Controlled Release Of Insulin Research Articles

Synthesis of multi-responsive poly(NIPA-co-DMAEMA)-PBA hydrogel nanoparticles in aqueous solution for application as glucose-sensitive insulin-releasing nanoparticles.

This study aimed to present an innovative method for synthesizing pH-thermo-glucose responsive poly(NIPA-co-DMAEMA)-PBA hydrogel nanoparticles via single-step aqueous free radical polymerization. The synthesis process involved free radical polymerization in an aqueous solution, and the resulting nanoparticles were characterized for their physical and chemical properties by 1H NMR, Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). Insulin-loaded poly(NIPA-co-DMAEMA)-PBA hydrogel nanoparticles were prepared and evaluated for their insulin capture and release properties at different pH and temperature, in addition to different glucose concentrations, with the release profile of insulin quantitatively evaluated using the Bradford method. 1H NMR results confirmed successful PBA incorporation, and DLS outcomes consistently indicated a transition to a more hydrophobic state above the Lower Critical Solution Temperature (LCST) of NIPA and DMAEMA. While pH responsiveness exhibited variation, insulin release generally increased with rising pH from acidic to neutral conditions, aligning with the anticipated augmentation of anionic PBA moieties and increased hydrogel hydrophilicity. Increased insulin release in the presence of glucose, particularly for formulations with the lowest mol % PBA, along with a slight increase for the highest mol % PBA formulation when increasing glucose from 1 to 4mg/mL, supported the potential of this approach for nanoparticle synthesis tailored for glucose-responsive insulin release. This work successfully demonstrates a novel method for synthesizing responsive hydrogel nanoparticles and underscores their potential for controlled insulin release in response to glucose concentrations. The observed pH-dependent insulin release patterns and the influence of PBA content on responsiveness highlight the versatility and promise of this nanoparticle synthesis approach for applications in glucose-responsive drug delivery systems. Poly(NIPA) nanoparticles containing PBA moieties are normally synthesized in two or more steps in the presence of organic solvents. Here we propose a new method for the synthesis of multiresponsive hydrogel poly(NIPA-co-DMAEMA)-PBA nanoparticles in aqueous medium in a single reaction to provide a fast and effective strategy for the production of glucose-responsive multi-systems in aqueous media from free radical polymerization.

Glucose-Responsive Self-Regulated Injectable Silk Fibroin Hydrogel for Controlled Insulin Delivery.

Stimuli-responsive drug delivery systems are gaining importance in personalized medicine to deliver therapeutic doses in response to disease-specific stimulation. Pancreas-mimicking glucose-responsive insulin delivery systems offer improved therapeutic outcomes in the treatment of type 1 and advanced stage of type 2 diabetic conditions. Herein, we present a glucose-responsive smart hydrogel platform based on phenylboronic acid-functionalized natural silk fibroin protein for regulated insulin delivery. The modified protein was synergistically self-assembled and cross-linked through β-sheet and phenylboronate ester formation. The dynamic nature of the bonding confers smooth injectability through the needle. The cross-linked hydrogel structures firmly hold the glucose-sensing element and insulin in its pores and contribute to long-term sensing and drug storage. Under hyperglycemic conditions, the hydrogen peroxide generated from the sensing element induces hydrogel matrix degradation by oxidative cleavage, enabling insulin release. In vivo studies in a type 1 diabetic Wistar rat model revealed that the controlled insulin release from the hydrogel restored diabetic glucose level to physiological conditions for 36 h. This work establishes the functional modification of silk fibroin into a glucose-responsive hydrogel platform for regulated and functional insulin delivery application.

A Closed Loop Stimuli-Responsive Concanavalin A-Loaded Chitosan-Pluronic Hydrogel for Glucose-Responsive Delivery of Short-Acting Insulin Prototyped in RIN-5F Pancreatic Cells.

