Changes In Plasma Glucose Research Articles

The effect of vitamin D3 supplementation on the incidence of type 2 diabetes in healthy older adults not at high risk for diabetes (FIND): a randomised controlled trial.

Vitamin D insufficiency is associated with an elevated risk of type 2 diabetes, but evidence from randomised trials on the benefits of vitamin D supplementation is limited, especially for average-risk populations. The Finnish Vitamin D Trial (FIND) investigated the effects of vitamin D3 supplementation at two different doses on the incidence of type 2 diabetes in a generally healthy older adult population. FIND was a 5 year randomised placebo-controlled, parallel-arm trial among 2271 male and female participants aged ≥60 years and ≥65 years, respectively, from a general Finnish population who were free of CVD or cancer and did not use diabetes medications. The study had three arms: placebo, 1600 IU/day of vitamin D3 or 3200 IU/day of vitamin D3. A non-study group statistician carried out sex-stratified simple randomisation in a 1:1:1 ratio, based on computerised random number generation. The participants, investigators and study staff were masked to group assignment. National health registries were used to collect event data. A representative subcohort of 505 participants had more detailed in-person investigations at months 0, 6, 12 and 24. During the mean follow-up of 4.2 years, there were 38 (5.0%), 31 (4.2%) and 36 (4.7%) type 2 diabetes events in the placebo (n=760), 1600 IU/day vitamin D3 (n=744; vs placebo: HR 0.81; 95% CI 0.50, 1.30) and 3200 IU/day vitamin D3 (n=767; vs placebo: HR 0.92, 95% CI 0.58, 1.45) arms, respectively (p-trend=0.73). When the two vitamin D3 arms were combined and compared with the placebo arm, the HR was 0.86 (95% CI 0.58, 1.29). In the analyses stratified by BMI (<25 kg/m2 [n=813, number of type 2 diabetes events=12], 25-30 kg/m2 [n=1032, number of events=38], ≥30 kg/m2 [n=422, number of events=54]), the HRs in the combined vitamin D3 arms vs the placebo were 0.43 (95% CI 0.14, 1.34), 0.97 (0.50, 1.91) and 1.00 (0.57, 1.75), respectively (p-interaction <0.001). In the subcohort, the mean (SD) baseline serum 25-hydroxyvitamin D3 (25(OH)D3) concentration was 74.5 (18.1) nmol/l. After 12 months, the concentrations were 72.6 (17.7), 99.3 (20.8) and 120.9 (22.1) nmol/l in the placebo, 1600 IU/day vitamin D3 and 3200 IU/day vitamin D3 arms, respectively. In the subcohort, no differences were observed in changes in plasma glucose or insulin concentrations, BMI or waist circumference during the 24 month follow-up (p values ≥0.19). Among generally healthy older adults who are not at high risk for diabetes and who have serum 25(OH)D3 levels that are sufficient for bone health, vitamin D3 supplementation did not significantly reduce the risk of developing diabetes. ClinicalTrials.gov NCT01463813.

Efficacy of Alogliptin/Metformin Fixed-Dose Combination Tablets and Vildagliptin/Metformin Fixed-Dose Combination Tablets on Glycemic Control in Real-World Clinical Practice for the Patients with Type 2 Diabetes: A Multicenter, Open-Label, Randomized, Parallel Group, Comparative Trial.

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

The effect of blood flow-restrictive resistance training on the risk of atherosclerotic cardiovascular disease in middle-aged patients with type 2 diabetes: a randomized controlled trial.

