New Horizons: Next-Generation Insulin Analogs: Structural Principles and Clinical Goals

Design of “first-generation” insulin analogs over the past three decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool-kit—integrating protein sequence, chemical modification and formulation—has thus led to improved prandial and basal formulations for the treatment of diabetes mellitus. Although PK/PD changes were modest in relation to prior formulations of human and animal insulins, significant clinical advantages in efficacy (mean glycemia) and safety (rates of hypoglycemia) were obtained. Continuing innovation is providing further improvements to achieve ultra-rapid and ultra-basal analog formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogs seek to exploit therapeutic mechanisms: glucose-responsive (“smart”) analogs, pathway-specific (“biased”) analogs, and organ-targeted analogs. Smart insulin analogs and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogs may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will impact utilization and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale and potential clinical applications.

Omniligase-1-mediated ligation for insulin analog synthesis in solu-tion and on phage surface

The B-chain C-terminal region of insulin has been mutated or modified to achieve improved therapeutic efficacies. For ex-ample, all FDA-approved insulin analogs have altered C-terminal segments, which leads to improved pharmacokinetic prop-erties and provide significant clinical benefits on blood sugar regulation. Nonetheless, there is still no efficient method to synthesize insulin analogs with the altered C-terminal region. Herein, we report a facile synthesis using omniligase-1 to li-gate an insulin core with a peptide segment in high conversion. We further apply this ligation to M13 phage surface modifi-cations and demonstrate that the phage displayed insulin molecules can bind to insulin receptor ectodomain in an insulin-dependent manner. These results pave the way for building phage display insulin library for therapeutic selections and demonstrate the feasibility of using omniligase-1 to display other disulfide-rich peptides and proteins on phage.

The first and only combination of basal and prandial insulin analogs degludec and aspart: the position of Russian endocrinologists

Insulin therapy for diabetes mellitus is the most effective way to control glycemia with the progression of the disease and the ineffectiveness of other sugar-lowering drugs. At the same time, the existing limitations of traditional insulin preparations, along with increasing attention to the individualized treatment of this disease, are pushing developers to create drugs that most closely reproduce the effect of natural human insulin. In this regard, the appearance of a combination of insulin analogs, the action profile of which practically imitates insulin secretion by a healthy pancreas, presents new possibilities in the treatment of diabetes mellitus. Insulin degludec / insulin aspart (IDegAsp, Ryzodeg®, Novo Nordisk, Denmark) is the first and only soluble combination preparation containing 70% of the ultra-long-acting insulin analogue degludec and 30% of the ultra-short-acting insulin analogue aspart in one injection, which meets the need for both basal and prandial insulin. The combined drug has nothing in common with traditional mixed insulin preparations (both human and analog) and provides doctors and patients with significant advantages over the latter. The article presents the position of Russian experts-diabetologists with extensive experience in the use of IDegAsp regarding the role and place of the drug in real clinical practice. Data from real clinical practice confirm that IDegAsp is a reasonable choice for starting and intensifying insulin therapy for type 2 diabetes mellitus when basal and prandial glycemic control is required. The use of the drug is most appropriate in patients who are on basal, biphasic, basal-plus/basal-bolus regimens and who do not achieve the goals of glycemic control during prior therapy. One of the leading reasons for choosing IDegAsp may also be a lower risk of developing hypoglycemia compared to insulin analogues of previous generations — biphasic insulin aspart and basal insulin glargine 100 U/ml. In addition, IDegAsp is a simple, flexible and safe insulin therapy for patients on premix therapy and basal-plus/basis-bolus regimens who require basal and prandial glycemic control. IDegAsp is a simple, flexible and safe insulin therapy. The greatest benefit of this drug use can be obtained by patients for whom adherence to a complex therapy regimen is difficult (the elderly, with cognitive impairment, after a stroke, with dementia), as well as patients who have an active lifestyle, accompanied by irregular food intake. It is important to note that since January 1, 2021, there is no need for a decision by a special medical commission to prescribe (IDegAsp) Ryzodeg®. This fact, as well as a significant price reduction at the end of 2020, opens up broader prospects for using the drug in the routine practice of a Russian endocrinologist.