The optimal treatment of diabetes (in particular, type 1 diabetes-T1D) remains a challenge. Closed-loop systems (implants/inserts) provide significant advantages for glucose responsivity and providing real-time sustained release of rapid-acting insulin. Concanavalin A (ConA), a glucose affinity agent, has been used to design closed-loop insulin delivery systems but not without significant risk of leakage of ConA from the matrices and poor mechanical strength of the hydrogels impacting longevity and control of insulin release. Therefore, this work focused on employing a thermoresponsive co-forming matrix between Pluronic F-127 (PL) and structurally robust chitosan (CHT) via EDC/NHS coupling (i.e., covalent linkage of -NH2 from CHT and ConA to the -COOH of PL). The system was characterized for its chemical structure stability and integrity (FTIR, XRD and TGA), injectability, rheological parameters and hydrogel morphology (Texture Analysis, Elastosens TM Bio2 and SEM). The prepared hydrogels demonstrated shear-thinning for injectability with a maximum force of 4.9 ± 8.3 N in a 26G needle with sol-gel transitioning from 25 to 38 °C. The apparent yield stress value of the hydrogel was determined to be 67.47 Pa. The insulin loading efficiency within the hydrogel matrix was calculated to be 46.8%. Insulin release studies revealed glucose responsiveness in simulated glycemic media (4 and 10 mg/mL) over 7 days (97%) (305 nm via fluorescence spectrophotometry). The MTT studies were performed over 72 h on RIN-5F pancreatic cells with viability results >80%. Results revealed that the thermoresponsive hydrogel is a promising alternative to current closed-loop insulin delivery systems.

Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound

Insulin therapy is the most effective way to control the blood glucose value of diabetic patients. The most effective administration route for insulin is subcutaneous injection because bioavailability for non-injection administration is low and unstable. However, patients often need a multiple daily insulin injection regimen to control basal and postprandial blood glucose, which causes various complications. Controlled pulsatile drug release technology using ultrasound as an external stimulus source is a very promising method to avoid multiple injections of insulin. However, most of the drug-loaded microbubbles used for ultrasound-mediated treatment have a short half-life, which limits their use in controlled pulsatile drug release. More importantly, how to control insulin release is still a challenge. In this paper, chitosan poly-acrylic acid nanobubbles as drug carriers of insulin were prepared to achieve a visually controlled pulsatile release of insulin triggered by focused ultrasound. The experimental results in vivo demonstrated that nanobubbles were stable enough to achieve long-term visualization for 7 days after intramuscular injection in rats. Under the guidance of ultrasound imaging, it is visible to find the position and observe the gray values change of nanobubbles. Thus, when triggered by focused ultrasound, the amount of insulin could be accurately pulsatile released from nanobubbles. In vivo experiments in rats showed that the visually controlled pulsatile release of insulin could be achieved for a long time, up to 3 consecutive days. The blood glucose level could be repeatedly reduced by focused ultrasound irradiation with just one injection. Our research provided a promising way for visually controlled pulsatile release of insulin, which would significantly reduce the injection frequency of insulin.

Managing Diabetes with Hydrogel Drug Delivery

AbstractDiabetes is one of the most pressing healthcare challenges facing society. Dysfunctional insulin signaling causes diabetes, leading to blood glucose instability and many associated complications. While the administration of exogenous insulin is then essential for achieving glucose control, issues with dosing accuracy and timing remain. Hydrogel‐based drug delivery systems have been broadly explored for controlled protein release, including for applications in long‐lasting and oral insulin delivery. More recently, efforts have focused on injectable hydrogels with glucose‐directed controlled release of insulin and glucagon, aiming for more autonomous and biomimetic approaches to blood glucose control. These materials typically use protein‐based sensing mechanisms or glucose binding by synthetic aryl boronates for glucose‐directed release. Despite advancements in this area, there remains a need for more precise timing of therapeutic availability to afford healthy blood glucose homeostasis, providing an opportunity for further research and innovation. This review summarizes the current state of hydrogel‐based delivery of insulin and glucagon, with insights into the potential benefits, future directions, and challenges that must be overcome to achieve clinical impact.

Glucose‐Responsive Microneedle Patch With Variable Crosslinking Density and Flexible Core–Shell Structure for Insulin Delivery

AbstractDeveloping glucose‐responsive microneedle patches with features of simple preparation, high insulin loading, and safety has a great contribution to the treatment of diabetic patients. In this work, a novel glucose‐responsive core–shell microneedle patch is prepared from biocompatible materials by a facile process. The exterior glucose‐responsive shell is composed of polyvinyl alcohol (PVA) and ɛ‐polylysine modified with phenylboronic acid , and the inner flexible core is prepared by pure PVA loaded with insulin. The shell shows superior glucose‐induced swelling and controlled insulin release ability due to the decomposition of borate ester bonds under the synergistic effect of glucose and water. The microneedle patch also features flexibility and high insulin loading capacity (36 IU cm−2). It shows high puncture efficiency (92%) and maintains a relatively complete morphology after being removed, enabling to reduce material residues in the skin. Moreover, the microneedle patch reveals a good hypoglycemic effect in diabetic rats, achieves a hypoglycemic rate similar to that of direct injection after swelling, and works effectively to prevent excess insulin transmission. The high glucose‐responsive ability, simple preparation, high loading capacity, rapid hypoglycemic speed, high conformability to skin, and low component dissolution make this microneedle patch a suitable candidate for diabetic treatment.

