin glargine, Lantus group showed lower MBG, GV, and lower PT (BG > 10.0 mmol/L, BG > 13.9 mmol/L) than Basalin group. In summary, for T2DM population with HbA1c ≤ 7%, Lantus may be a better choice compared with Basalin.

Preventive Effect of Gonggan (Citrus Reticulata Blanco Var. Gonggan) Peel Extract on Ethanol/HCl-Induced Gastric Injury in Mice via an Anti-oxidative Mechanism.

Gonggan (Citrus reticulata Blanco var. gonggan) is one of the most popular citruses. In this study, the effect of Gonggan peel extract (GPE) on gastric injury was investigated. The components in GPE were analysed by HPLC and the gastric injury model in mice was established by ethanol/hydrochloric acid. After treatment by GPE, the pathological changes of gastric tissue were observed by optical microscope. The levels of oxidative stress and inflammation were measure by kit. And the mRNA expression of related gene was determined by qPCR assay. HPLC result showed GPE mainly contained the flavonoids narirutin, hesperidin, nobiletin, tangeretin and 5-demethylnobiletin. Morphological and pathological analysis of gastric tissue revealed that GPE could relieve gastric injury. Also, GPE increased the levels of SOD, GSH-Px, and CAT and decreased the level of MDA. Moreover, GPE decreased the levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1ß, and IL-6 to suppress inflammation. In addition, the q-PCR results showed that GPE upregulated the mRNA expression of SOD1, SOD2, γ-GCS, GSH-Px, CAT, and IκBα and downregulated the mRNA expression of NF-κB. In conclusion, GPE alleviated gastric injury caused by ethanol/hydrochloric acid by inhibiting oxidative stress and the inflammatory response. The mechanism by which GPE protects gastric tissues may involve the antioxidative pathway. Therefore, GPE has great potential to be developed as a product to prevent gastric injury.

Effects of GLP-1 Receptor Agonists on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus: A 52-Week Clinical Study.

INTRODUCTION: Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM. METHODS: In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n = 19), dulaglutide group (n = 19), insulin glargine group (n = 10), and placebo (n = 17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry. RESULTS: Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11 ± 0.24% vs. 7.40 ± 0.16%, P = 0.007), dulaglutide (8.77 ± 0.37% vs. 7.06 ± 0.28%, P < 0.001), and insulin glargine (8.57 ± 0.24% vs. 7.23 ± 0.25%, P < 0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P = 0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P < 0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P < 0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P < 0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P = 0.001). CONCLUSIONS: Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.

Diabetic Endothelial Cells Differentiated From Patient iPSCs Show Dysregulated Glycine Homeostasis and Senescence Associated Phenotypes.

Induced pluripotent stem cells derived cells (iPSCs) not only can be used for personalized cell transfer therapy, but also can be used for modeling diseases for drug screening and discovery in vitro. Although prior studies have characterized the function of rodent iPSCs derived endothelial cells (ECs) in diabetes or metabolic syndrome, feature phenotypes are largely unknown in hiPSC-ECs from patients with diabetes. Here, we used hiPSC lines from patients with type 2 diabetes mellitus (T2DM) and differentiated them into ECs (dia-hiPSC-ECs). We found that dia-hiPSC-ECs had disrupted glycine homeostasis, increased senescence, and impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. These signature phenotypes will be helpful to establish dia-hiPSC-ECs as models of endothelial dysfunction for understanding molecular mechanisms of disease and for identifying and testing new targets for the treatment of endothelial dysfunction in diabetes.

LncRNA LINC00958 Activates mTORC1/P70S6K Signalling Pathway to Promote Epithelial-Mesenchymal Transition Process in the Hepatocellular Carcinoma.

The study aimed to investigate the influence of LINC00958 on the EMT process of hepatocellular carcinoma (HCC). In our study, The LINC00958 was up-regulated in HCC tissues and cell lines. LINC00958 silencing inhibited cell proliferation, migration, and EMT process of HCC. The analysis of TCGA and StarBase showed that NUDT19 was a direct target of LINC00958 and was positively regulated by LINC00958. Besides, NUDT19 activated mTORC1/P70S6K signalling pathway. Both NUDT19 overexpression and mTORC1 activator MYH1485 reversed the inhibitory effect of LINC00958 silencing on proliferation, migration, and EMT process of HCC. In conclusion, LINC00958 silencing inhibited the proliferation, migration, and EMT process of HCC via inhibiting NUDT19 mediated mTORC1/P70S6K signalling pathway.

