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.

Preparation and Evaluation of Insulin-loaded Nanoparticles based on Hydroxypropyl-β-cyclodextrin Modified Carboxymethyl Chitosan for Oral Delivery

Novel insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan（CMC-HP-β-CD） were prepared to improve the oral bioavailability of insulin. The CMC-HP-β-CD was characterized by FT-IR spectroscopy and 1H-NMR spectra. The insulin-loaded nanoparticles were prepared through crosslinking with calcium ions, and the morphology and size of the prepared nanoparticles were characterized by transmission electron microscopy（TEM） and dynamic light scattering（DLS）. Cumulative release in vitro study was performed respectively in simulated gastric medium fluid（SGF, p H=1.2）, simulated intestinal fluid（SIF, p H=6.8） and simulated colonic fluid（SCF, p H=7.4）. The encapsulation efficiency of insulin was up to 87.14 ± 4.32% through high-performance liquid chromatography（HPLC）. Statistics indicated that only 15% of the encapsulated insulin was released from the CMC-HP-β-CD nanoparticles in 36 h in SGF, and about 50% of the insulin could be released from the nanoparticles in SIF, whereas more than 80% was released in SCF. In addition, the solution containing insulin nanoparticles could effectively reduce the blood glucose level of diabetic mice. The cytotoxicity test showed that the samples had no cytotoxicity. CMC-HP-β-CD nanoparticles are promising candidates as potential carriers in oral insulin delivery systems.

Oral delivery of insulin with Desmodium gangeticum root aqueous extract protects rat hearts against ischemia reperfusion injury in streptozotocin induced diabetic rats

Objective:To evaluate the effect of insulin administered via oral route with the help of aqueous extract of Desmodium gangeticum(DG) root in rendering cardio protection against ischemia reperfusion injury in diabetic rats.Methods:Diabetes mellitus was induced in rats by theβ-cell toxin,streptozotocin(STZ,60 mg/kg).Isolated rat(IR) heart was used to investigate the effect of insulin mixed DG pretreatment on ischemia reperfusion injury.Mitochondrial respiratory enzymes and microsomal enzymes were used to assess the metabolic recovery of myocardium. Cardiac marker enzymes were used to find the functional recovery,which were compared with that of the STZ treated IR rats.Results:Compared with IR control group,rat treated with insulin mixed DG showed a significant functional and metabolic recovery of myocardium from the insult of ischemia reperfusion.Even though orally administered insulin mixed DG displayed a slow but prolonged hypoglycemic effect,the cardio protection it provided was more significant than when it was given intra peritoneal.Furthermore the above result indicates that insulin mixed DG can overcome the barriers in the gastrointestinal tract and be absorbed.Conclusions:The above results indicate the efficacy of insulin mixed DG in protecting the heart from ischemia reperfusion induced injury in diabetic rats.Furthermore the study gives additional information that herbal extracts can be used to transport insulin across the membrane and found to be a feasible approach for developing the oral delivery of insulin,as well as other peptide drugs.

Assembling structurally customizable synthetic carriers of si RNA through thermodynamically self-regulated process

This study demonstrates that our previously reported polywraplex, a synthetic siRNA carrier consisting of a uni-molecular polyplex core of customizable size and a self-assembled triblock copolymer envelop, may be constructed using dendrimers as the crosslinking junctions. Replacing the branched low molecular weight PEI with polyamidoamine(PAMAM) dendrimer in the zeta potential regulated polymerization resulted in the similar network structured cationic polymer with electron microscopically visible crosslinking junctions. This visibility may offer a convenient way to characterize the molecular structure of the rationally designed networked siRNA-packing cationic polymer without altering its chemical properties and biologic functions. A series of physical-chemical characterizations and biological assays, comprising size, zeta potential, pre-phagocytic siRNA leaking and degradation, and silencing of functional genes, confirmed that the advanced properties of polywraplexes remained with the dendrimer junctions. Although sixth generation PAMAM dendrimer was used as the crosslinking junctions in the size-customizable polymerization for electron microscopic observation, lower generation dendrimer should also work in case more practical and structurally defined cationic polymer is needed.

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.

Alternative routes of insulin delivery

Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications.Patient compliance has really been a major concern for this route of administration.Several alternative routes of administration are under consideration for effective glycemic control,including oral,inhaled,buccal,nasal,and patch routes.One of the approaches involving inhaled insulin has now reached the market.Several other candidates may reach the market in the near future,the promising one being oral insulin.