Neuroscience: Moving thoughts control insulin release

Insulin release has mostly been studied in the context of metabolic signals. An electrophysiology approach inDrosophila now reveals regulation of insulin-producing cell activity by neuronal circuits controlling locomotion. Even without actual movement, activating these circuits is sufficient to inhibit neuropeptide release.

Controlled release of silica-coated insulin-loaded chitosan nanoparticles as a promising oral administration system

BackgroundOral insulin administration has recently become one of the most exciting research subjects. Different approaches have been carried out to get an effective oral insulin delivery system using nanotechnology. The development of a delivery system that overcomes the difficulties of oral insulin administration, achieving high stability and minimal side effects, is still an urgent need. Therefore, this study is considered one of the efforts to design a new prospective drug delivery nano-composite (silica-coated chitosan-dextran sulfate nanoparticles).MethodsChitosan-dextran sulfate nanoparticles (CS-DS NPs) were prepared via a complex coacervation method and then coated with silica. Uncoated and silica-coated CS-DS NPs were physically characterized via different techniques. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) analysis, and atomic force microscopy (AFM) have been used to investigate the chemical elements, size, morphology, and surface properties of the prepared formulations. Differential scanning calorimetry (DSC) to assess the thermal properties of formed nano-formulations. Fourier transform infrared (FT-IR) spectroscopy investigated the silica coat and chitosan interaction. The encapsulation efficiency was evaluated using high-performance liquid chromatography (HPLC) analysis. The insulin release profile of nano-formulations was performed with and without silica coat at two different pHs (5.5,7), nearly simulating the environment of the gastrointestinal tract (GIT).ResultsThe silica-coated CS-DS NPs revealed interesting physicochemical properties exemplified by suitable core particle size obtained by TEM images (145.31 ± 33.15 nm), hydrodynamic diameter (210 ± 21 nm), high stability indicated by their zeta potential value (-32 ± 3.2 mV), and adequate surface roughness assessed by AFM. The encapsulation efficiency of insulin-loaded chitosan nanoparticles (ICN) was (66.5%) higher than that of insulin-chitosan complex nanoparticles (ICCN). The silica-coated ICN demonstrated a controlled insulin release profile at pHs (5.5 and 7) compared with uncoated ICN.ConclusionThe silica-coated ICN can be an efficient candidate as a desired oral delivery system, overcoming the common obstacles of peptides and proteins delivery and achieving high stability and controlled release for further applications.

Functionalized zein nanoparticles targeting neonatal Fc receptor to enhance lung absorption of peptides

Peptides have a distinguished therapeutic potential for several chronic conditions, and more than 80 peptides exist in the global market. However, most of these marketed peptide drugs are currently delivered intravenously or subcutaneously due to their fast degradation and limited absorption through non-invasive routes. The pulmonary route is favored as a non-invasive route. Neonatal Fc receptor (FcRn) is expressed in adult human lungs and has a role in enhancing the pulmonary absorption of monoclonal antibodies. In this work, we developed and characterized candidate protein delivery systems for the pulmonary administration of peptides. The prepared bare and loaded zein nanoparticles (ZNPs), targeted, physically, and covalently PEGylated ZNPs showed hydrodynamic diameters between 137 and 155 nm and a narrow distribution index. Insulin, which was used as a protein model, showed an association efficiency of 72%, while the FcRn-targeted peptide conjugation efficiency was approximately 68%. The physically adsorbed poloxamer 407 on insulin-loaded ZNPs showed slower and controlled insulin release. The in vitro cell culture model consists of the NCI-H441 epithelial cell line, which confirmed its expression of the targeted receptor, FcRn. The safety of ZNPs was verified after incubation with both cell lines of the in vitro pulmonary model, namely NCI-H441 and HPMEC-ST1.6R, for 24 h. It was observed that targeted ZNPs enhanced insulin permeability by showing a higher apparent permeation coefficient than non-targeted ZNPs. Overall, both targeted PEGylated ZNPs showed to be suitable peptide carriers and adequately fit the demands of delivery systems designed for pulmonary administration.Graphical