Flash Glucose Monitoring Improves Glucose Control in People with Type 2 Diabetes Mellitus Receiving Anti-diabetic Drug Medication.

OBJECTIVE: To investigate the effects of Flash Glucose Monitoring (FGM) on glucose profile in people with Type 2 Diabetes Mellitus (T2DM) receiving anti-diabetic drug medication. METHODS: This is a prospective non-randomized uncontrolled study. 111 people with T2DM were enrolled and received FGM for 14 days. There was no change of anti-diabetic medication during the 14 days. The plasma glucose concentration on day 2 was used as baseline and the day 13 was considered as study end point. The parameters to compare were mean plasma glucose (MPG), glucose variations, and incidence of hypoglycemia during the FGM period. The multivariate linear stepwise regression analysis was applied to determine the independent factors that affect MPG difference. RESULTS: This study analyzed the data of a total of 111 people with T2DM (male 60 and female 51). The general clinical data of these patients were as follows: age: 65.0±6.7 years old; duration of diabetes: 11.6±6.8 years; HbA1c: 61.2±13.3 mmol/mol; body mass index (BMI): 25.2±3.2 kg/m². Using FGM, people with T2DM were able to change daily diet and exercise through which significant reductions in MPG on days 12 or 13 were achieved as compared with that of day 2 (P=0.04 or P=0.003, respectively). The glucose variations, such as standard deviation (SD) of plasma glucose, coefficient of variation (CV), and mean amplitude of glycemic excursion (MAGE), progressively declined starting from day 6 as compared with baseline (P=0.016, P=0.003, or P=0.012, respectively). The incremental area over the curve (AOC) of the hypoglycemia (<3.9 mmol/L) had a significant reduction starting from the day 3 (P=0.001). When people with T2DM were divided into 3 groups based on the tertile of HbA1c (high, middle, and low concentrations), the reduction of MPG in patients with high concentration of HbA1c were much larger than that in middle and low concentration group patients (P=0.001 for both). The incidence of hypoglycemia was improved in the low concentration group (P=0.017). The optimal frequency of scanning time required to maintain euglycemia was 11.7 times/day as calculated by the receiver operating characteristic (ROC) analysis. CONCLUSION: Using FGM to monitor glucose concentration at 11.7 times/day, people with T2DM can achieve a better glucose control in addition to anti-diabetic drug medication through changing daily diet and exercise, especially in patients with high concentration of HbA1c (>66.1 mmol/mol).

Effect of Dapagliflozin on Glycemic Variability in Patients with Type 2 Diabetes under Insulin Glargine Combined with Other Oral Hypoglycemic Drugs.

AIM: To evaluate the effect of an inhibitor of sodium-glucose cotransporter 2 (SGLT-2 inhibitor, dapagliflozin) on glycemic variability in type 2 diabetes mellitus (T2D) under insulin glargine combined with oral hypoglycemic drugs, using a continuous glucose monitoring system (CGMS). METHODS: This prospective, self-controlled, single-center clinical trial recruited 36 patients with T2D under combined insulin glargine and oral hypoglycemic drugs. General clinical data were collected. Fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated hemoglobin (HbA1c), and C-peptide levels were assessed before and four weeks of dapagliflozin (10 mg per day) treatment. Blood glucose was monitored for 72 hours before and after treatment using CGMS. RESULTS: After treatment with dapagliflozin, FBG decreased from 6.74 ± 1.78 to 5.95 ± 1.13 mmol/L (p < 0.05); PBG decreased from 13.04 ± 2.99 to 10.92 ± 3.26 mmol/L (p < 0.05); HbA1c decreased from 7.37 ± 0.96% to 6.94 ± 0.80%. The proportion of patients with HbA1c < 7% increased from 27.8% to 58.3%, and the proportion of patients with HbA1c < 7% and without level 2 hypoglycemia increased from 27.8% to 55.6% (p < 0.05). CGMS data showed reduction of the 24 h MBG, MAGE, time-above-range (TAR, >10 mmol/L), high blood glucose index (HBGI), glucose management indicator (GMI), and incremental area under the curve of the glucose level more than 10 mmol/L (AUC > 10) and an increase of time-in-range (TIR, 3.9-10 mmol/L) with treatment. Homeostasis model assessment for pancreatic beta-cell function (HOMA-beta) increased significantly with treatment (p < 0.05), and fewer insulin doses were required after the treatment, without increasing in hypoglycemia and urinary tract infection. Further, a stratified analysis showed that patients with higher pretreatment HbA1c and waist-to-hip ratio (WHR) had greater improvement in glycemic control. CONCLUSION: Dapagliflozin may reduce blood glucose levels, ameliorate glycemic variability, and improve pancreatic beta-cell function in patients with T2D under insulin glargine combined with other oral hypoglycemic drugs, especially in those with poor glucose control and abdominal obesity.