Effects of Several Transmucosal Absorption Promoters on Buccally Administered Insulin in Rats

目的：研究吸收促进剂对大鼠胰岛素溶液（insulin solution,INS-SOL)口腔给药的吸收促进作用。方法：以血糖水平为指标，考察在各种吸收促进剂的影响下INS－SOL经正常大鼠口腔给药后的降血糖作用，以皮下注射为对照，计算不同条件下INS－SOL的药理生物利用度（pharmacological bioavailability,PA)。结果：不加吸收促进剂的条件下，10U·kg^-1的INS－SOL经口腔给药后的生物利用较低（PA＝6．9％）。十二烷基硫酸钠（5％，PA＝14．5％），苄泽78（5％，PA＝20．6％），脱氧胆酸钠（5％，PA＝6．5％）和卵磷酯（10％，PA＝13．8％）均显著地增加INS－SOL的降血糖作用。苄泽78（5％）可使INS－SOL（5U·kg^-1)的PA最高达到33％。结论：在适当的吸收促进剂的作用下INS－SOL经口腔给药后具有显著的降血糖效果。

胰岛素鼻腔给药治疗阿尔茨海默病研究进展

胰岛素近年来被认为与阿尔茨海默病(AD)等中枢退行性疾病密切相关,可能是治疗和改善AD患者记忆、认知能力的靶点。血脑屏障的存在使胰岛素皮下注射无法在大脑中达到期望浓度,而鼻腔途径是最简便有效的避开肝脏首过效应,直接递送药物进入中枢神经系统的靶向给药方式。已有相关临床试验证明胰岛素经鼻腔给药可以改善AD患者的认知能力。本文就不同胰岛素给药方式的优劣、胰岛素与AD之间的关系及使用鼻腔胰岛素治疗AD的疗效等进行综述。

胰岛素泵与基础-餐时胰岛素治疗GDM对新生儿预后的影响

目的:分析胰岛素泵与基础-餐时胰岛素治疗妊娠期糖尿病(GDM)对新生儿预后的影响。方法:选取2020年5月-2022年12月在宝鸡高新医院妇产科诊治的GDM患者147例,其中胰岛素泵组(72例)给予个体化胰岛素泵治疗,基础-餐时胰岛素组(75例)给予个体化基础-餐时胰岛素治疗,对比两组分娩孕周、治疗后孕期血糖达标及需剖宫产占比,对比两组新生儿1min Apgar评分以及早产儿、早产儿、巨大胎儿、胎儿急性窘迫、新生儿低血糖等围生儿期不良并发症,随访对比两组婴儿3个月、12个月婴儿肥胖情况。结果:两组分娩孕周、治疗后孕期血糖达标占比、需剖宫产占比以及新生儿1min Apgar评分均无差异(P>0.05);胰岛素泵组围生儿期不良并发症(2.8%)低于基础-餐时胰岛素组(12.0%),新生儿出生后12个月,胰岛素泵组发生婴儿肥胖占比(4.2%)低于基础-餐时胰岛素组(14.7%)(均P<0.05)。结论:胰岛素泵与基础-餐时胰岛素治疗GDM对患者孕期血糖控制效果相当,胰岛素泵治疗在减少围生儿期不良并发症以及出生后12个月时婴儿肥胖方面优于基础-餐时胰岛素治疗。

Transdermal drug delivery systems in diabetes management: A review

Diabetes mellitus is a chronic disease in which there is an insufficient production of insulin by the pancreas, or the insulin produced is unable to be utilized effectively by the body. Diabetes affects more than 415 million people globally and is estimated to strike about 642 million people in 2040. The WHO reported that diabetes will become the seventh biggest cause of mortality in 2030. Insulin injection and oral hypoglycemic agents remain the primary treatments in diabetes management. These often present with poor patient compliance. However, over the last decade, transdermal systems in diabetes management have gained increasing attention and emerged as a potential hope in diabetes management owing to the advantages that they offer as compared to invasive injection and oral dosage forms. This review presents the recent advances and developments in transdermal research to achieve better diabetes management. Different technologies and approaches have been explored and applied to the transdermal systems to optimize diabetes management. Studies have shown that these transdermal systems demonstrate higher bioavailability compared to oral administration due to the avoidance of first-pass hepatic metabolism and a sustained drug release pattern. Besides that, transdermal systems have the advantage of reducing dosing frequency as drugs are released at a predetermined rate and control blood glucose level over a prolonged time, contributing to better patient compliance. In summary, the transdermal system is a field worth exploring due to its significant advantages over oral route in administration of antidiabetic drugs and biosensing of blood glucose level to ensure better clinical outcomes in diabetes management.

Insulin therapies: Current and future trends at dawn

Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closedloop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future.