Glucose-responsive nanogate of poly(methacrylic acid) brush-glucosamine network capping on the holes of chips for controlled insulin release

BackgroundDiabetes mellitus is a disease caused by deficient glycemic control by the pancreas that has caused serious health issues globally. Patients must inject insulin manually to stabilize their blood glucose levels (BGLs). MethodsA hole array was fabricated on a silicon wafer to graft poly(methacrylic acid) (PMAA) brushes from the silicon surface via atom transfer radical polymerization. Glucosamine (GA) was sequentially immobilized on the PMAA chains to obtain a P(MAA-GA) brush surrounding the hole edges on the silicon surface. After loading insulin inside the holes, biphenyl-4,4′-diboronic acid (DBA) was used to cross-link the P(MAA-GA) chains through the formation of boronate esters to cap the hole and block the release of insulin. Significant findingsThe boronate esters were disassociated with glucose solution to open of the holes and the release of insulin, thus indicating a reversible association. The total amount of drug inside the chip was approximately 32.4 ± 1.8 g cm−2, which could be released at a rate of approximately 107 ± 5.7 ng h−1 cm−2 at a glucose concentration of 1 g L−1 for 270 h. Drug release was not significantly influenced by the presence of GA and amino acids, indicating excellent stability and selectivity of the chip.

A Closed-Loop Autologous Erythrocyte-Mediated Delivery Platform for Diabetic Nephropathy Therapy.

Failure to control blood glucose level (BGL) may aggravate oxidative stress and contribute to the development of diabetic nephropathy (DN). Using erythrocytes (ERs) as the carriers, a smart self-regulatory insulin (INS) release system was constructed to release INS according to changes in BGLs to improve patients’ compliance and health. To overcome the limited sources of ERs and decrease the risk of transmitting infections, we developed an in vitro, closed-loop autologous ER-mediated delivery (CAER) platform, based on a commercial hemodialysis instrument modified with a glucose-responsive ER-based INS delivery system (GOx-INS@ER). After the blood was drained via a jugular vein cannula, some of the blood was pumped into the CAER platform. The INS was packed inside the autologous ERs in the INS reactor, and then their surface was modified with glucose oxidase (GOx), which acts as a glucose-activated switch. In vivo, the CAER platform showed that the BGL responsively controlled INS release in order to control hyperglycemia and maintain the BGL in the normal range for up to 3 days; plus, there was good glycemic control without the added burden of hemodialysis in DN rabbits. These results demonstrate that this closed-loop extracorporeal hemodialysis platform provides a practical approach for improving diabetes management in DN patients.

Oral Glucose-Responsive Nanocarrier System for Management of Diabetes

Background: The regulation of postprandial blood glucose concentration in a diabetic person is a toilsome task by the conventional approaches. The continuous monitoring and subcutaneous injection of insulin are always imperative for diabetes management. To overcome the hurdle associated with the conventional system, a glucose-responsive nanoparticle (NP)-based approach was developed for oral insulin administration. The objective of the work is the formulation and characterization of a nanocarrier-based bio-responsive, self-regulated oral insulin drug delivery system. Methods: The mannose ligand-conjugated NPs were prepared by the inotropic gelation method in which insulin and glucose oxidase enclosed alginate nanocarrier cross-linked by tripolyphosphate. The prepared NPs were filled into the enteric-coated capsule and their release profile was determined at different pH and glucose concentrations. NPs were characterized by size distribution, % drug entrapment, enzyme activity, and in vivo and in vitro drug release studies. Results: The average size, surface potential, % drug entrapment of optimized NPs were 245.52 ± 3.37 nm, 22.12 ± 2.13, and 76.15±1.3%, respectively. The release of insulin from optimized NPs (GOx-ALG-MCNPs) (98.56±0.06%) occurs only at higher sugar concentrations (? 400 mg/dL) and prevents the release at low sugar concentrations (< 100 mg/dL). The enteric capsule shell protected the formulation to the gastric environment upon oral administration and directed them into the intestine. Mucoadhesion characteristics of NPs prolonged intestinal retention to make them available for cellular uptake. Glucose sensitivity and glucose-dependent effect on different pH environments study revealed that NPs released the drug only at higher concentrations of sugar solution while inhibiting the release at normal and lower sugar concentrations. Besides, compared to other prepared formulations, the GOx-ALG-MCNPs displayed controlled insulin release in response to glucose concentration. Conclusions: An important finding of GOx-ALG-MCNPs is auto-regulating, glucose-responsive behavior imparting a significantly controlled lowering of blood glucose in an animal model. The findings reveal that the developed glucose-responsive NPs may prove to be a potential strategy for oral insulin delivery. J Endocrinol Metab. 2022;12(4-5):146-160 doi: https://doi.org/10.14740/jem747

