Spermidine is essential for fasting-mediated autophagy and longevity.

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action.

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.

Estimated glomerular filtration rate slope and risk of primary and secondary major adverse cardiovascular events and heart failure hospitalization in people with type 2 diabetes: An analysis of the EXSCEL trial.

AIM: The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. MATERIALS AND METHODS: Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). RESULTS: Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. CONCLUSIONS: eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.

Impact of baseline ECG characteristics on changes in cardiac biomarkers and echocardiographic metrices after acute myocardial infarction treated with Empagliflozin.

The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first study demonstrating a significant reduction in NT-proBNP-levels as well as significant improvements in cardiac structure and function in patients after acute myocardial infarction treated with empagliflozin vs. placebo. However, hardly any data are available investigating the prognostic role of baseline electrocardiogram metrics in SGLT2-inhibitor-treated patients. This post-hoc analysis investigated the association of baseline ECG metrics collected in one centre of the trial (181 patients) with changes in structural and functional cardiac parameters as well as cardiac biomarkers in response to Empagliflozin treatment. A total of 181 patients (146 men; mean age 58 ± 14 years) were included. Median PQ-interval was 156 (IQR 144-174) milliseconds (ms), QRS width 92 (84-98) ms, QTc interval 453 (428-478) ms, Q-wave duration 45 (40-60) ms, Q-wave amplitude 0.40 (0.30-0.70) millivolt (mV), and heart rate was 71 (64-85) bpm. For functional cardiac parameters (LVEF and E/e') of the entire cohort, a greater decrease of E/e' from baseline to week 26 was observed in shorter QRS width (P = 0.005).Structural cardiac endpoints were only found to have a significant positive correlation between LVEDD and Q wave duration (P = 0.037). Higher heart rate was significantly correlated with better response in LVEF (P = 0.001), E/e' (P = 0.021), and NT-proBNP (P = 0.005). Empagliflozin-treatment showed no interaction with the results. Baseline ECG characteristics post AMI are neither predictive for beneficial NTproBNP effects of Empagliflozin post AMI, nor for functional or structural changes within 26 weeks post AMI.

Pre-Transplant Frequencies of FoxP3+CD25+ in CD3+CD8+ T Cells as Potential Predictors for CMV in CMV-Intermediate Risk Kidney Transplant Recipients.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum ß-hydroxybutyrate (3-ßOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-ßOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS: The mean 3-ßOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-ßOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-ßOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-ßOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-ßOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-ßOHB levels after AMI compared to placebo. Higher baseline 3-ßOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-ßOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-ßOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

From classical dualistic antagonism to hormone synergy: potential of overlapping action of glucagon, insulin and GLP-1 for the treatment of diabesity.

The increasing prevalence of 'diabesity', a combination of type 2 diabetes and obesity, poses a significant global health challenge. Unhealthy lifestyle factors, including poor diet, sedentary behaviour, and high stress levels, combined with genetic and epigenetic factors, contribute to the diabesity epidemic. Diabesity leads to various significant complications such as cardiovascular diseases, stroke, and certain cancers. Incretin-based therapies, such as GLP-1 receptor agonists and dual hormone therapies, have shown promising results in improving glycaemic control and inducing weight loss. However, these therapies also come with certain disadvantages, including potential withdrawal effects. This review aims to provide insights into the cross-interactions of insulin, glucagon, and GLP-1, revealing the complex hormonal dynamics during fasting and postprandial states, impacting glucose homeostasis, energy expenditure, and other metabolic functions. Understanding these hormonal interactions may offer novel hypotheses in the development of 'anti-diabesity' treatment strategies. The article also explores the question of the antagonism of insulin and glucagon, providing insights into the potential synergy and hormonal overlaps between these hormones.

Effects of Different Types of Intermittent Fasting Interventions on Metabolic Health in Healthy Individuals (EDIF): A Randomised Trial with a Controlled-Run in Phase.

The effects of intermittent fasting (IF) on health promotion in the healthy population remain controversial. Therefore, our study aimed to analyse the efficacy and feasibility of different IF protocols and evaluated the effects within a cohort with a controlled-run in phase on the body mass index (BMI) as the primary outcome, the body composition, and metabolic and haematological markers in healthy participants. A total of 25 individuals were randomised into three fasting groups: 16/8 fasting (n = 11), 20/4 fasting (n = 6), and alternate-day fasting (ADF, n = 8). Assessments were conducted at baseline (visit 1), after a four-week controlled-run in phase (visit 2), and after eight weeks of fasting (visit 3). Both the BMI (p = 0.01) and bodyweight (p = 0.01) were significantly reduced in the ADF group, which was not seen in the 16/8 and 20/4 groups (p > 0.05). Adherence was different but not statistically among the groups (16/8: 84.5 ± 23.0%; 20/4: 92.7 ± 9.5%; and ADF: 78.1 ± 33.5%, p = 0.57). Based on our obtained results, the data suggest that some fasting interventions might be promising for metabolic health. However, adherence to the specific fasting protocols remains challenging even for the healthy population.

