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IcoSema, a groundbreaking approach to diabetes management, combines insulin icodec and semaglutide to offer a transformative treatment option. Insulin icodec delivers consistent glucose-lowering effects with once-weekly dosing, while semaglutide, a GLP-1 agonist, stimulates insulin secretion and aids in weight loss. This comprehensive article evaluates the potential of IcoSema from a clinical pharmacology perspective, examining the pharmacokinetics, efficacy, safety, compliance and cost-effectiveness of its individual components, as well as considering comparable combination therapies like iGlarLixi and IDegLira. By analysing these crucial factors, the article aims to determine the potential of IcoSema in the field of diabetes management. The combination of insulin icodec and semaglutide has the potential to provide improved glycaemic control, weight management, and simplified treatment regimens, addressing common challenges faced in diabetes management. Safety, compliance and cost considerations are important aspects of evaluating this combination therapy. Ongoing trials investigating IcoSema are expected to provide valuable insights into its efficacy, safety and comparative effectiveness. By addressing concerns such as potential side effects, individual patient response and drug interactions, healthcare providers can optimize treatment outcomes and enhance the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article focuses the high cost of insulin is a serious problem for many people with diabetes. It mentions analog insulins are more expensive than human insulins, but there is no evidence that they are more effective. It highlights multiple studies have shown that human insulins are just as effective as analog insulins.

The article discusses the limitations of relying solely on the "time below range" (TBR) metric in continuous glucose monitoring for people with diabetes. It highlights that TBR may not capture the full risk of hypoglycemia and emphasizes the need to consider other factors like frequency and patterns of low blood sugar events to ensure individual safety and well-being. It suggests a holistic approach for healthcare professionals when assessing diabetes management.

Insulin exposure varies over 3 days of insulin infusion set (IIS) wear making day-to-day insulin dosing challenging for people with diabetes (PWD). Here we report pharmacodynamic (PD) and pharmacokinetic (PK) data extending these observations to 7 days of IIS wear. PWD (A1C ≤8.5%, C-peptide <0.6 nmol/L, ≥6 months pump use) were enrolled in a crossover euglycemic clamp pilot study comparing conventional Teflon angled IISs to an investigational extended-wear IIS. PK/PD data from 6 participants was obtained for 5 hours post-bolus. While PD data were unstable, PK profiles of insulin lispro (0.15 U/kg bolus) show statistically significant, progressive decreases from Day 0 to 7 for tmax (p<0.001), t50%(early) (p<0.002), t50%(late) (p<0.001), and Mean Residence Time (p<0.001). AUC0-300 declined by approximately 22% from Day 0 to 7 (n.s.). These results confirm/extend previous observations showing progressive acceleration of insulin exposure over IIS wear time. This may have implications for PWD and designers of closed-loop algorithms, although larger studies are necessary to confirm this. [ABSTRACT FROM AUTHOR]

An intelligent insulin delivery system targeting intestinal absorption and glucose responsiveness can enhance the bioavailability through oral insulin therapy, offering promising diabetes treatment. In this paper, a glucose and pH dual-response polymer hydrogel using carboxymethyl agarose modified with 3-amino-phenylboronic acid and l-valine (CPL) was developed as an insulin delivery carrier, exhibiting excellent biocompatibility and effective insulin encapsulation. The insulin encapsulated in the hydrogel (Ins-CPL) was released in a controlled manner in response to the in vivo stimulation of blood glucose and pH levels with higher levels of intracellular uptake and utilization of insulin in the intestinal environment simultaneously. Notably, the Ins-CPL hydrogel effectively regulated blood sugar in diabetic rats over a long period by simulating endogenous insulin, responding to changes in plasma pH and glucose levels, and overcoming the intestinal epithelium barrier. This indicates a significant boost in oral insulin bioavailability and broadens its application prospects.

Intranasal insulin is a putative neuroprotective therapy after cardiac arrest, but safety in humans at doses extrapolated from animal models is unknown. This phase I, open-label adaptive dose-escalation study explores the maximum tolerated dose of intranasal insulin in healthy human participants. Placebo or insulin at doses from 0 to 1000 units was given to healthy participants intranasally on repeated weekly visits. Serum glucose, insulin, and C-peptide levels were measured serially at 0, 15, 30, 60, 120, 180, and 240 min after administration. Twenty-four participants (12 female, median age 53, IQR 35-61) were enrolled. There was minimal change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose-dependent manner, reaching maximum concentrations at 15 min. C-peptide decreased over time from administration in all groups. One participant had severe hypoglycemia (24 mg/dL at 45 min) and a different participant had mild hypoglycemia (51 mg/dL at 30 min), both after receiving 600 U intranasal insulin. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. High-dose intranasal insulin up to 1000 U was generally well tolerated, with minimal measurable systemic absorption and without significant aggregate changes in mean glucose. Idiosyncratic episodic systemic absorption and hypoglycemia require further study and additional caution in potential clinical application. Further study of its target engagement and efficacy as a neuroprotective therapy after cardiac arrest at these doses is warranted., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Objective: IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM)., Methods: In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose., Results: Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC 0-t : ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (C max ): 1.12 [1.06; 1.18]. Semaglutide AUC 0-t was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide C max was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone., Conclusion: The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema., Clinical Trial: ClinicalTrials.gov identifier: NCT03789578., Competing Interests: Declarations Funding This study was funded by Novo Nordisk. Conflicts of interest L.W., L.A., S.T.B., T.K., N.R.K., E.N., L.N., T.M.P.R., D.B.S. and A.V. are employees and shareholders of Novo Nordisk. H.V.C. has no conflicts of interest to disclose. L.P.-M. is an employee and shareholder of Profil. Profil received research funds from Adocia, AstraZeneca, Betagenon, Biocon, Bioton, Crinetics, Eli Lilly, Genova, Nanexa, NeoDyne, Novo Nordisk, Sanofi, Spiden and Zealand Pharma. L.P.-M. received speaker honoraria from Eli Lilly, Gan and Lee Pharmaceuticals and Novo Nordisk. Availability of data and material Individual participant data will be shared in data sets in a de-identified/anonymised format. Datasets from Novo Nordisk sponsored clinical research completed after 2001 for product indications approved in both the EU and USA will be shared. Study protocol and redacted clinical study report will be available according to Novo Nordisk data sharing commitments. The data will be available permanently after research completion and approval of product and product use in both EU and USA. There is no end date. Data will be shared with bona fide researchers submitting a research proposal requesting access to data for use as approved by the independent review board according to the independent review board charter (see novonordisk-trials.com). The data will be made available on a specialised SAS data platform. Individual data from animal studies and in vitro studies will be shared upon reasonable request. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The clinical study was approved by an independent ethics committee (Ärztekammer Nordrhein, Düsseldorf, Germany; approval ID 2018242; approval date 12 November 2018). Animal studies were performed according to the Danish Act on Experiments on Animals, the Appendix A of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS 123), and European Union Directive 2010/63. The animal studies were performed under licenses granted by the Danish national Animal Experiments Inspectorate (no. 2010/561-1786 and no. 2015-15-0201-00540). Consent to participate Informed consent was obtained from all individual participants included in the clinical study. Consent for publication Not applicable. Code availability Not applicable. Author contributions L.W., N.R.K., L.N. and T.M.P.R. contributed to clinical study data analysis, critical manuscript revision and final manuscript approval; L.A., S.T.B., T.K., E.N., D.B.S. and A.V. contributed to animal and in vitro study design, data analysis, critical manuscript revision and final manuscript approval; H.V.C. and L.P.-M. contributed to clinical study data collection, critical manuscript revision and final manuscript approval., (© 2024. The Author(s).)