Synthesis and characterization of 4-formylphenylboronic acid cross-linked chitosan hydrogel with dual action: Glucose-sensitivity and controlled insulin release

The number of people affected by diabetes mellitus is increasing globally in each year. A cause of elevated blood glucose levels can result from a lack of insulin or insufficient utilization of produced insulin. However, diabetes, a metabolic disorder is a serious chronic disease and an acute public health problem. Glucose-sensitive hydrogels that have 3D network structure can act in response to glucose and garners immense attention in biomedical appliance especially for drug delivery. Herein, a novel, glucose- and pH-responsive intelligent hydrogel encompassing chitosan cross-linked to 4-formylphenylboronic acid is prepared via dynamical reversible chemical bonds (imine) between chitosan and 4-formylphenylboronic acid with potential of controlled release of insulin. The characteristic features of such hydrogels are confirmed by Fourier transformed infrared (FT-IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and swelling ratio. Of these, the glucose-sensitive polymeric carrier (hydrogel) based on 4-formylphenylboronic acid has the advantages of enhanced stability, long-term storage, reversible response to glucose with high entrapment efficiency and controlled drug release into the physiological condition. In this paper, chitosan cross-linked with 4-formylphenylboronic acid, comprising the realization of Schiff base bearing (–C=N–) linkage, leads to the generation of a hydrogel which works better than normal phenylboronic acid (PBA) under physiological setting. The ensuing outcome implies that the glucose-susceptible hydrogel has prospective appliance as a glucose-receptive matter for insulin transport.

Electrical signals regulate the release of insulin from electrodeposited chitosan composite hydrogel: An in vitro and in vivo study.

Electrical signal controlled drug release from polymeric drug delivery system provides an efficient way for accurate and demandable drug release. In this work, insulin was loaded on inorganic nanoplates (layered double hydroxides, LDHs) and coated on a copper wire by co-electrodeposition with chitosan. The formed structure in chitosan composite hydrogel entrapped insulin efficiently, which were proved by various techniques. In addition, the drug loaded chitosan composite hydrogel demonstrated good biocompatibility as suggested by cell attachment. In vitro drug release experiment showed fast responsive pulsed release of insulin by biasing electrical signals. The in vivo experiment in diabetic rats revealed controllable insulin release in plasma and stable decrease of blood glucose can be achieved by using appropriate electrical signal. In addition, HE staining suggested negligible effect to the tissue by electrical signals. This work suggests that the electrical signal controlled insulin release from chitosan composited hydrogel may be a promising administration route for insulin.

An all-in-one CO gas therapy-based hydrogel dressing with sustained insulin release, anti-oxidative stress, antibacterial, and anti-inflammatory capabilities for infected diabetic wounds