The aim of this study was to investigate the effects of blood flow-restrictive resistance training (BFR-RT) on improving metabolic abnormalities, blood pressure (BP), obesity, and 10-year atherosclerotic cardiovascular disease (ASCVD) risk in middle-aged patients with type 2 diabetes mellitus (T2DM). We conducted a parallel-group, single blind randomized controlled trial. Participants who met the inclusion criteria were randomly divided into control group, BFR-RT group and aerobic exercise (AE) group. Control group received health education and follow-up; Two exercise groups received supervised collective training for a period of six months, three times per week. AE group trained at moderate-intensity for 60 minutes each time, while BFR-RT group trained at low-intensity for 40 minutes each time. The primary outcomes were change in 10-year ASCVD risk index and level, and the secondary outcomes included changes in fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), blood lipids, BP, and obesity level within and across the three groups at baseline, the third and sixth months of intervention. Among 93 individuals (control group, n=31; AE, n=30; BFR-RT, n=32) were analyzed. At baseline, there were no significant differences in various indicators among the three groups (p>0.05). After intervention, the 10-year ASCVD risk index and risk level of both exercise groups significantly decreased compared to the control group and baseline (p<0.05), and the risk reduction became more pronounced over time. In the sixth month of intervention, the 10-year ASCVD risk index in the AE group decreased by 27.40%, and that in the BFR-RT group decreased by 26.78%. Meanwhile, apart from lipoprotein (a) and diastolic blood pressure, both exercise groups showed significant improvements in FPG, HbA1c, dyslipidemia, systolic blood pressure, and obesity indicators compared to the control group and baseline (p<0.05). There was no significant difference in various indicators between the two exercise groups (p>0.05). BFR-RT could reduce the 10-year ASCVD risk in middle-aged T2DM patients for by improving metabolic abnormalities, BP and obesity, and its effect was similar to that of moderate-intensity AE. https://www.chictr.org.cn/showproj.html?proj=178886, identifier ChiCTR2300074357.

Effects of vitamin D supplementation on diabetic foot ulcer healing: a meta-analysis.

To systematically review the effect of vitamin D supplementation on diabetic foot ulcer (DFU) healing. The PubMed, Web of Science, Science direct, Ebsco host, CNKI, WanFang, VIP, and CBM databases were electronically searched to collect randomized controlled trials (RCTs) on the impact of vitamin D supplementation on DFUs from inception to 19 November 2022. Two researchers independently screened the literature, extracted the data and assessed the risk of bias of the included studies. Meta-analysis was then performed by using RevMan 5.3 software. A total of seven studies involving 580 patients were included. The results of meta-analysis showed that compared with control group, the wound healing efficiency rate (RR = 1.42, 95%CI 1.03 to 1.95, P= 0.03) and wound reduction rate (MD = 13.11, 95%CI 4.65 to 21.56, P < 0.01) of the experimental group were higher; the change values of the wound area (MD = -3.29, 95%CI -4.89 to 1.70, P < 0.01) and 25 (OH) D (MD = 9.63, 95%CI 6.96 to 12.31, P < 0.01) were larger. Supplementation of vitamin D on DFU patients can improve glucose metabolism and insulin indexes: hemoglobin A1c (MD = -0.44, 95%CI -0.62 to -0.26, P < 0.01), fasting insulin (MD = -3.75, 95%CI -5.83 to -1.67, P < 0.01), HOMA - β (MD = -5.14, 95%CI -8.74 to -1.54, P < 0.01), and quantitative insulin sensitivity check index (MD = 0.02, 95%CI 0.01 to 0.02, P < 0.01). It can also improve inflammation and oxidative stress markers: high sensitivity C-reactive protein (MD = -0.83, 95%CI -1.06 to -0.59, P < 0.01), erythrocyte sedimentation rate (MD = -15.74, 95%CI -21.78 to -9.71, P<0.01), nitric oxide (MD = 1.81, 95%CI 0.07 to 3.55, P= 0.04), and malondialdehyde (MD = -0.43, 95%CI -0.61 to -0.24, P<0.01). There was no statistically significant difference in changes of fasting plasma glucose, homeostasis model of assessment-insulin resistance, total antioxidant capacity, glutathione, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol (P>0.05). The current evidence suggests that vitamin D supplementation can significantly promote DFU healing by lowering blood sugar and alleviating inflammation and oxidative stress. Key messages What is already known on this topic Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus, with high morbidity, mortality and resource utilization. Vitamin D has the effect of lowering blood sugar, improving insulin sensitivity, and increasing anti-inflammatory response. Clinical research on vitamin D supplementation for the treatment of DFU is increasing, but due to the lack of combing and integration, the actual efficacy of vitamin D in patients is unclear. What this study adds This meta-analysis has shown that vitamin D supplementation can significantly promote DFU healing by lowering blood glucose and alleviating inflammation and oxidative stress. How this study might affect research, practice or policy This study preliminarily found the effectiveness of vitamin D supplementation on the healing of DFU, which can provide a reference for the treatment of DFU by medical staff.

A Pregnancy and Postnatal RCT Among Women With Gestational Diabetes Mellitus and Overweight/Obesity: The PAIGE2 Study.