Impact of a 4-week intensive track and field training intervention on glycaemia in adolescents with type 1 diabetes: The ChilDFiT1 study.

AIM: To investigate the safety and efficacy of track and field training compared with intensification of insulin treatment only in adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: Eighteen adolescents (seven females) with T1D were included (age 15.1 ± 1.1 years, HbA1c 7.3% ± 1.0% [56.3 ± 10.9 mmol/mol]). After a 4-week observational control phase, participants were randomized to either stand-alone intensive glycaemic management (IT; telemedicine or on-site visits, three times/week) or additionally performed track and field exercise (EX; three 60-minute sessions/week) for 4 weeks. Glycaemia was assessed via continuous glucose monitoring during observational control and intervention phases. RESULTS: Time in range (70-180 mg/dL; 3.9-10.0 mmol/L) significantly improved from the observational control phase to the exercise intervention phase in EX (69% ± 13% vs. 72% ± 11%, P = .049), but not in IT (59% ± 22% vs. 62% ± 16%, P = .399). Time below range 1 (54-69 mg/dL; < 3.9 mmol/L) improved in IT (3.1% ± 1.9% vs. 2.0% ± 0.8%, P = .017) and remained stable in EX (2.0% ± 1.7 vs. 1.9% ± 1.1%, P = .999). The EX group's HbA1c ameliorated preintervention to postintervention (mean difference: ΔHbA1c -0.19% ± 0.17%, P = .042), which was not seen within the IT group (ΔHbA1c -0.16% ± 0.37%, P = .40). Glucose standard deviation was reduced significantly in EX (55 ± 11 vs. 51 ± 10 mg/dL [3.1 ± 0.6 vs. 2.8 ± 0.6 mmol/L], P = .011), but not in IT (70 ± 24 vs. 63 ± 18 mg/dL [3.9 ± 1.3 vs. 3.5 ± 1.0 mmol/L], P = .186). CONCLUSION: Track and field training combined with intensive glycaemic management improved glycaemia in adolescents with T1D, which was not observed in the non-exercise group.

Effects of empagliflozin in women and men with acute myocardial infarction: An analysis from the EMMY trial.

OBJECTIVE: Women have a higher comorbidity burden and a lower survival rate after acute myocardial infarction (AMI) than men. This analysis aimed to investigate the impact of sex on the effect of treatment with the sodium glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin immediately after an AMI. METHODS: Participants were randomized to either empagliflozin or placebo and followed for 26 weeks after initiating the treatment no later than 72 hours after a percutaneous coronary intervention following an AMI. We analyzed the impact of sex on the beneficial effects of empagliflozin observed for heart failure biomarkers as well as structural and functional cardiac parameters. RESULTS: Women had higher NT-proBNP levels at baseline (median 2117pg/mL, IQR 1383-3267 pg/mL versus 1137 pg/mL, IQR 695-2050 pg/mL; p < 0.001) and were older than men (median 61y, IQR 56-65y versus 56y, IQR 51-64y, p = 0.005). The beneficial effects of empagliflozin on NT-proBNP levels (Pinteraction = 0.984), left ventricular ejection fraction (Pinteraction = 0.812), left ventricular end systolic volume (Pinteraction = 0.183), or left ventricular end diastolic volume (Pinteraction = 0.676) were independent of sex. CONCLUSIONS: Empagliflozin exhibited similar benefits in women and men when administered immediately after an AMI.

Glycated haemoglobin, HOMA2-B, C-peptide to glucose ratio and type 2 diabetes clusters as predictors for therapy failure in individuals with type 2 diabetes without insulin therapy: A registry analysis.