Relationship Between Estimated Glycosylated Hemoglobin Using Flash Glucose Monitoring and Actual Measured Glycosylated Hemoglobin in a Chinese Population.

INTRODUCTION: The aim of this study was to investigate the relationship between actual measured glycated hemoglobin (HbA1c) and estimated glycated hemoglobin (EA1c) in the flash glucose monitoring (FGM) system in Chinese patients with type 2 diabetes. METHODS: This study was conducted in Nanjing First Hospital. Each patient used FGM twice in a 3-month period (during the first 14 days immediately after baseline and during a second 14-day period from days 76 to 90 after baseline). HbA1c measurements were made using a high-performance liquid chromatography assay before the start of the first FGM period (baseline) and at the end of the second FGM period. RESULTS: A total of 74 patients (35 men; mean age ± standard deviation [SD] 67.6 ± 5.2 years) were enrolled in the study. The mean (± SD) duration of diabetes was 11.9 ± 7.8 months. The first and second HbA1c measurements were both higher than the EA1c (both p < 0.001). Mean glucose (MG) gradually decreased over time and was the lowest on day 14. Linear regression showed that only HbA1c at baseline affected the gap between HbA1c and EA1c (ß = 0.319, p = 0.01) when the educational level, age, gender, duration of diabetes, body mass index, HbA1c at baseline, and number of scans daily were included as independent variables. The best model for calculating EA1c was EA1c% = MG mmol/L × 0.669 - 0.213 × 8th MG + 3.351 when MG > 9.7 mmol/L, and EA1c % = (MG mmol/L + 2.590)/1.590 when MG ≤ 9.7 mmol/L. The correlation coefficient for EA1c and HbA1c in this model (model 7) is higher than that reported the original model in the FGM system 1 (0.955 vs. 0.822, respectively; p < 0.001). CONCLUSIONS: The EA1c used by FreeStyle Libre™ is lower than the actual measured HbA1c. Improvement in the glucose levels during FGM in these patients may contribute to the lowering of EA1c. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov, number NCT03785301.

The Accuracy and Precision of the Continuously Stored Data from Flash Glucose Monitoring System in Type 2 Diabetes Patients during Standard Meal Tolerance Test.

BACKGROUND: The purpose of this study was to investigate the accuracy of the continuously stored data from the Abbott FreeStyle Libre flash glucose monitoring (FGM) system in Chinese diabetes patients during standard meal tests when glucose concentrations were rapidly changing. Subjects and Methods. Interstitial glucose levels were monitored for 14 days in 26 insulin-treated patients with type 2 diabetes using the FGM system. Standard meal tests were conducted to induce large glucose swings. Venous blood glucose (VBG) was tested at 0, 30, 60, and 120 min after standard meal tests in one middle day of the first and second weeks, respectively. The corresponding sensor glucose values were obtained from interpolating continuously stored data points. Assessment of accuracy was according to recent consensus recommendations with median absolute relative difference (MARD) and Clarke and Parkes error grid analysis (CEG and PEG). RESULTS: Among 208 paired sensor-reference values, 100% were falling within zones A and B of the Clarke and Parkes error grid analysis. The overall MARD was 10.7% (SD, 7.8%). Weighted least squares regression analysis resulted in high agreement between the FGM sensor glucose and VBG readings. The overall MTT results showed that FGM was lower than actual VBG, with MAD of 22.1 mg/dL (1.2 mmol/L). At VBG rates of change of -1 to 0, 0 to 1, 1 to 2, and 2 to 3 mg/dl/min, MARD results were 11.4% (SD, 8.7%), 9.4% (SD, 6.5%), 9.9% (SD, 7.5%), and 9.5% (SD, 7.7%). At rapidly changing VBG concentrations (>3 mg/dl/min), MARD increased to 19.0%, which was significantly higher than slow changing BG groups. CONCLUSIONS: Continuously stored interstitial glucose measurements with the FGM system were found to be acceptable to evaluate VBG in terms of clinical decision during standard meal tests. The continuously stored data from the FGM system appeared to underestimate venous glucose and performed less well during rapid glucose changes.