Colon-targeted delivery offers several benefits for oral protein delivery, such as low proteolytic enzyme activity, a natural pH environment, and extended residence time, which improve the bioavailability of the encapsulated protein. Therefore, we hypothesize that developing a novel colonic nanocarrier system, featuring modified chitosan that is soluble at physiological pH and coated with a colon-degradable polymer, will provide an effective delivery system for oral insulin. This study aims to synthesize insulin-loaded pectin-trimethyl chitosan nanoparticles (Ins-P-TMC-NPs) as an oral insulin delivery system and to evaluate its efficacy both in vitro and in vivo. N-trimethyl chitosan (TMC), synthesized via a methylation method, was used to prepare insulin-TMC nanoparticles coated with pectin via the ionic gelation method. The nanoparticles were characterized for their physicochemical properties, cumulative release profile, and surface morphology. The in vitro biological cytotoxicity and cellular uptake of the nanoparticles were evaluated against HT-29 cells. The in vivo blood glucose-lowering effect and histological toxicity were assessed in diabetic male Sprague-Dawley rats. The results showed that Ins-P-TMC-NPs were spherical, with an average size of 379.40 ± 40.26 nm, a polydispersity index of 24.10 ± 1.03 %, a zeta potential of +17.20 ± 0.52 mV, and a loading efficiency of 83.21 ± 1.23 %. Compared to uncoated TMC nanoparticles, Ins-P-TMC-NPs reduced insulin loss in simulated gastrointestinal fluid by approximately 67.23 ± 0.97 % and provided controlled insulin release in simulated colonic fluid. In vitro bioactivity studies revealed that Ins-P-TMC-NPs were non-toxic, with cell viability of 91.12 ± 0.91 % after 24 h of treatment, and exhibited high cellular uptake in the HT-29 cell line with a fluorescence intensity of 37.80 ± 2.40 after 4 h of incubation. Furthermore, the in vivo study demonstrated a sustained reduction in blood glucose levels after oral administration of Ins-P-TMC-NPs, peaking after 8 h with a blood glucose reduction of 87 ± 1.03 %. Histological sections showed no signs of toxicity when compared to those of healthy rats. Overall, the developed colon-targeted oral insulin delivery system exhibits strong potential as a candidate for effective oral insulin administration., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The objective of this research was to optimize the composition and performance of chitosan-coated solid lipid nanoparticles carrying insulin (Ch-In-SLNs) and to assess the potential of piperine in enhancing the intestinal permeability of insulin from these SLNs in vitro. The SLNs were formulated from glyceryl behenate (GB), soya lecithin, and poloxamer® 407, and then coated with a combination of chitosan and piperine to facilitate insulin penetration across the gastrointestinal (GI) mucosa. A Box-Behnken Design (BBD) was utilized to optimize the Ch-In-SLNs formulations, with PDI, particle size, zeta potential, and association efficiency (AE) serving as the response variables. The resulting Ch-In-SLNs exhibited excellent monodispersity (PDI = 0.4), optimal particle size (654.43 nm), positive zeta potential (+36.87 mV), and low AE values. The Ch-In-SLNs demonstrated sustained release of insulin for 12 h in simulated gastric fluid (SGF) and intestinal fluid (SIF), with increased release in the latter. After incubation in SGF and SIF for 12 h, the insulin SLNs retained 54 and 41 % of their initial insulin load, respectively, indicating effective protection from gastric enzymes. Permeation studies using goat intestine and Caco-2 cell lines indicated improved insulin permeation in the presence of piperine. Additionally, cell uptake studies confirmed the role of piperine in enhancing insulin permeation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61 N/Needle, and skin penetration rate was 97%, with a penetration depth of 215 μm. The tips of the FD-MNP dissolved completely within approximately 60 s after skin penetration, which is much faster than conventional MNP (180 s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery., (© 2024. Controlled Release Society.)

The nasal route of administration can bypass the blood-brain barrier in order to obtain a higher concentration in the brain, thus offering a feasible alternative route of administration for diseases associated with the central nervous system. The advantages of the intranasal administration and the potential favorable therapeutic effects of intranasally administered insulin led to the formulation of carboxymethyl chitosan (CMC) and sodium hyaluronate (NaHA) hydrocolloidal systems with insulin for nasal administration, targeting nose-to-brain delivery and the initial assessment of these systems. The influence of the formulation variables on the response parameters defined as surface properties, rheology, and in vitro release of insulin were analyzed using experimental design and statistical programs (Modde and Minitab software). The systems recorded good wetting and adhesion capacity, allowing the spread of the hydrocolloidal systems on the nasal mucosa. The samples had a pseudoplastic flow and the rapid release of the insulin was according to our objective. According to the physico-chemical characterization and preliminary assessment, these formulations are appropriate for administration on the nasal mucosa, but further studies are necessary to demonstrate the beneficial therapeutic actions and the safety of using intranasal insulin.

Purpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers., Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract., Results: The nano-micelles, with a particle size of <100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (C max ) and AUC 0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h., Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Kang et al.)