AIM: Some people with type 2 diabetes mellitus (T2D) and declining ß-cell function do require insulin over time. Various laboratory parameters, indices of glucose metabolism or phenotypes of T2D (clusters) have been suggested, which might predict future therapy failure (TF), indicating the need for insulin therapy initiation. This analysis evaluated glycated haemoglobin (HbA1c), homeostatic model assessment (HOMA)2-B, C-peptide to glucose ratio (CGR) and diabetes clusters as predictive parameters for the occurrence of glycaemic TF in individuals diagnosed with T2D without previous insulin therapy. MATERIALS AND METHODS: In total, 159 individuals with T2D [41% female, median age 50 (IQR: 53-69) years, diabetes duration 9 (5-15) years], without insulin therapy were prospectively evaluated for the occurrence of a composite primary endpoint, including HbA1c increasing or remaining >8.0% (64 mmol/mol) 3 months after baseline on non-insulin glucose-lowering agents, insulin initiation or hospital admissions because of acute hyperglycaemic events. Diabetes clusters were formed according to previously described characteristics. Only severe autoimmune diabetes clusters were excluded because of a small amount of glutamate decarboxylase antibody-positive participants. The other clusters were distributed as mild age-related diabetes 33%; severe insulin-deficient diabetes 31%; mild obesity-related diabetes 20%; and severe insulin-resistant diabetes 15%. RESULTS: During a median observation of 57 months, higher tertiles of HbA1c at baseline, HOMA2-B, as well as a lower CGR were significantly predictive for the occurrence of the primary endpoint. The probability of meeting the primary endpoint was the highest for mild obesity-related diabetes [hazard ratio 3.28 (95% confidence interval 1.75-6.2)], followed by severe insulin-deficient diabetes [hazard ratio 2.03 (95% confidence interval 1.1-3.7)], mild age-related diabetes and the lowest for severe insulin-resistant diabetes. The best performance to predict TF with an area under the curve (AUC) of 0.77 was HbA1c at baseline, followed by HOMA2-B (AUC 0.69) and CGR (AUC 0.64). CONCLUSION: HbA1c, indices of insulin secretion capacity (HOMA2-B and CGR) and T2D clusters might be applicable tools to guide practitioners in the decision of whether insulin is required in people already diagnosed with T2D. These findings need to be validated in prospective studies.

Low glucose availability potentiates the effects of metformin on model T cell activation and exhaustion markers in vitro.

Modulation of immune cell metabolism is one of promising strategies to improve cancer immunotherapies. Metformin is an anti-diabetic drug with potential anti-cancer effects, ranging from normalization of blood glucose and insulin levels, direct anti-proliferative effects on cancer cells to emerging immunomodulatory effects on anti-tumor immunity. Metformin can reduce tumor hypoxia and PD-L1 expression, as well as normalize or improve T cell function and potentiate the effect of immune checkpoint inhibitors, making it a promising adjuvant to immunotherapy of tumors with poor response such as triple negative breast cancer (TNBC). However, although the effects of metformin on cancer cells are glucose-dependent, the role of glucose in modulating its effect on T cells has not been systematically studied. We thus investigated the effect of metformin as a function of glucose level on Jurkat cell and PBMC T cell models in vitro. While low metformin concentrations had little effect on T cell function, high concentration reduced proliferation and IFN-γ secretion in both models and induced a shift in T cell populations from memory to effector subsets. The PD-1/CD69 ratio was improved by high metformin in T cells from PBMC. Low glucose and metformin synergistically reduced PD-1 and CD69 expression and IFN-γ secretion in T cells from PBMC. Low glucose level itself suppressed Jurkat cell function due to their limited metabolic plasticity, but had limited effects on T cells from PBMC apart from reduced proliferation. Conversely, high glucose did not strongly affect either T cell model. Metformin in combination with glycolysis inhibitor 2-deoxy-D-glucose (2DG) reduced PD-1 in Jurkat cells, but also strongly suppressed their function. However, low, physiologically achievable 2DG concentration itself reduced PD-1 while mostly maintaining IL-2 secretion and, interestingly, even strongly increased IFN-γ secretion regardless of glucose level. Overall, glucose metabolism can importantly influence some of the effects of metformin on T cell functionality in the tumor microenvironment. Additionally, we show that 2DG could potentially improve the anti-tumor T cell response.

Incidence of Diabetes Mellitus and Its Impact on Outcomes in Patients Undergoing Surgical Pancreatectomy for Non-Malignant and Malignant Pancreatobiliary Diseases-A Retrospective Analysis.

Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.

SGLT2 Inhibitors in Long COVID Syndrome: Is There a Potential Role?

The coronavirus disease (COVID)-19 has turned into a pandemic causing a global public health crisis. While acute COVID-19 mainly affects the respiratory system and can cause acute respiratory distress syndrome, an association with persistent inflammatory stress affecting different organ systems has been elucidated in long COVID syndrome (LCS). Increased severity and mortality rates have been reported due to cardiophysiological and metabolic systemic disorders as well as multiorgan failure in COVID-19, additionally accompanied by chronic dyspnea and fatigue in LCS. Hence, novel therapies have been tested to improve the outcomes of LCS of which one potential candidate might be sodium-glucose cotransporter 2 (SGLT2) inhibitors. The aim of this narrative review was to discuss rationales for investigating SGLT2 inhibitor therapy in people suffering from LCS. In this regard, we discuss their potential positive effects-next to the well described "cardio-renal-metabolic" conditions-with a focus on potential anti-inflammatory and beneficial systemic effects in LCS. However, potential beneficial as well as potential disadvantageous effects of SGLT2 inhibitors on the prevalence and long-term outcomes of COVID-19 will need to be established in ongoing research.