To effectively treat diabetic wounds, the development of versatile medical dressings that can long-term regulate blood glucose and highly effective anti-oxidative stress, antibacterial and anti-inflammatory are critical. Here, an all-in-one CO gas-therapy-based versatile hydrogel dressing (ICOQF) was developed via the dynamic Schiff base reaction between the amino groups on quaternized chitosan (QCS) and the aldehyde groups on benzaldehyde-terminated F108 (F108-CHO) micelles. CORM-401 (an oxidant-sensitive CO-releasing molecules) was encapsulated in the hydrophobic core of F108-CHO micelles and insulin was loaded in the three-dimensional network structure of ICOQF. The dynamic Schiff base bonds not only endowed ICOQF with good tissue adhesion, injectability and self-healing, but also gave it sustained and controllable insulin release ability. In addition, ICOQF could quickly generate CO in inflamed wound tissue by consuming reactive oxygen species. The generated CO could effectively anti-oxidative stress by activating the expression of heme oxygenase; antibacterial by inducing the rupture of bacterial cell membranes and mitochondrial dysfunction and inhibiting the synthesis of adenosine triphosphate; and anti-inflammatory by inhibiting the proliferation of activated macrophages and promoting the polarization of the M1 phenotype to the M2 phenotype. Due to these outstanding properties, ICOQF significantly promoted the healing of STZ-induced MRSA-infected diabetic wounds accompanied by good biocompatibility. This study clearly shows that ICOQF is a versatile hydrogel dressing with great application potential for the management of diabetic wounds. Statement of significanceThe development of some versatile hydrogel dressings that can not only provide a prolonged and controlled insulin release property but also utilize a non-antibiotic treatment modality for highly effective antibacterial, anti-inflammatory, and anti-oxidative stress effects is vital for the successful treatment of diabetic wounds. Herein, we developed an all-in-one CO gas-therapy-based versatile hydrogel dressing (ICOQF) with sustained and controllable insulin release abilities. Moreover, ICOQF could not only quickly release CO in the inflamed wound tissue by consumption of reactive oxygen species but also utilize the generated CO to highly effectively anti-oxidative stress, antibacterial, and anti-inflammatory. ICOQF therapy substantially promoted the healing of STZ-induced MRSA-infected diabetic wounds. Overall, this work provides a multifunctional hydrogel dressing for the management of diabetic wounds.

Glucose inhibits glucagon secretion by decreasing [Ca2+]c and by reducing the efficacy of Ca2+ on exocytosis via somatostatin-dependent and independent mechanisms

ObjectiveThe mechanisms by which glucose stimulates insulin secretion from β-cells are well established and involve inhibition of ATP-sensitive K+ (KATP) channels, followed by a rise in [Ca2+]c that triggers exocytosis. However, the mechanisms by which glucose controls glucagon release from α-cells are much less known. In particular, it is debated whether the sugar controls glucagon secretion by changing α-cell [Ca2+]c, and whether KATP channels or paracrine factors are involved. The present study addresses these issues. MethodsWe tested the effect of a decrease or an increase of glucose concentration (Gx, with x = concentration in mM) on α-cell [Ca2+]c and glucagon secretion. α-cell [Ca2+]c was monitored using GluCreGCaMP6f mice expressing the Ca2+-sensitive fluorescent protein, GCaMP6f, specifically in α-cells. [Ca2+]c was compared between dispersed α-cells and α-cells within islets to evaluate the potential contribution of an indirect effect of glucose. The same protocols were used for experiments of glucagon secretion from whole islets and [Ca2+]c measurements to test if changes in glucagon release mirror those in α-cell [Ca2+]c. ResultsBlockade of KATP channels by sulfonylureas (tolbutamide 100 μM or gliclazide 25 μM) strongly increased [Ca2+]c in both dispersed α-cells and α-cells within islets. By contrast, glucose had no effect on [Ca2+]c in dispersed α-cells, whereas it affected it in α-cells within islets. The effect of glucose was however different in islets expressing (Sst+/+) or not somatostatin (SST) (Sst−/−). Decreasing glucose concentration from G7 to G1 modestly increased α-cell [Ca2+]c, but to a slightly larger extent in Sst+/+ islets than in Sst−/− islets. This G1-induced [Ca2+]c rise was also observed in the continuous presence of sulfonylureas in both Sst+/+ and Sst−/− islets. Increasing glucose concentration from G7 to G20 did not affect α-cell [Ca2+]c in Sst+/+ islets which remained low, whereas it strongly increased it in Sst−/− islets. The observations that this increase was seen only in α-cells within islets but never in dispersed α-cells and that it was abrogated by the gap junction inhibitor, carbenoxolone, point to an indirect effect of G20 and suggest that, in Sst−/− islets, G20-stimulated β-cells entrain α-cells whereas, in Sst+/+ islets, the concomitant release of SST keeps α-cell [Ca2+]c at low levels. The [Ca2+]c lowering effect of endogenous SST is also supported by the observation that SST receptor antagonists (SSTR2/3) increased [Ca2+]c in α-cells from Sst+/+ islets. All these [Ca2+]c changes induced parallel changes in glucagon release. To test if glucose also controls glucagon release independently of [Ca2+]c changes, additional experiments were performed in the continuous presence of 30 mM K+ and the KATP channel opener diazoxide (250 μM). In these conditions, α-cell [Ca2+]c within islets was elevated and its steady-state level was unaffected by glucose. However, decreasing the glucose concentration from G7 to G1 stimulated glucagon release whereas increasing it from G1 to G15 inhibited it. These effects were also evident in Sst−/− islets, and opposite to those on insulin secretion. ConclusionsWe propose a model according to which glucose controls α-cell [Ca2+]c and glucagon secretion through multiple mechanisms. Increasing the glucose concentration modestly decreases [Ca2+]c in α-cells independently of their KATP channels and partly via SST. The involvement of SST increases with the glucose concentration, and one major effect of SST is to keep α-cell [Ca2+]c at low levels by counteracting the effect of an entrainment of α-cells by β-cells when β-cells become stimulated by glucose. All these [Ca2+]c changes induce parallel changes in glucagon release. Glucose also decreases the efficacy of Ca2+ on exocytosis by an attenuating pathway that is opposite to the well-established amplifying pathway controlling insulin release in β-cells.