Preparation of Ionic Liquid Functionalized Silica Nanoparticles for Oral Drug Delivery

The objective of this study is to utilize the pH sensitivity of modified silica nanoparticles (SNIL) by imidazole-based ionic liquid for oral delivery of insulin. In the first time, the imidazole was covalently attached to the 3-trimethoxysily-lpropyl chloride with replacement of all the chlorine atoms. Then, a silica nanoparticle was modified by N-(3-trimeth-oxysilylpropyl) imidazole. The nanocapsule (NCIL) was achieved after the etching of the modified silica nanoparticle template with hydrofluoric acid. The nanoparticles connected through an ionic liquid-like network were characterized by FTIR and SEM. Insulin was entrapped in these carriers and the in vitro release profiles were established separately in both enzyme-free simulated gastric and intestinal fluids (SGF, pH 1) and (SIF, pH 7.4), respectively. When these drug-loaded nanoparticles was placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the modified silica nanoparticle was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules.

Association of types of diabetes and insulin dependency on birth outcomes

BACKGROUND Diabetes rates among pregnant women in the United States have been increasing and are associated with adverse pregnancy outcomes.AIM To investigate differences in birth outcomes(preterm birth,macrosomia,and neonatal death)by diabetes status.METHODS Cross-sectional design,using linked Missouri birth and death certificates(singleton births only),2010 to 2012(n=204057).Exposure was diabetes non-diabetic,pre-pregnancy diabetes-insulin dependent(PD-I),pre-pregnancy diabetes-non-insulin dependent(PD-NI),gestational diabetes-insulin dependent(GD-I),and gestational diabetes-non-insulin dependent(GD-NI).Outcomes included preterm birth,macrosomia,and infant mortality.Confounders included demographic characteristics,adequacy of prenatal care,body mass index,smoking,hypertension,and previous preterm birth.Bivariate and multivariate logistic regression assessed differences in outcomes by diabetes status.RESULTS Women with PD-I,PD-NI,and GD-I remained at a significantly increased odds for preterm birth(aOR 2.87,aOR 1.77,and aOR 1.73,respectively)and having a very large baby[macrosomia](aOR 3.01,aOR 2.12,and aOR 1.96,respectively);in reference to non-diabetic women.Women with GDNI were at a significantly increased risk for macrosomia(aOR1.53),decreased risk for their baby to die before their first birthday(aOR 0.41)and no difference in risk for preterm birth in reference to non-diabetic women.CONCLUSION Diabetes is associated with the poor birth outcomes.Clinical management of diabetes during pregnancy and healthy lifestyle behaviors before pregnancy can reduce the risk for diabetes and poor birth outcomes.

Self-Assembled Core-Shell Poly(ethylene glycol)-POSS Nanocarriers for Drug Delivery

In this work, novel nanostructured core-shell poly(ethylene glycol) (PEG)-polyhedral oligosilsesquioxane (POSS) nanoparticles were used to encapsulate insulin as new drug delivery carriers. The morphologies, particle size and ζ potential of the pure nanostructured core-shell PEG-POSS and the corresponding insulin-loaded PEG-POSS nanoparticles were investigated by transmission electron microscopy (TEM) and laser diffraction particle sizer. TEM analysis demonstrated that pure and insulin-loaded self-assembled PEG-POSS nanoparticles were of spherical shape with core-shell nanostructure, and were well-dispersed and uniform in size distribution. Insulin release test showed that insulin was well-protected inside PEG-POSS nanoparticles at gastric pH for 2hrs, and was released at intestinal pH (pH 6-7) where the absorption and activation of the drug are necessary. We therefore believe that such nanostructured PEG-POSS nanoparticles could be useful as a potential carrier for insulin drug delivery systems.

Structural rearrangements of polymeric insulin-loaded nanoparticles interacting with surface-supported model lipid membranes

The design and screening of nanoparticles for therapeutic applications (nanodrugs) belong to an emerging research area, where surface based analytical techniques are promising tools. This study reports on the interaction of electrostatically assembled nanoparticles, developed for non-invasive administration of human insulin, with cell membrane mimics. Interactions between the nanoparticles and differently charged surface-supported model membranes were studied in real-time with the quartz crystal microbalance with dissipation monitoring (QCM-D) technique, in some experiments combined with optical reflectometry. Based on the experimental observations, we conclude that structural rearrangements of the nanoparticles occur upon adsorption to negatively charged lipid membranes. The degree of nanoparticle deformation will have important implications for the induced release of the protein drug load. The presented results provide an example of how a surface-based experimental platform can be used for evaluation of nanosized drug carriers.