(Hybrid) Closed-Loop Systems: From Announced to Unannounced Exercise.

Physical activity and exercise have many beneficial effects on general and type 1 diabetes (T1D) specific health and are recommended for individuals with T1D. Despite these health benefits, many people with T1D still avoid exercise since glycemic management during physical activity poses substantial glycemic and psychological challenges - which hold particularly true for unannounced exercise when using an AID system. Automated insulin delivery (AID) systems have demonstrated their efficacy in improving overall glycemia and in managing announced exercise in numerous studies. They are proven to increase time in range (70-180 mg/dL) and can especially counteract nocturnal hypoglycemia, even when evening exercise was performed. AID-systems consist of a pump administering insulin as well as a CGM sensor (plus transmitter), both communicating with a control algorithm integrated into a device (insulin pump, mobile phone/smart watch). Nevertheless, without manual pre-exercise adaptions, these systems still face a significant challenge around physical activity. Automatically adapting to the rapidly changing insulin requirements during unannounced exercise and physical activity is still the Achilles' heel of current AID systems. There is an urgent need for improving current AID-systems to safely and automatically maintain glucose management without causing derailments - so that going forward, exercise announcements will not be necessary in the future. Therefore, this narrative literature review aimed to discuss technological strategies to how current AID-systems can be improved in the future and become more proficient in overcoming the hurdle of unannounced exercise. For this purpose, the current state-of-the-art therapy recommendations for AID and exercise as well as novel research approaches are presented along with potential future solutions - in order to rectify their deficiencies in the endeavor to achieve fully automated AID-systems even around unannounced exercise.

Retinal venular vessel diameters are smaller during ten days of bed rest.

Older individuals experience cardiovascular dysfunction during extended bedridden hospital or care home stays. Bed rest is also used as a model to simulate accelerated vascular deconditioning occurring during spaceflight. This study investigates changes in retinal microcirculation during a ten-day bed rest protocol. Ten healthy young males (22.9 ± 4.7 years; body mass index: 23.6 ± 2.5 kg·m-2) participated in a strictly controlled repeated-measures bed rest study lasting ten days. High-resolution images were obtained using a hand-held fundus camera at baseline, daily during the 10 days of bed rest, and 1 day after re-ambulation. Retinal vessel analysis was performed using a semi-automated software system to obtain metrics for retinal arteriolar and venular diameters, central retinal artery equivalent and central retinal vein equivalent, respectively. Data analysis employed a mixed linear model. At the end of the bed rest period, a significant decrease in retinal venular diameter was observed, indicated by a significantly lower central retinal vein equivalent (from 226.1 µm, CI 8.90, to 211.4 µm, CI 8.28, p = .026), while no significant changes in central retinal artery equivalent were noted. Prolonged bed rest confinement resulted in a significant (up to 6.5%) reduction in retinal venular diameter. These findings suggest that the changes in retinal venular diameter during bedrest may be attributed to plasma volume losses and reflect overall (cardio)-vascular deconditioning.

Speckle-Tracking Analysis of the Right and Left Heart after Peak Exercise in Healthy Subjects with Type 1 Diabetes: An Explorative Analysis of the AppEx Trial.

In eight healthy participants with Type 1 diabetes (T1D) exercise-related dynamic cardiac remodeling was analyzed by performing two-dimensional echocardiography, including deformation analysis of the left-ventricular (LV) global longitudinal strain (LV-GLS), and the deformation pattern of the left atrium (LA) and right ventricle (RV) at rest and post-peak performance on a bicycle. The feasibility echocardiographic speckle-tracking analysis was performed on eight asymptomatic participants with T1D (n = 8, male n = 5, age: 23-65 years). The obtained echocardiographic data were compared for various echocardiographic parameters at rest and post exercise. Across our participating T1D individuals no structural echocardiographic abnormalities of concern could be revealed. All participating T1D subjects showed preserved contractile reserve of the LV and no significant diastolic dysfunction. Significant differences were found for the phasic LA contractile strain pattern at rest and post exercise (p < 0.001), whereby the dynamic RV (p = 0.5839 and p = 0.7419) and LV strain pattern (p = 0.5952) did not reveal significant differences in comparison to resting conditions. This descriptive secondary outcome analysis describes preserved contractile reserve of the LV and elucidates dynamic modification of the phasic LA contractile deformation pattern in asymptomatic T1D individuals after exhaustive exercise on a bicycle.