This study examined the influence of a pregnancy and postnatal multicomponent lifestyle intervention for women with gestational diabetes mellitus (GDM) and overweight/obesity from 6 weeks to 12 months postnatal. The primary outcome was weight at 12 months. Secondary outcomes included change in body mass index (BMI), waist circumference (WC) and fasting plasma glucose (FPG). The study involved 235 pregnant women with GDM and BMI ≥ 25 kg/m2 during pregnancy. Intervention components included an educational session, activity tracker (Fitbit), monthly phone calls, weekly motivational text messages, 12-week voucher for a commercial weight management organization and anthropometric, biochemical, and clinical measurements taken at 6 weeks, 6 months, and 12 months postnatal. The control group received routine local maternity care. A mean weight change of -2.0 (SD 7.1) kg was observed in the intervention group compared with -0.6 (SD 8.0) kg in the control group, difference -1.4 (95% CI -4.4, 1.5) kg from 6 weeks to 12 months postnatal, but this was not statistically significant (P = .34). Neither were significant differences obtained for any secondary outcomes: BMI -0.6 (-1.6, 0.5) kg/m2, WC -1.0 (-5.1, 3.2) cm and FPG 0.07 (-0.15, 0.29) mmol/L. This lifestyle intervention among women with overweight/obesity and GDM resulted in a statistically nonsignificant 1.4 kg greater weight loss compared with routine care at 12 months postnatal. Further research is needed to understand how the different components of this lifestyle intervention might be better applied to elicit more successful results.

Characterizing and identifying of miRNAs involved in berberine modulating glucose metabolism of Megalobrama amblycephala.

The present study, as one part of a larger project that aimed to investigate the effects of dietary berberine (BBR) on fish growth and glucose regulation, mainly focused on whether miRNAs involve in BBR's modulation of glucose metabolism in fish. Blunt snout bream Megalobrama amblycephala (average weight of 20.36 ± 1.44g) were exposed to the control diet (NCD, 30% carbohydrate), the high-carbohydrate diet (HCD, 43% carbohydrate) and the berberine diet (HCB, HCD supplemented with 50mg/kg BBR). After 10weeks' feeding trial, intraperitoneal injection of glucose was conducted, and then, the plasma and liver were sampled at 0h, 1h, 2h, 6h, and 12h. The results showed the plasma glucose levels in all groups rose sharply and peaked at 1h after glucose injection. Unlike the NCD and HCB groups, the plasma glucose in the HCD group did not decrease after 1h, while remained high level until at 2h. The NCD group significantly increased liver glycogen content at times 0-2h compared to the other two groups and then liver glycogen decreased sharply until at times 6-12h. To investigate the role of BBR that may cause the changes in plasma glucose and liver glycogen, miRNA high-throughput sequencing was performed on three groups of liver tissues at 2h time point. Eventually, 20 and 12 differentially expressed miRNAs (DEMs) were obtained in HCD vs NCD and HCB vs HCD, respectively. Through function analyzing, we found that HCD may affect liver metabolism under glucose loading through the NF-κB pathway; and miRNAs regulated by BBR mainly play roles in adipocyte lipolysis, niacin and nicotinamide metabolism, and amino acid transmembrane transport. In the functional exploration of newly discovered novel:Chr12_18892, we found its target gene, adenylate cyclase 3 (adcy3), was widely involved in lipid decomposition, amino acid metabolism, and other pathways. Furthermore, a targeting relationship of novel:Chr12_18892 and adcy3 was confirmed by double luciferase assay. Thus, BBR may promote novel:Chr12_18892 to regulate the expression of adcy3 and participate in glucose metabolism.

The effect of microbiome-modulating therapeutics on glucose homeostasis in metabolic syndrome: A systematic review, meta-analysis, and meta-regression of clinical trials

