From the Clinical to the Bench: Exploring the Insulin Modulation Effects of Tacrolimus and Belatacept.

Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show that late conversion from CNIs to belatacept, a costimulation blocker, improves HbA1c in kidney transplant recipients with PTD or de novo diabetes. This study investigates whether the observed effects on PTD stem solely from CNI withdrawal or if belatacept influences PTD independently. The study assessed the impact of tacrolimus and belatacept on insulin secretion in MIN6 cells (a beta cell line) and rat islets. Tacrolimus and belatacept were administered to the cells and islets, followed by assessments of cell viability and insulin secretion. Tacrolimus impaired insulin secretion without affecting cell viability, while belatacept showed no detrimental effects on either parameter. These findings support clinical observations of improved HbA1c upon switching from tacrolimus to belatacept. Belatacept holds promise in islet or pancreas transplantation, particularly in patients with unstable diabetes. Successful cases of islet transplantation treated with belatacept without severe hypoglycemia highlight its potential in managing PTD. Further research is needed to fully understand the metabolic changes accompanying the transition from CNIs to belatacept. Preserving insulin secretion emerges as a promising avenue for investigation in this context.

Diabetes in spotlight: current knowledge and perspectives of photobiomodulation utilization.

Introduction: Diabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation. Methods: This review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well all clinical trials, both planned and completed, available on ClinicalTrials database. Results: This review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM's full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM's impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance. Conclusion: Clinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted.

12-Month Real-Life Efficacy of the MiniMed 780G Advanced Closed-Loop System in Patients Living with Type 1 Diabetes: A French Observational, Retrospective, Multicentric Study.

Aim: To evaluate the evolution of glycemic outcomes in patients living with type 1 diabetes (T1D) after 1 year of use of the MiniMed 780G advanced hybrid closed-loop (AHCL) system. Methods: We conducted an observational, retrospective, multicentric study in 20 centers in France. The primary objective was to evaluate the improvement in glycemic control after 1-year use of AHCL. The primary endpoint was the variation of time in range (TIR) between pre-AHCL and after 1-year use of AHCL. Secondary objectives were to analyze the glycemic outcomes after 3, 6, and 12 months of AHCL use, the safety, and the long-term observance of AHCL. Results: Two hundred twenty patients were included, and 200 were analyzed for the primary endpoint. 92.7% of patients continued to use AHCL. After 1 year of use of AHCL, TIR was 72.5% ± 10.6% (+9.1%; 95% confidence interval [CI] [7.6-10.5] compared to pre-AHCL initiation, P < 0.001), HbA1c 7.1% ± 0.7% (-0.5%; 95% CI [-0.6 to -0.4]; P < 0.001), time below range 2.0% [1.0; 3.0] (0.0% [-2.0; 0.0], P < 0.001), and time above range 24.8% ± 10.9% (-7.3%; 95% CI [-8.8 to -5.7]; P < 0.001). More patients achieved the glycemic treatment goals of HbA1c <7.0% (45.1% vs. 18.1%, P < 0.001) and TIR >70% (59.0% vs. 29.5% P < 0.001) when compared with pre-AHCL. Five patients experienced severe hypoglycemia events and two patients experienced ketoacidosis. Conclusion: After 1 year of use of AHCL, people living with T1D safely improved their glucose control and a higher proportion of them achieved optimal glycemic control.

MiniMedTM 780G Advanced Hybrid Closed-Loop System Study in Pregnant Women with Type 1 Diabetes.

Background: Evaluate the impact of the MiniMed™ 780G advanced hybrid closed-loop (AHCL) system on the glucose profile of pregnant women with type 1 diabetes (T1D) and maternal-neonatal complications. Methods: From April 2021 to September 2022, pregnant women with T1D treated with the AHCL system were included in an observational multicenter retrospective study. Continuous glucose monitoring parameters were analyzed monthly during pregnancy as well as maternal-neonatal complications. Results: Thirteen pregnant women, including a twin pregnancy (age: 33 ± 3 years, hemoglobin A1c [HbA1c]: 7.3% ± 0.7%, insulin doses: 0.72 ± 0.21 U/kg/day) were analyzed. At delivery, gestational age was 37 ± 2 weeks. During first 2 weeks of pregnancy, time in range (TIR, 63-140 mg/dL) was 46% (34-55) and increased to 54% (51-59) (P < 0.01), 64% (48-68) (P < 0.01), and 66% (60-70) (P < 0.001) during the first, second, and third trimester, respectively. During the night, TIR (63-140 mg/dL) was >70% throughout pregnancy. Time below the range <63 mg/dL increased from 0.5% (0-2) to 1.3% (0.7-2.2), 2% (1.2-3.5) (P < 0.05), and 1.3% (1.31-3) (P < 0.05) during the first, second, and third trimester, respectively. At delivery, insulin doses increased to 0.89 ± 0.35 IU/kg/day (P < 0.01), and HbA1c decreased to 6.4% ± 0.6% (P = 0.005). The reported carbohydrate amount increased from 167 ± 363 g/d during early pregnancy to 243 ± 106 g/d (P < 0.01) at delivery. The birthweight was 3134 ± 711 g, with 5/14 macrosomia and 2/14 neonatal hypoglycemia. Moreover, 5/13 patients had a preeclampsia and 9/13 a cesarean section, including three cases of scarred uterus. The Clinical Trial Registration number is: CE-2022-55. Conclusion: The AHCL system provided good glucose control during pregnancy and recommendation targets were reached during the nocturnal period only. The maternal and neonatal complications remained high.