Background: Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injection. However, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Methods: To promote penetration across the intestinal epithelium and achieve enhanced and safe glucose-responsive oral insulin delivery, pH and H 2 O 2 dual-sensitive nanoparticles (NPs) were constructed. The NPs were loaded of glucose oxidase (GOx) and insulin by pH and H 2 O 2 dual-sensitive amphiphilic polymer incorporated with phenylboronic ester-conjugated poly(2-hydroxyethyl methacrylate) and poly(carboxybetaine) (PCB). The dual-sensitive NPs were utilized for the treatment of type 1 diabetes mellitus (T1DM) after oral administration. Results: The dual-sensitive NPs could enhance the transport of insulin across the intestinal epithelium into blood facilitated by zwitterionic PCB. By virtue of the generated low pH and high H 2 O 2 with GOx in hyperglycemic environment, the pH and H 2 O 2 dual-sensitive NPs were disassembled to achieve rapid and sustained release of insulin. After oral administration of the dual-sensitive NPs in enteric capsules into T1DM mouse model, the oral bioavailability of insulin reached 20.24%, and the NPs achieved hypoglycemic effect for a few hours longer than subcutaneously injected insulin. Importantly, the pH and H 2 O 2 dual-sensitive NPs could ameliorate the local decline of pH and rise of H 2 O 2 to avoid the toxic side effect. Conclusion: Therefore, this work would provide a promising platform for the enhanced and safe treatment of diabetes mellitus., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Successful oral insulin administration can considerably enhance the quality of life (QOL) of diabetes patients who must frequently take insulin injections. However, Oral insulin administration is seriously hampered by gastrointestinal enzymes, wide pH range, mucus and mucosal layers, which limit insulin oral bioavailability to ≤2 %. Herein, we developed a simple, inexpensive and safe dual β-cyclodextrin/dialdehyde glucan-coated keratin nanoparticle (β-CD-K-IN-DG). The resulted β-CD-K-IN-DG not only gave the ultra-high insulin loading (encapsulation efficiency (98.52 %)), but also protected insulin from acid and enzymatic degradation. This β-CD-K-IN-DG had a notable hypoglycemic effect, there was almost 80 % insulin release after 4 h of incubation under hyperglycemic conditions. Ex vivo results confirmed that β-CD-K-IN-DG possessed high mucus-penetration ability. Transepithelial transport and uptake mechanism studies revealed that bypass transport pathway and endocytosis promoted β-CD-K-IN-DG entered intestinal epithelial cells, thus increased the bioavailability of insulin (12.27 %). The improved stability of insulin during in vivo transport implied that β-CD-K-IN-DG might be a potential tool for the effective oral insulin administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This manuscript has been published as “Keratin-based Nanoparticles for Oral Delivery of Insulin (doi:10.21203/rs.3.rs-3807836/v1)” on the preprint server Research Square at https://www.researchsquare.com/home. DOIs issued by Research Square have a specific DOI structure for preprints. This allows them to be linked to the final published journal article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: A new generation of basal insulin analogs enabling once-weekly administration is currently under development. Weekly basal insulins have the potential to overcome limitations exhibited by current daily basal insulins. The pharmacokinetic and glucodynamic characteristics differ significantly between weekly and daily basal insulins and will require paradigm shifts in how basal insulins are dosed., Methods: An overview of pharmacokinetic and glucodynamic principles of basal insulins is presented. Specifically, the pharmacokinetic and glucodynamic properties of daily basal insulins and how these differ for the new weekly basal insulins are discussed. Finally, models and simulations are used to describe the impact of weekly insulin properties on dosing., Results: Two approaches have been used to extend the half-lives of these insulins, creating fusion proteins with reduced clearance and reduced receptor-mediated degradation of the insulin. The resulting prolonged exposure-response profiles affect dosing and the impact of dosing errors. Specifically, the impact of loading doses, missed doses, and double doses, and the effect on glycemic variability of a once weekly basal insulin option are demonstrated using pharmacokinetic/glucodynamic models and simulations., Conclusions: The transition from daily to weekly basal insulin dosing requires an understanding of the implications of the prolonged exposure-response profiles to effectively and confidently incorporate these weekly basal insulins into clinical practice. By reviewing the application of pharmacokinetic and glucodynamic principles to daily basal insulin analogs, the differences with weekly basal insulins, and the impact of these properties on dosing, this review intends to explain the principles behind weekly basal insulin dosing., Competing Interests: Disclosure J.L., J.B.V., J.C., and K.S. are employees and shareholders in Eli Lilly and Company. T.R.P. reports grant support paid the Medical University of Graz by Arecor, AstraZeneca, Novo Nordisk and Sanofi; personal compensation for consultation from Arecor, AstraZeneca, Eli Lilly, Novo Nordisk and Sanofi. R.J. was an Executive Director of Diabetes Global Medical Affairs at Lilly, during which he contributed to this article. R.J. is currently a Senior Director, Clinical Development Strategy, at Novo Nordisk Inc, which provided no review of, or other support for, this article. J.B.B. reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by Dexcom, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion Inc, Boehringer-Ingelheim, CeQur, Cirius Therapeutics Inc, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns Inc, Valo and Zealand Pharma; stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health; and board membership of the Association of Clinical and Translational Science., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Oral insulin (INS) is predicted to have the most therapeutic advantages in treating diabetes to repress hepatic glucose production through its potential to mimic the endogenous insulin pathway. Many oral insulin delivery systems have been investigated. Layered double hydroxide (LDH) as an inorganic material has been widely used in drug delivery thanks to its appealing features such as good biocompatibility, low toxicity, and excellent loading capability. However, when used in oral drug delivery, the effectiveness of LDH is limited due to the acidic degradation in the stomach. In this study, to overcome these challenges, chitosan (Chi) and alginate (Alg) dual-coated LDH nanocomposites with the loading of insulin (Alg-Chi-LDH@INS) were developed by the layered-by-layered method for oral insulin delivery with dynamic size of ~ 350.8 nm, negative charge of ~  - 13.0 mV, and dispersity index 0.228. The insulin release profile was evaluated by ultraviolet-visible spectroscopy. The drug release profiles evidenced that alginate and chitosan coating partially protect insulin release from a burst release in acidic conditions. The analysis using flow cytometry showed that chitosan coating significantly enhanced the uptake of LDH@INS by Caco-2 cells compared to unmodified LDH and free insulin. Further in the in vivo study in streptozocin-induced diabetic mice, a significant hypoglycemic effect was maintained following oral administration with great biocompatibility (~ 50% blood glucose level reduction at 4 h). This research has thus provided a potential nanocomposite system for oral delivery of insulin., (© 2024. Crown.)