BackgroundMetabolic syndrome (MetS) is a chronic disorder featuring overweight/obesity, high blood pressure, and dysfunction of lipid and carbohydrate metabolism. Microbiome-modulating probiotics, prebiotics, synbiotics and fecal microbiota transplant (FMT) are promising adjunct therapies for improving parameters of glucose homeostasis and insulinemia. MethodsWe conducted a comprehensive systematic review, meta-analyses, and meta-regressions to investigate the effect of the abovementioned microbiome therapies on various biomarkers after screening clinical trials published through April 2023. We pooled data using random effects meta-analyses, reporting them as mean differences (MDs) with 95 % confidence intervals (CIs), and conducting univariate linear model meta-regressions. ResultsData from 21 trial comparisons across 19 studies (n = 911) revealed that, compared to placebo/control, microbiome-modulating therapies were associated with statistically significant changes in fasting plasma glucose (MD: 4.03 mg/dL [95%CI: 6.93; −1.13]; p effect = 0.006, I2 = 89.8 %), and fasting insulin (MD: 2.56 μU/mL [95%CI: 4.28; −0.84]; p effect = 0.004, I2 = 87.9 %), but not insulin resistance or sensitivity indices and HbA1c. Age, baseline BMI, baseline biomarker value, pro/synbiotic dosage, trial duration, nutraceutical type, and WHO region were factors affecting the efficacy of these interventions at producing changes in biomarkers, signaling the potential role of personalized precision medicine adjunct therapy for deranged glucose homeostasis in patients with MetS. Nevertheless, presence of heterogeneity calls for further investigation before their clinical application. ConclusionsProbiotics, prebiotics, synbiotics and FMT supplementation improved fasting glucose and insulin in patients with MetS. Further large-scale and high-quality trials are required before potential clinical applications.

Deep serum lipidomics identifies evaluative and predictive biomarkers for individualized glycemic responses following low-energy diet-induced weight loss: a PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) substudy

BackgroundWeight loss through lifestyle interventions, notably low-energy diets, offers glycemic benefits in populations with overweight-associated prediabetes. However, >50% of these individuals fail to achieve normoglycemia after weight loss. Circulating lipids hold potential for evaluating dietary impacts and predicting diabetes risk. ObjectivesThis study sought to identify serum lipids that could serve as evaluative or predictive biomarkers for individual glycemic changes following diet-induced weight loss. MethodsWe studied 104 participants with overweight-associated prediabetes, who lost ≥8% weight via a low-energy diet over 8 wk. High-coverage lipidomics was conducted in serum samples before and after the dietary intervention. The lipidomic recalibration was assessed using differential lipid abundance comparisons and partial least squares discriminant analyses. Associations between lipid changes and clinical characteristics were determined by Spearman correlation and Bootstrap Forest of ensemble machine learning model. Baseline lipids, predictive of glycemic parameters changes postweight loss, were assessed using Bootstrap Forest analyses. ResultsWe quantified 439 serum lipid species and 9 related organic acids. Dietary intervention significantly reduced diacylglycerols, ceramides, lysophospholipids, and ether-linked phosphatidylethanolamine. In contrast, acylcarnitines, short-chain fatty acids, organic acids, and ether-linked phosphatidylcholine increased significantly. Changes in certain lipid species (e.g., saturated and monounsaturated fatty acid-containing glycerolipids, sphingadienine-based very long-chain sphingolipids, and organic acids) were closely associated with clinical glycemic parameters. Six baseline bioactive sphingolipids primarily predicted changes in fasting plasma glucose. In addition, a number of baseline lipid species, mainly diacylglycerols and triglycerides, were predictive of clinical changes in hemoglobin A1c, insulin and homeostasis model assessment of insulin resistance. ConclusionsNewly discovered serum lipidomic alterations and the associated changes in lipid-clinical variables suggest broad metabolic reprogramming related to diet-mediated glycemic control. Novel lipid predictors of glycemic outcomes could facilitate early stratification of individuals with prediabetes who are metabolically less responsive to weight loss, enabling more tailored intervention strategies beyond 1-size-fits-all lifestyle modification advice.The PREVIEW lifestyle intervention study was registered at clinicaltrials.gov as NCT01777893 (https://clinicaltrials.gov/study/NCT01777893).

Effects of ginseng berry saponins from panax ginseng on glucose metabolism of patients with prediabetes: A randomized, double-blinded, placebo-controlled, crossover trial