Islets-on-Chip: A Tool for Real-Time Assessment of Islet Function Prior to Transplantation.

Islet transplantation improves metabolic control in patients with unstable type 1 diabetes. Clinical outcomes have been improving over the last decade, and the widely used beta-score allows the evaluation of transplantation results. However, predictive pre-transplantation criteria of islet quality for clinical outcomes are lacking. In this proof-of-concept study, we examined whether characterization of the electrical activity of donor islets could provide a criterion. Aliquots of 8 human donor islets from the STABILOT study, sampled from islet preparations before transplantation, were characterized for purity and split for glucose-induced insulin secretion and electrical activity using multi-electrode-arrays. The latter tests glucose concentration dependencies, biphasic activity, hormones, and drug effects (adrenalin, GLP-1, glibenclamide) and provides a ranking of CHIP-scores from 1 to 6 (best) based on electrical islet activity. The analysis was performed online in real time using a dedicated board or offline. Grouping of beta-scores and CHIP-scores with high, intermediate, and low values was observed. Further analysis indicated correlation between CHIP-score and beta-score, although significance was not attained (R = 0.51, p = 0.1). This novel approach is easily implantable in islet isolation units and might provide means for the prediction of clinical outcomes. We acknowledge the small cohort size as the limitation of this pilot study.

First Generation of a Modular Interoperable Closed-Loop System for Automated Insulin Delivery in Patients With Type 1 Diabetes: Lessons From Trials and Real-Life Data.

BACKGROUND: DBLG1 (Diabeloop Generation 1) stands as one of the five commercially available closed-loop solution worldwide for patients with type 1 diabetes as of 2023. Our aim was to provide an overview of all data obtained with this system regarding outcomes and populations, with an emphasis on interoperability. METHODS: This report includes all available sources of data (three randomized control trials and five surveys on real-life data). Collection ran from March 3, 2017 to April 30, 2022. RESULTS: We gathered data from 6859 adult patients treated with closed-loop from three to 12 months. Overall, all sources of data showed that time in range (TIR) 70 to 180 mg/dL, starting from 47.4% to 56.6%, improved from 12.2 to 17.3 percentage points. Time in hypoglycemia was reduced by 48% in average (range: 26%-70%) and reached a level of 1.3% in the largest and most recent cohort. In patients with excessive time in hypoglycemia at baseline (≥5%), closed-loop allowed a reduction in time below range (TBR) by 59%. The comparison of days with declared physical activity versus days without physical activity did not show differences in TBR. The improvement in TIR observed with three different pump systems (Vicentra Kaleido, n = 117; Sooil Dana-I, n = 84; and Roche Insight, n = 6684) ranged from 15.4 to 17.3 percentage points. DISCUSSION: These data obtained in different European countries were consistent throughout all reports, showing that this closed-loop system is efficient (high improvement in TIR), safe (remarkably low level of TBR), and interoperable (three pump settings so far).

Effect of a lifestyle intervention to prevent weight gain at initiation of insulin pump therapy in type 2 diabetes: A randomized, controlled, multicentre trial.

Insulin pump therapy improves glycaemic control in individuals with type 2 diabetes. However, it may be associated with weight gain. AIM: To test the effectiveness of a six-month dietary and physical activity intervention, compared to usual care, on weight gain prevention after initiation of insulin pump. METHODS: Multicentre randomized, controlled trial of 54 individuals. Primary endpoint was between group difference in weight gain at six-months. RESULTS: Weight gain after 6 months of insulin pump treatment did not differ between groups: mean 3.2 (3.9) kg in the control group and 3.9 (3.8) kg in the intervention group, (p = 0.56). HbA1c improved without difference between groups. Post-hoc multivariate analysis of all participants found that weight gain was independently associated with younger age, active smoking, and the magnitude of HbA1c reduction. A 1 % decrease in HbA1c was associated with an increase of 0.94 kg [95 % Confidence Interval 0.47; 1.41], p < 0.001. CONCLUSIONS: Treatment intensification by insulin pump therapy in patients with type 2 diabetes is effective to improve glycaemic control. A gain of about 1 kg per 1 % drop in HbA1c can be expected after insulin treatment intensification. This weight gain was not prevented by a home-base, individualized, 6-months lifestyle intervention program.

