Biological Assessment of the NO-Dependent Endothelial Function.

Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of great interest but are currently lacking. The direct measurement of circulating NO remains a challenge due by its high reactivity and short half-life. The current techniques measure stable products from the NO signaling pathway or metabolic end products of NO that do not accurately represent its bioavailability and, therefore, endothelial function per se. In this review, we will concentrate on an original technique of low temperature electron paramagnetic resonance spectroscopy capable to directly measure the 5-α-coordinated heme nitrosyl-hemoglobin in the T (tense) state (5-α-nitrosyl-hemoglobin or HbNO) obtained from fresh venous human erythrocytes. In humans, HbNO reflects the bioavailability of NO formed in the vasculature from vascular endothelial NOS or exogenous NO donors with minor contribution from erythrocyte NOS. The HbNO signal is directly correlated with the vascular endothelial function and inversely correlated with vascular oxidative stress. Pilot studies support the validity of HbNO measurements both for the detection of endothelial dysfunction in asymptomatic subjects and for the monitoring of such dysfunction in patients with known cardiovascular disease. The impact of therapies or the severity of diseases such as COVID-19 infection involving the endothelium could also be monitored and their incumbent risk of complications better predicted through serial measurements of HbNO.

Combined Algorithm-Based Adaptations of Insulin Dose and Carbohydrate Intake During Exercise in Children With Type 1 Diabetes: Results From the CAR2DIAB Study.

Objectives: To evaluate the evolution of subcutaneous glucose during two sessions of monitored aerobic exercise in children or adolescents with type 1 diabetes after adaptation of insulin doses and carbohydrate intake according to a combined algorithm. Methods: Twelve patients with type 1 diabetes (15.1 ± 2 years; diabetes duration: 9.5 ± 3.1 years) performed two series of exercise sessions after cardiac evaluation. The first series (TE#1) consisted in a monitored exercise of moderate to vigorous intensity coupled with a bout of maximum effort. The second series of exercises (TE#2) was carried out in real life during exercises categorized and monitored by connected watches. TE#2 sessions were performed after adaptation of insulin doses and fast-acting carbohydrates according to decision algorithms. Results: Patients did not experience episodes of severe hypoglycemia, symptomatic hyperglycemia, or hyperglycemia associated with ketosis. Analysis of CGM data (15 h) during TE#2 sessions revealed an overall improvement in glycemic average [± standard deviation] (104 ± 14 mg/dl vs. 122 ± 17 mg/dl during TE#1; p < 0.001), associated with a decrease in proportion of hyperglycemia in periods ranging from 4 h to 15 h after performing the exercises. The proportion of hypoglycemia was not changed, except during the TE#2 +4-8 h period, where a significant increase in hypoglycemia <60 mg/dl was observed (25% vs. 6.2%; p = 0.04), yet without concurrent complications. Conclusion: In our pediatric series, the application of algorithmic adaptations of insulin doses and carbohydrate intake has globally improved glycemic control during 15 h after real-time exercises performed by children and adolescents with type 1 diabetes.

Early Treatment with Empagliflozin and GABA Improves ß-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice.

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to ß-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect ß-cell mass against glucotoxicity and to increase ß-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-ß cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on ß-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of ß-cell mass after new-onset T1D.