胰岛素泵持续强化治疗对妊娠期糖尿病患者血糖控制及新生儿分娩结局效果研究

目的 探讨胰岛素泵持续强化治疗对妊娠期糖尿病(GDM)患者血糖控制及新生儿分娩结局效果研究。方法 随机数字表法将GDM患者70例分成参照组及观察组,各35例,参照组实施常规胰岛素治疗,观察组实施胰岛素泵持续强化治疗;比较两组空腹血糖(FPG)以及餐后2h血糖(plasma glucose 2 hours after meal,2hPG)控制状况的变化,新生儿分娩总不良结局以及产妇不良事件总发生率。结果 治疗后FPG以及2HPG均减少,观察组比参照组减低更明显(P<0.05)。观察组新生儿分娩总不良结局(14.29%)显著低于参照组(37.14%)(P<0.05)。观察组产妇不良事件总发生率(20.00%)明显低于参照组(42.86%)(P<0.05)。结论 应用胰岛素泵持续强化治疗GDM患者,能有效控制患者血糖,降低新生儿分娩不良结局以及产妇不良事件的发生率。

门冬胰岛素联合地特胰岛素治疗妊娠糖尿病优化分娩结局的研究

目的分析门冬胰岛素+地特胰岛素治疗妊娠糖尿病(gestational diabetes,GDM)优化分娩结局的临床效果。方法选取2022年3月—2023年3月在厦门大学附属第一医院治疗的300例GDM患者进行分析,根据随机数表法分为两组(观察组150例,对照组150例),对照组行门冬胰岛素疗法,观察组行门冬胰岛素+地特胰岛素疗法,对比两组患者治疗效果。结果观察组血糖水平优于对照组,差异有统计学意义(P<0.05),两组餐后2 h血糖对比,差异无统计学意义(P>0.05)。观察组血糖恢复时长优于对照组,观察组脂肪因子数据优于对照组,观察组患者胰岛素抵抗情况优于对照组,差异有统计学意义(P<0.05),两组胰岛素空腹水平对比,差异无统计学意义(P>0.05)。观察组患者的不良分娩结局为1.33%,对照组为2.67%,差异无统计学意义(P>0.05)。结论对GDM患者采用门冬胰岛素+地特胰岛素进行治疗,对改善患者的血糖有积极作用,可以优化其分娩结局。

门冬胰岛素联合不同剂量维生素D对GDM患者糖脂代谢、胰岛素抵抗及分娩结局的影响

目的:探讨门冬胰岛素联合不同剂量维生素D治疗妊娠期糖尿病(GDM)对患者糖脂代谢、胰岛素抵抗及分娩结局的影响。方法:本院2018年1月—2022年1月收治的93例GDM患者按照随机数字表法分为低剂量组46例和高剂量组47例,分别给予门冬胰岛素联合低剂量维生素D(10U/次)或(30U/次)治疗1个月。观察两组治疗后糖脂代谢指标及胰岛素抵抗变化,随访两组分娩结局。结果:治疗后与低剂量组比较,高剂量组空腹血糖(5.29±0.76 mmol/L)、餐后2 h血糖(6.64±0.82 mmol/L)、糖化血红蛋白(5.11±0.34)%水平更低,空腹胰岛素(11.89±1.04 mU/L)、胰岛素抵抗指数(3.24±0.41)水平更低,β细胞功能指数(0.98±0.13 mmol/L)水平更高,总胆固醇(3.21±0.75 mmol/L)、甘油三酯(3.03±0.86 mmol/L)、低密度脂蛋白(3.12±0.76)更低,剖宫产(17.0%)、早产(23.4%)、胎膜早破(12.8%)、巨大儿(8.5%)发生率更低(均P<0.05)。结论:门冬胰岛素联合高剂量维生素D更利于GDM患者改善血糖、血脂水平,减轻胰岛素抵抗,降低母婴并发症。

光固化3D打印微针在透皮给药系统中的研究进展

微针是一种新型的透皮给药方式,因具有无痛、生物利用度高及易给药等特点而被广泛关注。介绍了微针的分类和释药机制、光固化3D打印微针技术的原理和优缺点及其应用,重点分析了光固化3D打印微针在皮肤疾病治疗、胰岛素递送、癌症治疗和美容医疗方面应用的研究进展,阐述了光固化3D打印微针具有可以显著提高药物经皮渗透率、提高给药精确性、减少全身副作用的独特优势。最后,对光固化3D打印微针当前面临的材料生物相容性差、载药量低和现行法规不完善等问题进行探讨,并对其发展前景进行了展望。