Insight into continuous glucose monitoring: from medical basics to commercialized devices.

According to the latest statistics, more than 537 million people around the world struggle with diabetes and its adverse consequences. As well as acute risks of hypo- or hyper- glycemia, long-term vascular complications may occur, including coronary heart disease or stroke, as well as diabetic nephropathy leading to end-stage disease, neuropathy or retinopathy. Therefore, there is an urgent need to improve diabetes management to reduce the risk of complications but also to improve patient's quality life. The impact of continuous glucose monitoring (CGM) is well recognized, in this regard. The current review aims at introducing the basic principles of glucose sensing, including electrochemical and optical detection, summarizing CGM technology, its requirements, advantages, and disadvantages. The role of CGM systems in the clinical diagnostics/personal testing, difficulties in their utilization, and recommendations are also discussed. In the end, challenges and prospects in future CGM systems are discussed and non-invasive, wearable glucose biosensors are introduced. Though the scope of this review is CGMs and provides information about medical issues and analytical principles, consideration of broader use will be critical in future if the right systems are to be selected for effective diabetes management.

High prevalence with no gender difference of likely eating disorders in type 1 mellitus diabetes on insulin pump.

AIM: The aim of this study was to determine the prevalence of likely eating disorders and insulin misuse in a prospective cohort of adults with type 1 diabetes mellitus (T1DM) treated with insulin pump therapy. METHODS: This prospective study was held at the participants' home. The participants completed the SCOFF questionnaire as well as a question related to insulin misuse. Information about lifestyle, medical history, insulin pump and Continuous Glucose Monitoring (CGM) data were collected. RESULTS: The analysis covered 198 participants with a median age of 51 [95% CI 38; 62] years. The prevalence of likely eating disorders was 21.7% (95% CI 16.3; 28.2) in the study population and 20.6% (95% CI 14.3; 28.6) and 24.2% (95% CI 14.6; 37.0) in males and females respectively. The prevalence of insulin misuse was 39.0% (95% CI 30.8; 47.7). There was no significant difference in prevalence between males and females for likely eating disorders and insulin misuse. The analysis of CGM data revealed no factors related to glycaemic control associated with likely eating disorders. CONCLUSION: The results of this study indicate that the prevalence of likely eating disorders is high even in a middle-aged population with a T1DM and satisfactory glucose control.

Regional CZT myocardial perfusion reserve for the detection of territories with simultaneously impaired CFR and IMR in patients without obstructive coronary artery disease: a pilot study.

OBJECTIVES: To assess the diagnostic performances of CZT myocardial perfusion reserve (MPR) for the detection of territories with simultaneous impaired coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) in patients without obstructive coronary artery disease. METHODS: Patients were prospectively included before being referred for coronary angiography. All patients underwent CZT MPR before invasive coronary angiography (ICA) and coronary physiology assessment. Rest and dipyridamole-induced stress myocardial blood flow (MBF) and MPR were quantified using 99mTc-SestaMIBI and a CZT camera. Fractional flow reserve (FFR), Thermodilution CFR, and IMR were assessed during ICA. RESULTS: Between December 2016 and July 2019, 36 patients were included. 25/36 patients presented no obstructive coronary artery disease. A complete functional assessment was performed in 32 arteries. No territory presented a significant ischemia on CZT myocardial perfusion imaging. A moderate yet significant correlation was observed between regional CZT MPR and CFR (r = 0.4, P = .03). Sensitivity, specificity, positive and negative predictive value, and accuracy of regional CZT MPR versus the composite invasive criterion (impaired CFR and IMR) were 87 [47% to 99%], 92% [73% to 99%], 78% [47% to 93%], 96% [78% to 99%], and 91% [75% to 98%], respectively. All territories with a regional CZT MPR ≤ 1.8 showed a CFR < 2. Regional CZT MPR values were significantly higher in arteries with CFR ≥ 2 and IMR < 25 (negative composite criterion, n = 14) than in those with CFR < 2 and IMR ≥ 25 (2.6 [2.1 to 3.6] versus 1.6 [1.2 to 1.8]), P < .01). CONCLUSION: Regional CZT MPR presented excellent diagnostic performances for the detection of territories with simultaneously impaired CFR and IMR reflecting a very high cardiovascular risk in patients without obstructive coronary artery disease.

Cost-Effectiveness Evaluation of a Remote Monitoring Programme Including Lifestyle Education Software in Type 2 Diabetes: Results of the Educ@dom Study.