The detachable dissolving microneedles (DDMNs) feature an array of needles capable of being separated from the base sheet during administration. Here they were fabricated to address delivery efficiency and storage stability of insulin. The constructed insulin-DDMN is multi-layered, with 1) a hard tip cover layer; 2) a layer of regular short-acting insulin (RI) mixed with hyaluronic acid (HA) and sorbitol (Sor) which occupies the taper tip region of the needles; 3) a barrier layer situated above the RI layer; and 4) a fast-dissolving layer connecting the barrier layer to the base sheet. RI entrapped in DDMNs exhibited enhanced thermal stability; it could be stored at 40 °C for 35 days without losing significant biological activity. Differential scanning calorimetric analysis revealed that the HA-Sor matrix could improve the denaturation temperature of the RI from lower than room temperature to 186 °C. Tests in ex vivo porcine skin demonstrated RI delivery efficiency of 91±1.59 %. Experiments with diabetic rats revealed sustained release of RI, i.e., when compared to subcutaneous injection with the same RI dose, RI-DDMNs produced slower absorption of insulin into blood circulation, delayed onset of hypoglycemic effect, longer serum insulin half-life, and longer hypoglycemic duration., Competing Interests: Declaration of Competing Interest This work was funded by Center of Excellence in Materials and Bio-Interfaces at Chulalongkorn University and Mineed Technology Company. T.P. was financially supported by the Second Century Fund (C2F) from Chulalongkorn University. Mineed Technology Company owns the detachable microneedle patent., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

C‐peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C‐peptide (CPpostdosing) is not an occasional phenomenon. This was a retrospective study that included 33 men who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp) aiming to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of injected insulin. The time profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C‐peptide were recorded. The subjects were divided into 2 groups at a ratio of 2:1: group A ([CPpostdosing]max>baseline CP [CPbaseline]), group B ([CPpostdosing]max ≤ CPbaseline). The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C‐peptide. The basal glucose, CPbaseline, basal human insulin, homeostatic model assessment of insulin resistance, IAsp dose, and demographic statistics were all comparable between the 2 groups except the "clamped" glucose. The average clamped glucose was 99.7% (group A) and 94.9% (group B) of baseline. After correction for clamped glucose, GIR area under the concentration‐time curve from time 0 to 8 hours was higher in group A (P <.05) under comparable IAsp exposure. Endogenous insulin area under the concentration‐time curve from time 0 to 8 hours calculated from C‐peptide was different from that measured from human insulin in group A (P <.05), whereas no statistical difference between these measures was observed in group B. Hence, blood glucose should be controlled below the baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous insulin–corrected pharmacokinetics estimated by C‐peptide may be inaccurate with insufficient endogenous insulin suppression. [ABSTRACT FROM AUTHOR]

Insulin, an essential peptide hormone, conjointly regulates blood glucose levels by its receptor and it is used as vital drug to treat diabetes. This therapeutic hormone may undergo different chemical modifications during industrial processes, pharmaceutical formulation, and through its endogenous storage in the pancreatic β-cells. Insulin is highly sensitive to environmental stresses and readily undergoes structural changes, being also able to unfold and aggregate in physiological conditions. Even; small changes altering the structural integrity of insulin may have significant impacts on its biological efficacy to its physiological and pharmacological activities. Insulin analogs have been engineered to achieve modified properties, such as improved stability, solubility, and pharmacokinetics, while preserving the molecular pharmacology of insulin. The casually or purposively strategies of chemical modifications of insulin occurred to improve its therapeutic and pharmaceutical properties. Knowing the effects of chemical modification, formation of aggregates, and nanoparticles on protein can be a new look at the production of protein analogues drugs and its application in living system. The project focused on effects of chemical modifications and nanoparticles on the structure, stability, aggregation and their results in effective drug delivery system, biological activity, and pharmacological properties of insulin. The future challenge in biotechnology and pharmacokinetic arises from the complexity of biopharmaceuticals, which are often molecular structures that require formulation and delivery strategies to ensure their efficacy and safety., Competing Interests: Declaration of competing interest This research is supported by the Postdoc grant of the Semnan University (Number: 21380). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

An inter-drug approach, applying pharmacokinetic information for insulin analogs in different animal species, rat, dog and pig, performed better compared to allometric scaling for human translation of intra-venous half-life and only required data from a single animal species for reliable predictions. Average fold error (AFE) between 1.2-1.7 were determined for all species and for multispecies allometric scaling AFE was 1.9. A slightly larger prediction error for human half-life was determined from in vitro human insulin receptor affinity data (AFE on 2.3-2.6). The requirements for the inter-drug approach were shown to be a span of at least 2 orders of magnitude in half-life for the included drugs and a shared clearance mechanism. The insulin analogs in this study were the five fatty acid protracted analogs: Insulin degludec, insulin icodec, insulin 320, insulin 338 and insulin 362, as well as the non-acylated analog insulin aspart., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Diabetes mellitus is a chronic disease leading to the death of millions a year across the world. Insulin is required for Type 1, Type 2, and gestational diabetic patients, however, there are various modes of insulin delivery out of which oral delivery is noninvasive and convenient. Moreover, factors like insulin degradation and poor intestinal absorption play a crucial role in its bioavailability and effectiveness. This review discusses various types of engineered nanoparticles used in-vitro, in-vivo, and ex-vivo insulin delivery along with their administration routes and physicochemical properties. Injectable insulin formulations, currently in use have certain limitations, leading to invasiveness, low patient compliance, causing inflammation, and side effects. Based on these drawbacks, this review emphasizes more on the non-invasive route, particularly oral delivery. The article is important because it focuses on how engineered nanoparticles can overcome the limitations of free therapeutics (drugs alone), navigate the barriers, and accomplish precision therapeutics in diabetes. In future, more drugs could be delivered with a similar strategy to cure various diseases and resolve challenges in drug delivery. This review significantly describes the role of various engineered nanoparticles in improving the bioavailability of insulin by protecting it from various barriers during non-invasive routes of delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Insulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol-disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol-disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile., (© 2024. The Author(s).)

The equivalent electrical circuit approach is explored to improve a bioimpedance-based transducer for measuring the bioavailability of synthetic insulin already presented in previous studies. In particular, the electrical parameter most sensitive to the variation of insulin amount injected was identified. Eggplants were used to emulate human electrical behavior under a quasi-static assumption guaranteed by a very low measurement time compared to the estimated insulin absorption time. Measurements were conducted with the EVAL-AD5940BIOZ by applying a sinusoidal voltage signal with an amplitude of 100 mV and acquiring impedance spectra in the range [1-100] kHz. 14 units of insulin were gradually administered using a Lilly's Insulin Pen having a 0.4 cm long needle. Modified Hayden's model was adopted as a reference circuit and the electrical component modeling the extracellular fluids was found to be the most insulin-sensitive parameter. The trnasducer achieves a state-of-the-art sensitivity of 225.90 ml1. An improvement of 223 % in sensitivity, 44 % in deterministic error, 7 % in nonlinearity, and 42 % in reproducibility was achieved compared to previous experimental studies. The clinical impact of the transducer was evaluated by projecting its impact on a Smart Insulin Pen for real-time measurement of insulin bioavailability. The wide gain in sensitivity of the bioimpedance-based transducer results in a significant reduction of the uncertainty of the Smart Insulin Pen. Considering the same improvement in in-vivo applications, the uncertainty of the Smart Insulin Pen is decreased from [Formula: see text]l to [Formula: see text]l.Clinical and Translational Impact Statement: A Smart Insulin Pen based on impedance spectroscopy and equivalent electrical circuit approach could be an effective solution for the non-invasive and real-time measurement of synthetic insulin uptake after subcutaneous administration., (© 2024 The Authors.)