BackgroundPrediabetes strongly increases the risk of type 2 diabetes and cardiovascular events. However, lifestyle intervention, the first-line treatment for prediabetes currently, was inconsistently beneficial for glucose metabolism, and the conventional medicines, such as metformin, is controversial for prediabetes due to the possible side effects. PurposeThis study was designed to evaluate the effects of Zhenyuan Capsule, a Chinese patented medicine consisting of ginseng berry saponins extracted from the mature berry of Panax Ginseng, on the glucose metabolism of prediabetic patients as a complementary therapy. Study design and methodsIn this randomized, double-Blinded, placebo-controlled, crossover trial, 195 participants with prediabetes were randomized 1:1 to receive either placebo followed by Zhenyuan Capsule, or vice versa, alongside lifestyle interventions. Each treatment period lasted 4 weeks with a 4-week washout period in between. The primary outcomes were the changes in fasting plasma glucose (FPG) and 2-h postprandial plasma glucose (2-h PG) from baseline. Secondary outcomes includes the changes in fasting and 2-h postprandial insulin and C-peptide, the homeostatic model assessment-insulin resistance (HOMA-IR) index and quantitative insulin sensitivity check index (QUICKI) from baseline. Blood lipids and adverse events were also assessed. ResultsCompared with placebo, Zhenyuan Capsule caused remarkable reduction in 2-h PG (-0.98 mmol/l) after adjusting treatment order. Zhenyuan Capsule also reduced the fasting and 2-h postprandial levels of insulin and C-peptide, lowered HOMA-IR index (-1.26), and raised QUICKI index (+0.012) when compared to placebo. Additionally, a significant increase in high density lipoprotein cholesterol (HDL-C; +0.25 mmol/l) was found in patients with Zhenyuan Capsule. No serious adverse event occurred during the study. ConclusionsAmong prediabetic patients, Zhenyuan Capsule further reduced 2-h PG level, alleviated insulin resistance and raised HDL-C level on the background of lifestyle interventions. The study protocol is registered with the Chinese Clinical Trial Registry (ChiCTR2000034000).

Dietary glycemic index and glycemic load predict longitudinal change in glycemic and cardio-metabolic biomarkers among old diabetic adults living in a resource-poor country

This study aims to investigate longitudinal associations between the dietary glycemic index (GI) and glycemic load (GL) and changes in glycemic and cardio-metabolic outcomes. A 28-month retrospective cohort study included 110 Vietnamese diabetic patients, collecting their dietary GI and GL values along with blood biochemical data from baseline 24-h dietary recall and medical records. Latent class growth modelling identified three distinct HbA1c trajectories during the follow-up period, with 51% of patients achieving good glycemic control. The adjusted linear mixed-effect model showed that 1 unit increase in logarithms in dietary GL was associated with a 0.14% increase in the log-HbA1c. Among poorly controlled diabetic patients, baseline GL values were positively correlated with increases in HbA1c; GI showed effects on changes in fasting plasma glucose and the triglyceride-glucose (TyG) index. No significant association was observed in patients with good glycemic control.

Comparative efficacy and safety of weekly tirzepatide versus weekly insulin in type 2 diabetes: A network meta-analysis of randomized clinical trials.

To compare the efficacy and safety profiles of recent innovations in type 2 diabetes mellitus (T2DM), which include once-weekly formulations such as tirzepatide, a dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist, and once-weekly insulin options such as icodec and basal insulin Fc. A systematic search of the PubMed, Scopus, Cochrane, and Web of Science databases was conducted. The network meta-analysis protocol was registered at OSF registries (https://osf.io/gd67x). The primary outcome of interest was change in glycated haemoglobin (HbA1c), with change in fasting plasma glucose (FPG), body weight, incidence of hypoglycaemia, and treatment discontinuation as secondary outcomes. Tirzepatide exhibited superior efficacy in reducing HbA1c levels compared with insulin therapies, with the 15-mg dose showing the most significant reduction (mean difference [MD] -1.27, 95% confidence interval [CI] -1.49; -1.0). In terms of FPG reduction, tirzepatide 15 mg ranked highest (MD -0.70, 95% CI -1.05; -0.34), followed by tirzepatide 10 mg and 5 mg. Additionally, tirzepatide led to substantial weight loss, with the 15-mg dose exhibiting the most pronounced effect (MD -12.13, 95% CI -13.98; -10.27). However, a higher incidence of adverse events (AEs) and treatment discontinuation were associated with tirzepatide, particularly at higher doses. Tirzepatide, particularly at higher doses, demonstrates superior efficacy in lowering HbA1c and reducing hypoglycaemia risk compared with weekly insulin. However, its use is also associated with a higher incidence of AEs and treatment discontinuation.

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Assessing heterogeneity in surrogacy using censored data.