INTRODUCTION: Telemedicine programs using health technological innovation to remotely monitor the lifestyles of patients with type 2 diabetes (T2D) can improve glycaemic control and thus reduce the incidence of complications as well as management costs. In this context, an assessment was made of the 1-year and 2-year cost-effectiveness of the EDUC@DOM telemonitoring and tele-education program. METHODS: The EDUC@DOM study was a multicentre randomized controlled trial conducted between 2013 and 2017 that compared a telemonitoring group (TMG) to a control group (CG) merged with health insurance databases to extract economic data on resource consumption. Economic analysis was performed from the payer perspective, and direct costs and indirect costs were considered. The clinical outcome used was the intergroup change in glycated haemoglobin (HbA1c) levels from baseline. Missing economic data were imputed using multiple imputation, and fitted values from a generalized linear mixed model were used to calculate the incremental cost-effectiveness ratio (ICER). Bootstrapped 95% confidence ellipses were drawn in the cost-effectiveness plan. RESULTS: The main analysis included data from 256 patients: 126 in the TMG and 130 in the CG. Incremental costs over 1 and 2 years were equal to €2129 and €5101, respectively, in favour of the TMG. Once imputed and adjusted for confounding factors, the TMG trends to a 21% cost decrease over 1 and 2 years of follow-up (0.79 [0.58; 1.08], p = 0.1452 and 0.79 [0.61; 1.03], p = 0.0879, respectively). The EDUC@DOM program led to a €1334 cost saving and a 0.17 decrease in HbA1c over 1 year and a €3144 cost saving and a 0.14 decrease in HbA1c over 2 years. According to the confidence ellipse, EDUC@DOM was a cost-effective strategy. CONCLUSION: This study provides additional economic information on telemonitoring and tele-education programs to enhance their acceptance and promote their use. In the light of this work, the EDUC@DOM program is a cost-saving strategy in T2D management. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Database on 27 September 2013 under no. NCT01955031 and bears ID-RCB no. 2013-A00391-44.

Sex disparities in COVID-19 outcomes of inpatients with diabetes: insights from the CORONADO study.

OBJECTIVE: Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19. METHODS: We performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation (IMV), death, intensive care unit (ICU) admission and home discharge at day 7 (D7) or day 28 (D28)) in 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736). RESULTS: The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR: 0.66 (0.49-0.88)), death (OR: 0.49 (0.30-0.79)) and ICU admission (OR: 0.57 (0.43-0.77)) at D7 but only with ICU admission (OR: 0.58 (0.43-0.77)) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only. CONCLUSIONS: In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.

Impact of a Remote Monitoring Programme Including Lifestyle Education Software in Type 2 Diabetes: Results of the Educ@dom Randomised Multicentre Study.

INTRODUCTION: Telemonitoring in type 2 diabetes (T2D) is mainly based on glucose monitoring. A new type of connected device which routinely gathers data on weight, physical activity and food intake could improve patients' diabetes control. The main aim of this study was to assess the efficacy of an at-home interventional programme incorporating such devices and lifestyle education software on diabetes control, i.e., change in HbA1c, compared to standard care. METHODS: This multicentre study randomly assigned 282 people with T2D to either a telemonitoring group (TMG) or a control group (CG) for a 1-year intervention period. While routine follow-up was maintained in the CG, TMG subjects were provided with interactive lifestyle educational software (with artificial intelligence algorithms) and connected objects (blood glucose meters, scales and actimeters) for use in their own homes and were remotely monitored by their diabetologists. Changes in HbA1c were compared between groups using a mixed linear model. RESULTS: The mean HbA1c dropped from 7.8 ± 0.8% (62 mmol/mol) to 7.4 ± 1.0% (57 mmol/mol) in the TMG and from 7.8 ± 0.8% (62 mmol/mol) to 7.6 ± 1.0% (60 mmol/mol) in the CG, resulting in an intergroup difference of - 0.16 (p = 0.06) in favour of TMG, after adjustment for confounding factors. Within TMG, the decrease in HbA1c was greater in frequent users: - 0.23% (p = 0.03) in the case of connections to telemonitoring synthesis above the median and - 0.21% (p = 0.05) in the case of connections to tele-education software above the median compared to the CG. Significant weight loss was observed in the TMG but only in women (p = 0.01). FINDINGS: The EDUC@DOM telemonitoring and tele-education device did not highlight a significant decrease in HbA1c levels compared to routine management although a slight, albeit significant improvement in glycaemic control was observed in the frequent user subgroup as well as significant weight loss but only in women. A high level of satisfaction with the connected device was recorded amongst all participants. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Database on September 27, 2013, under no. NCT01955031 and bears ID-RCB number 2013-A00391-44.