The aim of the study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T-glu (GP40321, test drug), and reference insulin glulisine in a hyperinsulinemic-euglycemic clamp procedure. During this study, 34 healthy male volunteers underwent the hyperinsulinemic-euglycemic clamp procedure following subcutaneous 0.3 U/kg injection of T-glu or reference insulin glulisine in a randomized, double-blind, crossover study. Plasma glucose levels were monitored every 5 minutes for 8 hours. Glucose infusion rate adjustment was based on the blood glucose measurements. Evaluation of PD was performed using the glucose infusion rate values, while PK was calculated using insulin concentrations measured via enzyme-linked immunosorbent assay. The study results showed that the 90% CI for the geometric mean ratios of primary PK and PD of T-glu and reference insulin glulisine were within 80%-125% comparability limits, and that the safety profiles were comparable. PK, PD, and safety similarity of T-glu and reference insulin glulisine was demonstrated., (© 2024, The American College of Clinical Pharmacology.)

This comprehensive review delves into the potential of intranasal insulin delivery for managing Alzheimer's Disease (AD) while exploring the connection between AD and diabetes mellitus (DM). Both conditions share features of insulin signalling dysregulation and oxidative stress that accelerate inflammatory response. Given the physiological barriers to brain drug delivery, including the blood-brain barrier, intranasal administration emerges as a non-invasive alternative. Notably, intranasal insulin has shown neuroprotective effects, impacting Aβ clearance, tau phosphorylation, and synaptic plasticity. In preclinical studies and clinical trials, intranasally administered insulin achieved rapid and extensive distribution throughout the brain, with optimal formulations exhibiting minimal systemic circulation. The detailed mechanism of insulin transport through the nose-to-brain pathway is elucidated in the review, emphasizing the role of olfactory and trigeminal nerves. Despite promising prospects, challenges in delivering protein drugs from the nasal cavity to the brain remain, including enzymes, tight junctions, mucociliary clearance, and precise drug deposition, which hinder its translation to clinical settings. The review encompasses a discussion of the strategies to enhance the intranasal delivery of therapeutic proteins, such as tight junction modulators, cell-penetrating peptides, and nano-drug carrier systems. Moreover, successful translation of nose-to-brain drug delivery necessitates a holistic understanding of drug transport mechanisms, brain anatomy, and nasal formulation optimization. To date, no intranasal insulin formulation has received regulatory approval for AD treatment. Future research should address challenges related to drug absorption, nasal deposition, and the long-term effects of intranasal insulin. In this context, the evaluation of administration devices for nose-to-brain drug delivery becomes crucial in ensuring precise drug deposition patterns and enhancing bioavailability., (© 2024. The Author(s).)

The smart oral administration Insulin device has the potential to improve glycemic management. It can reduce the risk of hypoglycemia associated with exogenous Insulin (INS) therapy while also avoiding many of the disadvantages associated with subcutaneous injections. Furthermore, diabetes mellitus (DM) is an endocrine illness characterized by inflammation, and it is critical to minimize the amount of inflammatory markers in diabetic patients while maintaining average blood glucose. In this study, a responsive nanosystem vitamin B12-Fucoidan-Concanavalin A (VB12-FU-ConA NPs) with anti-inflammatory action was developed for smart oral delivery of Insulin. Con A has high sensitivity and strong specificity as a glucose-responsive material. Fucoidan has anti-inflammatory, immunomodulatory, and hypoglycemic functions, and it can bind to Con A to form a reversible complex. Under high glucose conditions, free glucose competitively binds to Con A, which swells the nanocarrier and promotes Insulin release. Furthermore, in the low pH environment of the gastrointestinal tract, positively charged VB12 and anionic fucoidan bind tightly to protect the Insulin wrapped in the carrier, and VB12 can also bind to intestinal epithelial factors to improve transit rate, thereby promoting INS absorption. In vitro tests showed that the release of nanoparticles in hyperglycemic solutions was significantly higher than the drug release in normoglycemic conditions. Oral delivery of the nanosystems dramatically lowered blood glucose levels in type I diabetic mice (T1DM) during in vivo pharmacodynamics, minimizing the risk of hypoglycemia. Blood glucose levels reached a minimum of 8.1 ± 0.4 mmol/L after 8 h. Administering the nanosystem orally notably decreased the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in diabetic mice. The nano delivery system can be degraded and metabolized in the intestinal tract after being taken orally, demonstrating good biodegradability and biosafety. In conclusion, the present study showed that VB12-FU-ConA nanocarriers are expected to be a novel system for rationalizing blood glucose., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Buccal mucosa administration is a promising method for insulin (INS) delivery with good compliance. However, buccal mucosa delivery systems still face challenges of long-term mucosal adhesion, sustained drug release, and mucosal drug penetration. To address these issues, a double-layer film consisting of a hydroxypropyl methylcellulose/polyacrylic acid interpolymer complex (IPC)-formulated mucoadhesive layer and an ethylcellulose (EC)-formulated waterproof backing layer (IPC/EC film) was designed. Protamine (PTM) and INS were co-loaded in the mucoadhesive layer of the IPC/EC film (PTM-INS-IPC/EC film). In ex vivo studies with porcine buccal mucosa, this film exhibited robust adhesion, with an adhesion force of 120.2 ± 20.3 N/m 2 and an adhesion duration of 491 ± 45 min. PTM has been shown to facilitate INS mucosal transfer. Pharmacokinetic studies indicated that the PTM-INS-IPC/EC film significantly improved the absorption of INS, exhibiting a 1.45 and 2.24-fold increase in the area under the concentration-time curve (AUC 0-∞ ) compared to the INS-IPC/EC film and free INS, respectively. Moreover, the PTM-INS-IPC/EC film effectively stabilized the blood glucose levels of type 1 diabetes mellitus (T 1 DM) rats with post oral glucose administration, maintaining lower glucose levels for approximately 8 h. Hence, the PTM-INS-IPC/EC film provides a promising noninvasive INS delivery system for diabetes treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In humans, food intake and glucose infusion have been reported to increase subcutaneous blood flow. Since local blood flow influences the rate of insulin absorption from the subcutaneous tissue, we hypothesised that an increase in blood glucose levels—occurring as the result of glucose infusion or food intake—could modulate the pharmacokinetic properties of subcutaneously administered insulin. The pharmacokinetic profile of insulin aspart was assessed in 29 domestic pigs that were examined in a fed and fasted state or included in hyperinsulinaemic clamp studies of 4 vs. 10 mmol/L glucose prior to subcutaneous (30 nmol) or intravenous (0.1 nmol/kg) insulin administration. Results showed that food intake compared to fasting accelerated absorption and decreased clearance of insulin aspart (P < 0.05). Furthermore, higher c‐peptide but also glucagon levels were observed in fed compared to fasted pigs (P < 0.05). The pharmacokinetic profile of insulin aspart did not differ between pigs clamped at 4 vs. 10 mmol/L glucose. Hence, food intake rather than blood glucose levels within normal range modulates the pharmacokinetic properties of insulin aspart upon subcutaneous and intravenous administration in pigs. [ABSTRACT FROM AUTHOR]

Summary Objective Obesity is associated with delayed insulin absorption upon subcutaneous (s.c.) dosing in humans. The aim of this study was to investigate whether alterations in depot structure and kinetics of the s.c. injection depot contribute to this delay. Methods Rats fed a high‐fat diet (HFD) and low‐fat diet (LFD) were included in a series of insulin pharmacokinetic and imaging studies. Injection depots were visualized with micro X‐ray computed tomography imaging upon s.c. administration of insulin aspart mixed with the contrast agent iomeprol, and insulin aspart exposure was measured by means of luminescent oxygen channelling immunoassay. Results Body weight and fat mass were increased in rats fed an HFD vs. LFD (p

The article focuses on a study conducted by researcher Martin Fussenegger and colleagues, aiming to find innovative ways to produce and administer insulin within the body to help diabetics. They have developed a method using sound waves, specifically music, to trigger insulin release from designer cells enclosed in capsules implanted in the body. It found that certain music genres effectively stimulated insulin release in mice.

Purpose: We examined the impact of matrix food structure on post-prandial folate bioavailability (and other macronutrients) in human volunteers using a randomized, controlled, crossover experimental design. Methods: Twelve healthy male volunteers (22.6 ± 0.4 years old) were offered four food models (differing in matrix structure: Custard, Pudding, Sponge cake and Biscuit) to which 1 mg of folic acid was added, according to a randomized, controlled, crossover experimental design. Plasma folates, glucose, insulin, alpha amino nitrogen and triglycerides were measured over the post-prandial period (from T0 to T480 min). Results: Food matrix structure was capable of altering folate plasma availability. The highest folate availability was observed for pudding and to a lesser extent Sponge cake whereas the lowest was for the two matrices presenting extreme rheological properties: Custard (liquid) (P < 0.05 total AUC) and to a lesser extent Biscuit (hard solid) (P < 0.05, AUC 180 min). The analysis of plasma kinetics of appearance of other nutrients/metabolites helps to understand/explain the lower bioavailability of folates in Custard and Biscuit. Conclusion: A least overall efficient bio-accessibility of all macronutrients and folic acid is observed in the gut lumen for Biscuit (delayed/incomplete destructuration of biscuit along the digestive tract). On the contrary, the lower folic acid absorption observed with custard does not fit with the rapid plasma appearance of other nutrients and should require further investigation. [ABSTRACT FROM AUTHOR]

Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro , ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo , as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro , ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.

This report addresses the challenges of controlled drug delivery for peptide and protein therapeutics by introducing a novel approach of nano formulation fabricated in aqueous media applying stereo-interaction mechanism with poly(D-lactide)-polyethylene glycol (D-PLA-PEG). To overcome the inherent poor stability of peptide and protein therapeutics, stereocomplexation of the peptide, insulin, is applied, onto D-PLA-PEG in aqueous media. Nanoparticles of ≈400 nm are spontaneously formed when water-soluble D configured PLA-PEG diblock copolymer and L- configured insulin interlock into a stereocomplex, owing to their concave convex fitness. In vitro release of insulin from stereocomplex in phosphate buffer solution (PBS) pH 7.4 solution shows sustained release for 14 weeks. The therapeutic efficacy of the PLA-insulin stereocomplex nanoparticles are evaluated in diabetic Akita mice. Blood glucose levels and body weight are closely monitored for a period of 17 weeks, revealing a significant reduction in glucose levels of the Akita mice treated with insulin stereocomplex, as well as normal body weight gain. These findings suggest that the stereocomplex nanoparticles of insulin-D-PLA-PEG present a promising and effective sustained and extended release platform for insulin. Notably, the use of water-soluble D-PLA-PEG for stereocomplexation in water expands the applicability of this approach to fabricate controlled delivery systems for peptide and protein therapeutics., (© 2023 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Background: It has been shown that insulin acceleration by itself might not be sufficient to see clear improvements in glycemic metrics, and insulin therapy may need to be adjusted to fully leverage the extra safety margin provided by faster pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The objective of this work is to explore how to perform such adjustments on a commercially available automated insulin delivery (AID) system., Methods: Ultra-rapid lispro (URLi) is modeled within the UVA/Padova simulation platform using data from previously published clamp studies. The Control-IQ AID algorithm is selected as it leverages carbohydrate-to-insulin ratio (CR in g/U), correction factor (CF in mg/dL/U), and basal rate (BR in U/h) daily profiles that are fully customizable. An experiment roadmap is proposed to understand how to safely modify these profiles when switching from lispro to URLi., Results: Simulations show that a 7% decrease in CR (approximately an 8% increase in prandial insulin) and a 7.5% increase in BR lead to cumulative improvements in glucose control with URLi. Comparing with baseline metrics using lispro, a clinically significant increase in time in the range of 70 to 180 mg/dL (overall: 70.2%-75.2%, P < .001; 6 am-12 am: 62.4%-68.5%, P < .001) and a reduction in time below 70 mg/dL (overall: 1.8%-1.2%, P < .001; 6 am-12 am: 1.8%-1.3%, P < .001) were observed., Conclusion: Properly adjusting therapy parameters allows to fully leverage glucose control benefits provided by faster insulin analogues, opening opportunities to take another step forward into a next generation of more effective AID solutions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PC, JD, and JG receive research support and royalties from Dexcom handled by the University of Virginia’s Licensing and Ventures Group. MDD has received research support from Tandem, Dexcom, and Medtronic. MDB consults for Roche Diagnostics, Dexcom, Adocia, and Arecor; receives research support from Dexcom, Tandem, and Novo Nordisk.

Despite considerable progress, development of glucose-responsive insulins (GRIs) still largely depends on empirical knowledge and tedious experimentation-especially on rodents. To assist the rational design and clinical translation of the therapeutic, we present a Pharmacokinetic Algorithm Mapping GRI Efficacies in Rodents and Humans (PAMERAH) built upon our previous human model. PAMERAH constitutes a framework for predicting the therapeutic efficacy of a GRI candidate from its user-specified mechanism of action, kinetics, and dosage, which we show is accurate when checked against data from experiments and literature. Results from simulated glucose clamps also agree quantitatively with recent GRI publications. We demonstrate that the model can be used to explore the vast number of permutations constituting the GRI parameter space and thereby identify the optimal design ranges that yield desired performance. A design guide aside, PAMERAH more importantly can facilitate GRI's clinical translation by connecting each candidate's efficacies in rats, mice, and humans. The resultant mapping helps to find GRIs that appear promising in rodents but underperform in humans (i.e., false positives). Conversely, it also allows for the discovery of optimal human GRI dynamics not captured by experiments on a rodent population (false negatives). We condense such information onto a "translatability grid" as a straightforward, visual guide for GRI development. [ABSTRACT FROM AUTHOR]

Background In humans, subcutaneous administration of insulin in the abdominal region or arm is associated with a faster absorption compared to the thigh or buttocks. We hypothesised that this is partly caused by differences in injection depot structure and kinetics and that the variability in insulin exposure differs between injection sites. Material and methods Regional effects on insulin pharmacokinetics were evaluated in a series of studies in Sprague Dawley rats dosed subcutaneously with insulin aspart in the neck or flank. Injection depots were visualised using µCT after subcutaneous dosing with insulin aspart mixed with the contrast agent iomeprol, and insulin exposure was determined between the scans by Luminescent Oxygen Channeling Immunoassay. Results Insulin absorption was significantly delayed by subcutaneous dosing in the flank compared to the neck region (p<0.01 or less). This delay was associated with smaller depots, as measured by reduced depot volume and surface area (p<0.001). Furthermore, the delayed absorption correlated with a slower depot disappearance (p<0.001). Regional differences in depot variability were not reflected by similar differences in pharmacokinetic variability. Conclusion Structure and kinetics of subcutaneous injection depots—as detected by µCT scans—predict insulin exposure and may thus contribute to the regional differences in insulin pharmacokinetics. The present methodology is applicable for visualisation of insulin injection depots in vivo. Our results did however not support a link between the variability in depot size and insulin pharmacokinetics. [ABSTRACT FROM AUTHOR]

Slow insulin absorption prevents the development of a fully automated artificial pancreas with subcutaneous insulin delivery. We have hypothesized that glucagon could be used as a vasodilator to accelerate insulin absorption in a bihormonal subcutaneous artificial pancreas. The present proof-of-concept study is the first study to investigate the pharmacokinetics of insulin after subcutaneous administration of a low dose of glucagon at the site of subcutaneous insulin injection. Twelve anesthetized pigs were randomized to receive a subcutaneous injection of 10 IU insulin aspart with either 100 µg glucagon or the equivalent volume of placebo (0.9% saline solution) injected at the same site. Arterial samples were collected for 180 minutes to determine insulin, glucagon, and glucose concentrations. Glucagon did not influence the insulin concentration T max in plasma. The plasma insulin AUC 0–∞ was significantly larger after glucagon administration (P < 0.01). The glucagon group had significantly higher glucose concentrations in the first 30 minutes after insulin administration (P < 0.05). This proof-of-concept study indicates that glucagon may increase the total absorption of a single dose of subcutaneously injected insulin. This is a novel observation. However, we did not observe any reduction in insulin concentration T max , as we had hypothesized. Further, glucagon induced a significant, undesirable increase in early blood glucose concentrations. [ABSTRACT FROM AUTHOR]

With the rise in diabetes mellitus cases worldwide, oral delivery of insulin is preferred over subcutaneous insulin administration due to its good patient compliance and non-invasiveness, simplicity, and versatility. However, oral insulin delivery is hampered by various gastrointestinal barriers that result in low drug bioavailability and insufficient therapeutic efficiency. Numerous strategies have been developed to overcome these barriers and increase the bioavailability of oral insulin. Yet, no commercial oral insulin product is available to address all clinical hurdles because of various substantial obstacles related to the structural organization and physiological function of the gastrointestinal tract. Herein, we discussed the significant physiological barriers (including chemical, enzymatic, and physical barriers) that hinder the transportation and absorption of orally delivered insulin. Then, we showcased recent significant and innovative advances in oral insulin delivery technologies. Finally, we concluded the review with remarks on future perspectives on oral insulin delivery technologies and potential challenges for forthcoming clinical translation of oral insulin delivery technologies., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D)., Materials and Methods: This multicentre, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (non-switching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the non-switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (C max ) of SAR-Asp versus NN-Asp after the single dose at week 16., Results: The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the non-switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8-1.25. For C max in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8-1.25., Conclusions: PK exposure of SAR-Asp (switching group) and reference NN-Asp (non-switching group) were similar, supporting interchangeability between these two insulin aspart products., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes., Objective: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system., Methods: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans., Results: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq., Conclusions: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.

Aim: Insulin therapy require self-administration of subcutaneous injection leading to painful and inconvenient drug therapy. The aim is to fabricate nanoemulsion (NE) based insulin loaded microneedles with improved bioavailability and patient compliance. Materials & methods: Different ratios of polyvinyl alcohol and polyvinylpyrrolidone as polymers were prepared through micro-molding technique for microneedles. Characterization of were performed using scanning electron microscope, differential scanning calorimetry, Fourier-transform infrared spectroscopy and circular dichroism. Mechanical strength, hygroscopicity and pain perception of these microneedles were also evaluated. In vitro release, permeation and in vivo PK/PD study of NE-based microneedles were conducted. Results: NE-based microneedles of insulin have improved bioavailability and quick response. Conclusion: Microneedles loaded with insulin can be effectively delivered insulin transdermally to treat diabetes with increased convenience and patient compliance.

Background: Due to the lifestyle of people in the community in recent years, the prevalence of diabetes mellitus has increased, so New drugs and related treatments are also being developed., Introduction: One of the essential treatments for diabetes today is injectable insulin forms, which have their problems and limitations, such as invasive and less admission of patients and high cost of production. According to the mentioned issues, Theoretically, Oral insulin forms can solve many problems of injectable forms., Methods: Many efforts have been made to design and introduce Oral delivery systems of insulin, such as lipid-based, synthetic polymer-based, and polysaccharide-based nano/microparticle formulations. The present study reviewed these novel formulations and strategies in the past five years and checked their properties and results., Results: According to peer-reviewed research, insulin-transporting particles may preserve insulin in the acidic and enzymatic medium and decrease peptide degradation; in fact, they could deliver appropriate insulin levels to the intestinal environment and then to blood. Some of the studied systems increase the permeability of insulin to the absorption membrane in cellular models. In most investigations, in vivo results revealed a lower ability of formulations to reduce BGL than subcutaneous form, despite promising results in in vitro and stability testing., Conclusion: Although taking insulin orally currently seems unfeasible, future systems may be able to overcome mentioned obstacles, making oral insulin delivery feasible and producing acceptable bioavailability and treatment effects in comparison to injection forms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the etiology of breast malignancy, dietary habits and lifestyle-related risk factors in the coherence of cancer prevention guidelines, e.g., WCRF/AICR is well documented. In addition, the consumption of staple food products rich in carbohydrate as major calorie resources such as potato, bread, and ready-to-eat cereals are partly object to having roles in breast tumorigenesis. In this review, the possible associations of preservatives and nutritive risk factors of staple foods in dietary patterns with breast cancer development based on the experimental and observational cohort-based studies were discussed. In this regard, the influence kinetics of insulin, insulin-like growth factor-1, and insulin-activated AMPK/Akt pathway on sorts of starch and protein is a concerning biologic concept in promoting the risk of tumorigenesis. Hence, Akt-dependent controlled proliferation, induced apoptosis, and controlled oxidative stress in specific condition could be concentrated as the preventive strategies. Although preservatives such as sorbate, benzoate, and nitrate are considered Generally Recognized as Safe, there are some issues concerning the safety of their applications, including the possibility of allergies and immunosuppressive effects from benzoate, the formation of carcinogenic nitrosamines from nitrites, and interaction sorbate with nitrite in the stomach which consequently can be resulted in the production of a series of genotoxic compounds. [ABSTRACT FROM AUTHOR]

The article provides information on the dual-hormone artificial pancreas and discusses its benefits and drawbacks compared to the insulin-alone artificial pancreas. Topics discussed include rationale for the dual-hormone system, efficacy of dual-hormone systems, and practical considerations of the dual-hormone artificial pancreas.

Summary: Objective: Obesity is associated with delayed insulin absorption upon subcutaneous (s.c.) dosing in humans. The aim of this study was to investigate whether alterations in depot structure and kinetics of the s.c. injection depot contribute to this delay. Methods: Rats fed a high‐fat diet (HFD) and low‐fat diet (LFD) were included in a series of insulin pharmacokinetic and imaging studies. Injection depots were visualized with micro X‐ray computed tomography imaging upon s.c. administration of insulin aspart mixed with the contrast agent iomeprol, and insulin aspart exposure was measured by means of luminescent oxygen channelling immunoassay. Results: Body weight and fat mass were increased in rats fed an HFD vs. LFD (p < 0.05), whereas the lean mass was not. The HFD group exhibited delayed insulin absorption from the s.c. tissue (p < 0.001). This delay was associated with smaller injection depots upon s.c. dosing (p < 0.05) and correlated with a slower depot disappearance from the s.c. tissue (p < 0.05) compared with the LFD group. Depot disappearance from the s.c. tissue was inversely correlated with body fat mass (p < 0.05). Conclusions: Alterations in s.c. injection depot structure and kinetics may play a role in the obesity‐associated delay in insulin absorption. [ABSTRACT FROM AUTHOR]

Insulin replacement therapy is a fundamental treatment for glycemic control for managing diabetes. The engineering of insulin analogues has focused on providing formulations with action profiles that mimic as closely as possible the pattern of physiological insulin secretion that normally occurs in healthy individuals without diabetes. Hence, it may be helpful to practitioners to visualize insulin concentration profiles and associated glucose action profiles. Expanding on a previous analysis that established a pharmacokinetic (PK) model to describe typical profiles of insulin concentration over time following subcutaneous administration of various insulin formulations, the goal of the current analysis was to link the PK model to an integrated glucose‐insulin (IGI) systems pharmacology model. After the pharmacokinetic‐pharmacodynamic (PK‐PD) model was qualified by comparing model predictions with clinical observations, it was used to project insulin (PK) and glucose (PD) profiles of common insulin regimens and dosing scenarios. The application of the PK‐PD model to clinical scenarios was further explored by incorporating the impact of several hypothetical factors together, such as changing the timing or frequency of administration in a multiple‐dosing regimen over the course of a day, administration of more than 1 insulin formulation, or insulin dosing adjusted for carbohydrates in meals. Visualizations of insulin and glucose profiles for commonly prescribed regimens could be rapidly generated by implementing the linked subcutaneous insulin PK‐IGI model using the R statistical program (version 3.4.4) and a contemporary web‐based interface, which could enhance clinical education on glycemic control with insulin therapy. [ABSTRACT FROM AUTHOR]

Objective: A recent publication questioned the integrity of insulin purchased from U.S. retail pharmacies. We sought to independently validate the method used, isotope dilution solid-phase extraction (SPE) liquid chromatography mass spectrometry (LC-MS), and expand analysis to two U.S. Pharmacopeia (USP) methods (high-performance LC with ultraviolet detection and LC-MS).Research Design and Methods: Each method was used to evaluate nine insulin formulations, purchased at four pharmacies, within five geographic locations in the U.S.Results: All human and analog insulins measured by the USP methods (n = 174) contained the expected quantity of active insulin (100 ± 5 units/mL). When using isotope dilution SPE-LC-MS, units-per-milliliter values were well below product labeling due to unequal recovery of the internal standard compared with target insulin.Conclusions: Insulin purchased from U.S. pharmacies is consistent with product labeling. [ABSTRACT FROM AUTHOR]

The article examines the available evidence for U-500 insulin and the innovations for its delivery. U-500 was introduced to address the insulin needs of patients with severe insulin resistance. The pharmacokinetic/pharmacodynamic profile of U-500 shows similar overall insulin exposure when compared to human regular insulin U-100. The Humulin R U-500 KwikPen insulin from Eli Lilly was introduced to the market in 2016.

Neonatal hyperglycemia is common in extremely low birth weight (ELBW) infants because of physiologic stress, exogenous glucose infusion, and postnatal corticosteroid therapy for hypotension, adrenal insufficiency, and pulmonary immaturity. The use of long-acting insulin glargine has been described in the treatment of transient neonatal diabetes in the premature infant, but in these reports is a lack of regard to its use in the treatment of iatrogenic neonatal hyperglycemia. We present the case of an ELBW infant with significant hyperglycemia that was refractory to usual treatment but demonstrated a favorable response to long-acting subcutaneous insulin glargine. The pharmacokinetics on regular insulin and long-acting insulin are different. Regular insulin is broken down into biologically active monomers after subcutaneous injection, and long-acting insulin forms microprecipitates and is gradually released to the body at a neutral physiologic pH after subcutaneous injection. Pharmacokinetics of both regular insulin and long-acting insulin are not clear in ELBW infants. However, with further research on long-acting insulin, it can be used safely to achieve consistent euglycemia with once-daily administration in neonatal hyperglycemia. [ABSTRACT FROM AUTHOR]