Determining whether a surrogate marker can be used to replace a primary outcome in a clinical study is complex. While many statistical methods have been developed to formally evaluate a surrogate marker, they generally do not provide a way to examine heterogeneity in the utility of a surrogate marker. Similar to treatment effect heterogeneity, where the effect of a treatment varies based on a patient characteristic, heterogeneity in surrogacy means that the strength or utility of the surrogate marker varies based on a patient characteristic. The few methods that have been recently developed to examine such heterogeneity cannot accommodate censored data. Studies with a censored outcome are typically the studies that could most benefit from a surrogate because the follow-up time is often long. In this paper, we develop a robust nonparametric approach to assess heterogeneity in the utility of a surrogate marker with respect to a baseline variable in a censored time-to-event outcome setting. In addition, we propose and evaluate a testing procedure to formally test for heterogeneity at a single time point or across multiple time points simultaneously. Finite sample performance of our estimation and testing procedure are examined in a simulation study. We use our proposed method to investigate the complex relationship between change in fasting plasma glucose, diabetes, and sex hormones using data from the diabetes prevention program study.

Gluco-metabolic response to exogenous oxytocin in totally pancreatectomized patients and healthy individuals

Oxytocin has been proposed to possess glucose-stabilizing effects through the release of insulin and glucagon from the pancreas. Also, exogenous oxytocin has been shown to stimulate extrapancreatic glucagon secretion in depancreatized dogs. Here, we investigated the effect of exogenous oxytocin on circulating levels of pancreatic and gut-derived glucose-stabilizing hormones (insulin [measured as C-peptide], glucagon, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic polypeptide). We studied nine pancreatectomized (PX) patients and nine healthy controls (CTRLs) (matched on age and body mass index) before, during, and after an intravenous infusion of 10 IU of oxytocin administered over 12 min. Oxytocin did not increase plasma glucagon levels, nor induce any changes in plasma glucose, C-peptide, or GIP in any of the groups. Oxytocin decreased plasma glucagon levels by 19 ± 10 % in CTRLs (from 2.0 ± 0.5 [mean ± SEM] to 1.3 ± 0.2 pmol/l, P = 0.0025) and increased GLP-1 by 42 ± 22 % in PX patients (from 9.0 ± 1.0–12.7 ± 1.0 pmol/l, P = 0.0003). Fasting plasma glucose levels were higher in PX patients compared with CTRLs (13.1 ± 1.1 vs. 5.1 ± 0.1 mmol/l, P < 0.0001). In conclusion, the present findings do not support pancreas-mediated glucose-stabilizing effects of acute oxytocin administration in humans and warrant further investigation of oxytocin’s gluco-metabolic effects.

The Efficacy and Safety of Sodium-Glucose Co-transporter2 (SGLT2) Inhibitors in Real-World Clinical Practice: Potential Cautionary Use in Elderly Patients with Type2 Diabetes (T2D).

Sodium-glucose co-transporter2 (SGLT2) inhibitors have shown safe and therapeutic efficacy in randomized controlled trials (RCT) to reduce adverse cardiorenal events in high-risk patients with type2 diabetes (T2D). In this study, we investigated the efficacy and safety of SGLT2 intervention in patients with T2D in a real-world clinical practice to confirm the validity of the RCT results. As a retrospective study, we evaluated medical records from 596 patients with T2D treated with SGLT2 inhibitors (dapagliflozin or empagliflozin) in addition to their prior drug regimen to improve glucose control between 2015 and 2019 in the Endocrinology Department at Chungbuk National University Hospital. No control arm was evaluated to compare the effects of adding SGLT inhibitors to the pre-existing regimen. The primary objective was the measurement of glycated hemoglobin (HbA1c) from each individual patient over a 36-month period at 6-month intervals. The secondary parameters were the measurement of fasting plasma glucose (FPG) and body weight (Bwt) changes, as well as the monitoring of adverse events (AEs) and determining the reasons for drug discontinuation. HbA1c levels were reduced at each of the time points throughout the 36-month period and were significantly reduced by 12.5% (P < 0.01) from time0 (8.8 ± 1.3%) to 36months (7.7 ± 1.0%). FPG levels [from basal (180 ± 60mg/dL) to 36months (138 ± 38mg/dL)] and Bwt [from basal (74 ± 15kg) to 36months (72 ± 15kg)] were also significantly reduced (P < 0.01) for both measurements in the SGLT2 inhibitor add-on group. Similar to HbA1c profile, the FPG and Bwt were measured at a consistently lower level at 6months until the end of the study. The most common AEs were hypoglycemia (n = 57), genitourinary infection (GUI) (n = 31), and polyuria (n = 28). In the elderly population (≥ 75years old), AEs (31%) were generally more prevalent (P < 0.001) than those (21%) in the adult (< 75years old) patients. Over the study period, 211 (35%) patients either dropped or completely discontinued the use of the SGLT2 inhibitor, and the elderly patients tended to have a higher discontinuation rate (52%; P = 0.005) than the adults (33%). In this study, we demonstrated that SGLT2 inhibitors are an effective and durable hypoglycemic agent to control blood glucose levels with reduced maintenance of Bwt, but their use in the elderly (≥ 75years old) patients with T2D may warrant some additional caution due to increased probability of AEs and discontinuation of drug use.

IGlarLixi for type 2 diabetes: a systematic review and meta-analysis.

To assess the efficacy and tolerability of iGlarLixi-a novel, fixed-ratio, soluble combination of insulin glargine and lixisenatide-for the treatment of type 2 diabetes (T2D). The PubMed, Embase, Cochrane Library and ClinicalTrials.gov databases were searched from inception to November 15, 2023 to identify randomized controlled trials (RCTs) comparing iGlarLixi with a placebo or any other antidiabetic agent in adults with T2D. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated to evaluate the outcomes. A total of 10 trials enrolling 6071 T2D patients were included. Compared with placebos or other antidiabetic agents, iGlarLixi exerted beneficial effects on changes in HbA1c, the percentage of patients who achieved an HbA1c < 7%, the percentage of patients who achieved an HbA1c < 6.5%, the percentage of patients who achieved an HbA1c < 7.0% without weight gain and/or without severe or blood glucose-confirmed hypoglycemic episodes, changes in fasting plasma glucose, and changes in self-measured plasma glucose. Regarding safety, iGlarLixi did not increase the incidence of severe hypoglycemia or serious adverse events but did increase the incidence of gastrointestinal adverse events, symptomatic hypoglycemia, and adverse events (e.g., nausea, vomiting, diarrhea). iGlarLixi showed improved efficacy and safety in patients with T2D. Additional large, multicenter RCTs are warranted to obtain deeper insights into the efficacy and safety of iGlarLixi, thereby providing guidance for clinical treatment decisions.

Comparative efficacy and safety of weekly dulaglutide versus weekly insulin in type 2 diabetes: A network meta-analysis of randomized clinical trials

BackgroundAdvancements in type 2 diabetes mellitus (T2DM) therapy, notably with weekly agents like glucagon-like peptide-1 receptor agonists (GLP-RAs) such as dulaglutide, offer promising outcomes in clinical practice. The emergence of once-weekly insulin adds to this therapeutic arsenal. This research aims to explore and compare the efficacy and safety profiles of these agents in diabetes management, facilitating informed decision-making for optimizing their utilization in clinical practice. MethodsA systematic search of PubMed, Scopus, Cochrane, and Web of Science databases was conducted. The research protocol was registered at OSF registries (https://osf.io/gd67x). The primary outcome of interest was the change in hemoglobin A1C (HbA1c), with secondary outcomes including the change in fasting plasma glucose, body weight, prevalence of hypoglycemia, and treatment discontinuation due to adverse events. The evaluation of bias risk was conducted utilizing the RoB2 tool developed by the Cochrane Collaboration. Statistical analysis was performed using RStudio version 4.3.2 with the meta package version 7.0–0 and the netmeta package version 2.9–0. Confidence in network meta-analysis estimates was evaluated using the CINeMA (Confidence In Network Meta-Analysis). Heterogeneity was assessed by comparing the magnitude of the common between-study variance (τ2) for each outcome with empirical distributions of heterogeneity variances. ResultsDulaglutide 1.5 mg (mg) weekly demonstrated superior reduction in hemoglobin A1C (HbA1c) compared to insulin, with a mean difference (MD) of −0.35 (95 % CI: −0.51 to −0.19). Additionally, Dulaglutide 1.5 mg exhibited greater weight loss, with an MD of −3.12 (95 % CI: −3.55 to −2.68). However, it also showed a higher rate of adverse events, with an odds ratio (OR) of 1.40 (95 % CI: 1.12 to 1.75) compared to insulin. Both doses of Dulaglutide (1.5 mg and 0.75 mg) had lower prevalence of hypoglycemia compared to insulin, with ORs of 0.60 (95 % CI: 0.41 to 0.87) and 0.59 (95 % CI: 0.41 to 0.86), respectively. There was no significant difference in treatment discontinuation among the treatment groups. ConclusionDulaglutide, particularly at higher doses, demonstrates superior efficacy in lowering hemoglobin A1C and reducing hypoglycemia risk compared to Icodec insulin in type 2 diabetes management. However, its use is also associated with a higher incidence of adverse events. Clinicians should carefully consider these factors when selecting optimal treatment strategies for patients with type 2 diabetes mellitus.

A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin.

YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.

Improvement of periodontal parameters following intensive diabetes care and supragingival dental prophylaxis in patients with type 2 diabetes: A prospective cohort study.

This study aimed to investigate the effects of diabetes care on periodontal inflammation. This prospective cohort study included 51 Japanese patients with type 2 diabetes who underwent intensive diabetes care including educational hospitalization and regular outpatient treatment for 6 months. Dental prophylaxis without subgingival scaling was provided three times during the observational period. Associations between changes in periodontal parameters and glycaemic control levels were evaluated using multiple regression analysis. Overall, 33 participants (mean age: 58.7 ± 12.9) were followed up for 6 months. At baseline examination, 82% were diagnosed with Stage III or IV periodontitis. Haemoglobin A1c (HbA1c) level changed from 9.6 ± 1.8% at baseline to 7.4 ± 1.3% at 6 months. The ratio of probing pocket depth (PPD) ≥4 mm, bleeding on probing (BOP), full-mouth plaque control record (PCR), periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) also significantly improved. The reduction in PPD and PESA was significantly associated with changes in both HbA1c and fasting plasma glucose (FPG) levels, and the reduction in PISA was significantly associated with an improvement in FPG after adjusting for smoking, change in body mass index and full-mouth PCR. This is the first study to report a significant improvement in PPD and BOP after intensive diabetes care and dental prophylaxis without subgingival scaling. UMIN000040218.

Periodic mobile application (eMOM) with self-tracking of glucose and lifestyle improves treatment of diet-controlled gestational diabetes without human guidance: a randomized controlled trial

Digitalization with minimal human resources could support self-management among women with gestational diabetes and improve maternal and neonatal outcomes. This study aimed to investigate if a periodic mobile application (eMOM) with wearable sensors improves maternal and neonatal outcomes among women with diet-controlled gestational diabetes without additional guidance from healthcare personnel. Women with gestational diabetes were randomly assigned in a 1:1 ratio at 24 to 28 weeks' gestation to the intervention or the control arm. The intervention arm received standard care in combination with use of the periodic eMOM, whereas the control arm received only standard care. The intervention arm used eMOM with a continuous glucose monitor, an activity tracker, and a food diary 1 week/month until delivery. The primary outcome was the change in fasting plasma glucose from baseline to 35 to 37 weeks' gestation. Secondary outcomes included capillary glucose, weight gain, nutrition, physical activity, pregnancy complications, and neonatal outcomes, such as macrosomia. In total, 148 women (76 in the intervention arm, 72 in the control arm; average age, 34.1±4.0 years; body mass index, 27.1±5.0 kg/m2) were randomized. The intervention arm showed a lower mean change in fasting plasma glucose than the control arm (difference,-0.15 mmol/L vs-2.7 mg/mL; P=.022) and lower capillary fasting glucose levels (difference,-0.04 mmol/L vs-0.7 mg/mL; P=.002). The intervention arm also increased their intake of vegetables (difference, 11.8 g/MJ; P=.043), decreased their sedentary behavior (difference,-27.3 min/d; P=.043), and increased light physical activity (difference, 22.8 min/d; P=.009) when compared with the control arm. In addition, gestational weight gain was lower (difference,-1.3 kg; P=.015), and there were less newborns with macrosomia in the intervention arm (difference,-13.1 %; P=.036). Adherence to eMOM was high (daily use >90%), and the usage correlated with lower maternal fasting (P=.0006) and postprandial glucose levels (P=.017), weight gain (P=.028), intake of energy (P=.021) and carbohydrates (P=.003), and longer duration of the daily physical activity (P=.0006). There were no significant between-arm differences in terms of pregnancy complications. Self-tracking of lifestyle factors and glucose levels without additional guidance improves self-management and the treatment of gestational diabetes, which also benefits newborns. The results of this study support the use of digital self-management and education tools in maternity care.