Evaluation of hybrid closed-loop insulin delivery system in type 1 diabetes in real-world clinical practice:One-year observational study

BACKGROUND In 2016,the Food and Drug Administration approved the first hybrid closed-loop(HCL)insulin delivery system for adults with type 1 diabetes(T1D).There is limited information on the impact of using HCL systems on patient-reported outcomes(PROs)in patients with T1D in real-world clinical practice.In this independent study,we evaluated glycemic parameters and PROs over one year of continuous use of Medtronic’s 670G HCL in real-world clinical practice.AIM To assess the effects of hybrid closed loop system on glycemic control and quality of life in adults with T1D.METHODS We evaluated 71 patients with T1D(mean age:45.5±12.1 years;59%females;body weight:83.8±18.7 kg,body mass index:28.7±5.6 kg/m2,A1C:7.6%±0.8%)who were treated with HCL at Joslin Clinic from 2017 to 2019.We measured A1C and percent of glucose time-in-range(%TIR)at baseline and 12 months.We measured percent time in auto mode(%TiAM)for the last two weeks preceding the final visit and assessed PROs through several validated quality-of-life surveys related to general health and diabetes management.RESULTS At 12 mo,A1C decreased by 0.3%±0.1%(P=0.001)and%TIR increased by 8.1%±2.5%(P=0.002).The average%TiAM was only 64.3%±32.8%and was not associated with A1C,%TIR or PROs.PROs,provided at baseline and at the end of the study,showed that the physical functioning submodule of 36Item Short-Form Health Survey increased significantly by 22.9%(P<0.001).Hypoglycemia fear survey/worry scale decreased significantly by 24.9%(P<0.000);Problem Areas In Diabetes reduced significantly by-17.2%(P=0.002).The emotional burden submodules of dietary diversity score reduced significantly by-44.7%(P=0.001).Furthermore,analysis of Clarke questionnaire showed no increase in awareness of hypoglycemic episodes.WHO-5 showed no improvements in subject’s wellbeing among participants after starting the 670G HCL system.Finally,analysis of Pittsburgh Sleep Quality Index showed no difference in sleep quality,sleep latency,or duration of sleep from baseline to 12 mo.CONCLUSION The use of HCL in real-world clinical practice for one year was associated with significant improvements in A1C,%TIR,physical functioning,hypoglycemia fear,emotional distress,and emotional burden related to diabetes management.However,these changes were not associated with time in auto mode.

Impairment of Continuous Insulin Delivery Therapy and Analysis from Graeco-Latin Square Design Model

The desire to deliver measured amount of insulin continuously to patients with type I diabetes, for glycemic control, has attracted a lot of attention. Continuous subcutaneous insulin infusion has seen some success in recent years. However, occlusion of insulin delivery may prevent the patient from receiving the prescribed dosage, with adverse consequence. An in vitro study of insulin delivery is performed, using different insulin pumps, insulin analogs and operating conditions. The aim is to identify incidences of occlusion due to bubble formation in the infusion line. A detailed statistical analysis was performed on the data collected to determine any significant differences and deviations in insulin delivery rates that might be due to factors such as: pump type, the set basal flow rate, insulin type, vibration, and possible insulin occlusion due to air bubble formation within the infusion line. Our findings from the Graeco-Latin Square design model show that there are statistical differences due to the devices, and statistical identifiable clusters are used to distinguish the devices. Such hierarchical models used to describe the analyses, include the flow rate, the pump types, and the activity level.

The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery

Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores.In this study,we demonstrate that the upregulated intestinal transporter(PCFT),which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats,mediates the uptake of the folic acid-grafted nanoparticles(FNP).Specifically,the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway,Golgi-targeting pathway and basolateral exocytosis,featuring a high oral insulin bioavailability of 14.4%in the diabetic rats.Conversely,in cells with relatively low PCFT expression,the positive surface charge contributes to the cellular uptake of FNP,and FNP are mainly degraded in the lysosomes.Overall,we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway.This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.

Recent advances in glucose-responsive insulin delivery systems:novel hydrogels and future applications

Over the past several decades,there have been major advancements in the field of glucose sensing and insulin delivery for the treatment of type I diabetes mellitus.The introduction of closed-loop insulin delivery systems that deliver insulin in response to specific levels of glucose in the blood has shifted significantly the research in this field.These systems consist of encapsulated glucose-sensitive components such as glucose oxidase or phenylboronic acid in hydrogels,microgels or nanoparticles.Since our previous evaluation of these systems in a contribution in 2004,new systems have been developed.Important improvements in key issues,such as consistent insulin delivery over an extended period of time have been addressed.In this contribution,we discuss recent advancements over the last 5 years and present persisting issues in these technologies that must be overcome in order for these systems to be applicable in patients.

The complexation of insulin with sodium N-[8-(2-hydroxybenzoyl)amino]-caprylate for enhanced oral delivery:Effects of concentration, ratio, and pH

Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been reported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes,pH and other gastrointestinal barriers.In this study,we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration(insulin≥ 40μg/mL)-,ratio(SNAC/insulin≥ 20:1)-and pH(≥ 6.8)-dependent manner,thus contributing to a significantly high efficacy of oral insulin delivery.Specifically,absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol.Furthermore,the complexes accelerated the exocytosis of insulin to the basolateral side,thereby enhancing its intestinal mucosal permeability.Eudragit;S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient(P;) that was 6,6-fold higher than that of the insulin solution.In diabetic rats,hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into entericcoated capsules.Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states,indicating a negligible food effect.Collectively,this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.