Controlled Release of Insulin Based on Temperature and Glucose Dual Responsive Biomicrocapsules.

The treatment of diabetes lies in developing novel functional carriers, which are expected to have the unique capability of monitoring blood glucose levels continuously and dispensing insulin correctly and timely. Hence, this study is proposing to create a smart self-regulated insulin delivery system according to changes in glucose concentration. Temperature and glucose dual responsive copolymer microcapsules bearing N-isopropylacrylamide and 3-acrylamidophenylboronic acid as main components were developed by bottom-spray coating technology and template method. The insulinoma β-TC6 cells were trapped in the copolymer microcapsules by use of temperature sensitivity, and then growth, proliferation, and glucose-responsive insulin secretion of microencapsulated cells were successively monitored. The copolymer microcapsules showed favorable structural stability and good biocompatibility against β-TC6 cells. Compared with free cells, the biomicrocapsules presented a more effective and safer glucose-dependent insulin release behavior. The bioactivity of secreted and released insulin did not differ between free and encapsulated β-TC6 cells. The results demonstrated that the copolymer microcapsules had a positive effect on real-time sensing of glucose and precise controlled release of insulin. The intelligent drug delivery system is supposed to mimic insulin secretion in a physiological manner, and further provide new perspectives and technical support for the development of artificial pancreas.

Efficient oral insulin delivery enabled by transferrin-coated acid-resistant metal-organic framework nanoparticles.

Oral protein delivery is considered a cutting-edge technology to improve patients’ quality of life, offering superior patient compliance and convenience compared with injections. However, oral protein formulation has stagnated because of the instability and inefficient penetration of protein in the gastrointestinal tract. Here, we used acid-resistant metal-organic framework nanoparticles (UiO-68-NH2) to encapsulate sufficient insulin and decorated the exterior with targeting proteins (transferrin) to realize highly efficient oral insulin delivery. The UiO-68-NH2 nanocarrier with proper pore size achieved high insulin loading while protecting insulin from acid and enzymatic degradation. Through receptor-mediated transcellular pathway, the transferrin-coated nanoparticles realized efficient transport across the intestinal epithelium and controlled insulin release under physiological conditions, leading to a notable hypoglycemic effect and a high oral bioavailability of 29.6%. Our work demonstrates that functional metal-organic framework nanoparticles can protect proteins from the gastric environment and overcome the intestinal barrier, thus providing the possibility for oral biomacromolecule delivery.

Glycopolymer Nanoparticles with On-Demand Glucose-Responsive Insulin Delivery and Low-Hypoglycemia Risks for Type 1 Diabetic Treatment

Diabetic patients with type 1 or advanced type 2 stages need timely and precise insulin injection to regulate the daily blood glucose levels (BGLs). Otherwise, risks of serious or even deadly diabetes-associated complications occur. To achieve prolonged glucose regulation and low hypoglycemia risks, a novel on-demand glucose-responsive glycopolymer system was constructed for insulin delivery, which was self-assembled into nanoparticles by dynamic covalent bonds between two polymers: fluorophenylboronic acid-grafted polymer (poly-F) and polyol polymer (poly-G). Insulin was loaded during the assembly process. The nanoparticles showed excellent glucose responsiveness in vitro, with controlled insulin release at different glucose concentrations. In vivo treatment on type 1 diabetic mice showed prolonged BGL regulation and lower hypoglycemia risks. The mild preparation of the nanoparticles and outstanding glucose control shed light on the optional diabetic treatment for further clinical use.

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes