Can Arginine inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

Březina, Kryštof; Duboué-Dijon, Elise; Palivec, Vladimír; Jiráček, Jiřı́; Křížek, Tomáš; Viola, Cristina; Ganderton, Timothy R.; Brzozowski, A.M.; Jungwirth, Pavel

doi:10.26434/chemrxiv.6797525.v1

Cited by 7 publications

(10 citation statements)

References 44 publications

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“…Furthermore, studies in pigs indicate that niacinamide may increase skin blood flow via transient, local vasodilatation, among those with acceptable formulation stability, the one with the fastest absorption rate was chosen for further development. Recent investigations suggest that l-arginine also contributes to improved insulin stability through reduced insulin aggregation at high ionic strength [41].…”

Section: Faster Aspartmentioning

confidence: 99%

Fast-Acting Insulin Aspart: A Review of its Pharmacokinetic and Pharmacodynamic Properties and the Clinical Consequences

Heise

2019

Clin Pharmacokinet

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Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) with two added excipients, l-arginine and niacinamide, to ensure formulation stability with accelerated initial absorption after subcutaneous administration compared with previously developed rapid-acting insulins. The pharmacokinetic/pharmacodynamic properties of faster aspart have been characterised in clinical pharmacology trials with comparable overall methodology. In subjects with type 1 (T1D) or type 2 (T2D) diabetes, the serum IAsp concentration-time and glucose-lowering effect profiles are left-shifted for faster aspart compared with IAsp. In addition, faster aspart provides earlier onset, doubling of initial exposure, and an up to 2.5-fold increase in initial glucose-lowering effect within 30 min of subcutaneous injection, as well as earlier offset of exposure and effect. Similar results have been shown using continuous subcutaneous insulin infusion (CSII). The improved pharmacological properties of faster aspart versus IAsp are consistent across populations, i.e. in the elderly, children, adolescents and the Japanese. Thus, the faster aspart pharmacological characteristics more closely resemble the mealtime insulin secretion in healthy individuals, giving faster aspart the potential to further improve postprandial glucose control in subjects with diabetes. Indeed, change from baseline in 1-h postprandial glucose increment is in favour of faster aspart versus IAsp when used as basal-bolus or CSII treatment in phase III trials in subjects with T1D or T2D. This review summarises the currently published results from clinical pharmacology trials with faster aspart and discusses the potential clinical benefits of faster aspart compared with previous rapid-acting insulin products. Key PointsDespite the advantages of rapid-acting insulins over regular human insulin with respect to pharmacokinetic/ pharmacodynamic properties, there is still a need for accelerated insulin absorption and action to better mimic mealtime insulin secretion in the healthy state.Faster aspart provides an overall left-shift of the pharmacokinetic/pharmacodynamic profiles resulting in earlier onset, twice as large initial exposure, and up to 2.5-fold greater initial glucose-lowering effect within the first 30 min, as well as earlier offset of exposure and effect compared with insulin aspart.In phase III trials, the better resemblance of faster aspart pharmacological characteristics to healthy endogenous mealtime insulin secretion has been shown to lead to improved postprandial glycaemic control in subjects with diabetes relative to previously developed rapid-acting insulins.

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Section: Faster Aspartmentioning

confidence: 99%

Fast-Acting Insulin Aspart: A Review of its Pharmacokinetic and Pharmacodynamic Properties and the Clinical Consequences

Heise

2019

Clin Pharmacokinet

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“…35 We present a design in which payloads including human insulin were self-assembled as a core in the presence of the excipients, L-arginine (L-arg), and zinc chloride (ZnCl 2 ). While L-arg was included nominally to aid insulin stabilization, 36 we noted a recent demonstration of L-arg as an intestinal PE for insulin in rat small intestinal instillations. 37 The core particle was then cross-linked with silica to form insulin-entrapped silica-coated NPs (SiNPs).…”

Section: Introductionmentioning

confidence: 99%

Silica-Coated Nanoparticles with a Core of Zinc, l-Arginine, and a Peptide Designed for Oral Delivery

Hristov¹,

McCartney²,

Beirne³

et al. 2019

ACS Appl. Mater. Interfaces

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Nanoparticle constructs for oral peptide delivery at a minimum must protect and present the peptide at the small intestinal epithelium in order to achieve oral bioavailability. In a reproducible, scalable, surfactant-free process, a core was formed with insulin in ratios with two established excipients and stabilizers, zinc chloride and Larginine. Cross-linking was achieved with silica, which formed an outer shell. The process was reproducible across several batches, and physicochemical characterization of a single batch was confirmed in two independent laboratories. The silica-coated nanoparticles (SiNPs) entrapped insulin with high entrapment efficiency, preserved its structure, and released it at a pH value present in the small intestine. The SiNP delivered insulin to the circulation and reduced plasma glucose in a rat jejunal instillation model. The delivery mechanism required residual L-arginine in the particle to act as a permeation enhancer for SiNPreleased insulin in the jejunum. The synthetic process was varied in terms of ratios of zinc chloride and L-arginine in the core to entrap the glucagon-like peptide 1 analogue, exenatide, and bovine serum albumin. SiNP-delivered exenatide was also bioactive in mice to some extent following oral gavage. The process is the basis for a platform for oral peptide and protein delivery.

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“…V means approved. References: summary of product characteristics of the insulin preparations and references 8,16,18–28 …”

Section: Resultsmentioning

confidence: 99%

“…References: summary of product characteristics of the insulin preparations and references. 8,16,[18][19][20][21][22][23][24][25][26][27][28] Note that the duration of action of insulin in the tandem pump is fixed at 5 hours, therefore UFIs are not recommended. Note that Humalog U200 or Lyumjev U200 are reserved for the treatment of adults and cannot be used intravenously and must not be transferred from the KwikPen to any other insulin device, including CSII.…”

Section: Ultra-fast Insulin Analoguesmentioning

confidence: 99%

“…Niacinamide increases local blood flow and, in addition, stimulates the formation of monomers, thereby promoting a faster absorption of insulin aspart into the blood circulation and an earlier but also shorter (faster on and off) glucose-lowering effect than IAsp. 21,53 L-arginine was added as a stabilizing agent 22 (Figure 1).…”

Section: Fast-acting Insulin Aspartmentioning

confidence: 99%

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Rapid‐acting insulin analogues: Theory and best clinical practice in type 1 and type 2 diabetes

Block

Cauwenberghe

Bochanen

et al. 2022

Diabetes Obesity Metabolism

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Since the discovery of insulin 100 years ago, insulin preparations have improved significantly. Starting from purified animal insulins, evolving to human insulins produced by genetically modified organisms, and ultimately to insulin analogues, all in an attempt to mimic physiological insulin action profiles seen in individuals without diabetes. Achieving strict glucose control without hypoglycaemia and preventing chronic complications of diabetes while preserving quality of life remains a challenging goal, but the advent of newer ultra-rapid-acting insulin analogues may enable intensive insulin therapy without being too disruptive to daily life. Ultra-rapid-acting insulin analogues can be administered shortly before meals and give better coverage of mealtime-induced glucose excursions than conventional insulin preparations. They also increase convenience with timing of bolus dosing. In this review, we focus on the progress that has been made in rapid-acting insulins. We summarize pharmacokinetic and pharmacodynamic data, clinical trial data supporting the use of these new formulations as part of a basal-bolus regimen and continuous subcutaneous insulin infusion, and provide a clinical perspective to help guide healthcare professionals when and for whom to use ultra-fast-acting insulins.

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Can Arginine inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

Cited by 7 publications

References 44 publications

Fast-Acting Insulin Aspart: A Review of its Pharmacokinetic and Pharmacodynamic Properties and the Clinical Consequences

Fast-Acting Insulin Aspart: A Review of its Pharmacokinetic and Pharmacodynamic Properties and the Clinical Consequences

Silica-Coated Nanoparticles with a Core of Zinc, l-Arginine, and a Peptide Designed for Oral Delivery

Rapid‐acting insulin analogues: Theory and best clinical practice in type 1 and type 2 diabetes

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