The correlation of structural and binding affinity of insulin analog to the onset of action for diabetic therapy

Background: These days, insulin analog production has been improved and becoming popular. The advantages of insulin analog have been extensively reviewed in terms of effectiveness compared to human insulin. Each of the insulin analog industries has claimed their safety and efficacy based on in vivo and in vitro to overcome type 2 diabetes. Hereby, we report on the identification of highly effective analog-based insulin on structure and binding affinity computationally, to confirm its potential and give a broader point of view to insulin analog users. Methods: Five types of insulin analogs, Aspart, Glargine, Detemir, Lispro and Degludec, were analyzed. We grouped and clustered the sequence by alignment to identify the closeness and sequence similarity between samples, continued by superimposing analysis and undertaking binding affinity identification utilizing of a docking analysis approach. Results: Lispro had the least sequence similarity to other types, close to Aspart (96%) and Glargine (90.5%), while Detemir and Degludec showed 100% similarity we decide to only use Degludec for the next analysis. Furthermore, Lispro, Aspart, and Glargine exhibited structural similarity strengthened by the lack of significant difference in the RMSD data. Importantly, Aspart had the highest binding affinity score (-66.1 +/- 7.1 Kcal/mol) in the docking analysis to the insulin receptor (INSR) and similar binding site areas to human insulin. Conclusion: Our finding revealed that the strength of insulin analogs towards insulin receptors is identic with its rapid mechanism in the human body. Keywords: computation, docking, insulin analog, sequence similarity, structure Abstrak Latar belakang: Saat ini, produksi analog insulin meningkat dan menjadi popular. Keuntungan analog insulin telah ditinjau secara ekstensif dalam hal efektivitas dibandingkan dengan insulin manusia. Masing-masing industri analog insulin mengklaim keamanan dan kemanjurannya berdasarkan in vivo dan in vitro untuk mengatasi diabetes tipe 2. Kami melaporkan identifikasi insulin analog yang efektif berdasarkan struktur dan afinitas pengikatan secara komputasi, untuk mengonfirmasi potensi serta memberikan sudut pandang yang lebih luas kepada pengguna insulin analog. Metode: Lima jenis analog insulin, Aspart, Glargine, Detemir, Lispro, dan Degludec, dianalisis. Kami membandingkan dan mengelompokkan urutan tersebut dengan penyelarasan untuk mengidentifikasi kedekatan dan kesamaan urutan antar sampel dilanjutkan dengan superimposing analysis dan melakukan identifikasi binding affinity menggunakan pendekatan analisis docking. Hasil: Lispro memiliki kemiripan sekuen paling rendah dengan jenis lainnya, mendekati Aspart (96%) dan glargine (90,5%), sedangkan Determir dan Degludec menunjukkan kemiripan 100% sehingga kami menggunakan Degludec untuk analisis selanjutnya. Selain itu, Lispro, Aspart, dan Glargine menunjukkan kesamaan struktural yang diperkuat oleh rendahnya nilai signifikansi pada data RMSD. Perlu digarisbawahi bahwa Aspart memiliki skor afinitas pengikatan tertinggi (-66.1 +/- 7.1 kkal / mol) dalam analisis docking ke reseptor insulin (INSR) dan memiliki area pengikatan yang serupa dengan insulin manusia. Kesimpulan: Penemuan kami mengungkapkan bahwa kekuatan insulin analog sejalan dengan laju mekanismenya di dalam tubuh manusia Kata kunci: komputasi, docking, insulin analog, kemiripan sekuen, struktur

The promising future of insulin therapy in diabetes mellitus

The first therapeutic use of insulin by Frederick Banting and Charles Best in 1921 revolutionized the management of type 1 diabetes and considerably changed the lives of many patients with other types of diabetes. In the past 100 years, significant pharmacological advances took place in the field of insulin therapy, bringing closer the goal of optimal glycemic control along with decreased diabetes-related complications. Despite these developments, several challenges remain, such as increasing treatment flexibility, reducing iatrogenic hypoglycemia, and optimizing patient quality of life. Ongoing innovations in insulin therapy (e.g., new insulin analogs, alternative routes of insulin administration, and closed-loop technology) endeavor to overcome these hurdles and change the landscape of diabetes mellitus management. This report highlights recent advances made in the field of insulin therapy and discusses future perspectives.

Pharmacoeconomic comparison of the second generation insulin analogs and insulins on their base

Effective control of Diabetes Mellitus (DM) is an actual task from clinical and economic points of view. The second generation insulin analogs increase level of DM compensation without hypoglycemia. The economic aspects of their usage have been evaluated early, but it is still actual due to changes in prices and new data about clinical efficacy were published.Materials and methods: Clinical-economic comparison of insulin glargine 300 U/ml (iGla 300), insulin degludec (iDeg) and insulin degludec/ insulin aspart (iDegAsp) in the Russian conditions has been performed in naïve patients’ group as well as in the group of patients with previous insulintherapy. Number of patients with HbA1c <7 % was chosen as efficacy criterion. Direct and indirect costs (medications, treatment of CV-complications, GDP loses etc.) were indicated and calculated based on the constructed model.Results: iGla 300 can give an economy till 20 % for medication cost and till 10 % for direct medical expenditures in compare with iDeg in DM Type 1. For both patients’ groups iGla 300 can save 10-23 % of sources in compare with iGed and iDegAsp in DM Type 2. In DM2T iGla 300 had more efficacy and less cost in compare with iDeg in elderly patients with renal insufficiency.Conclusion: An effective control of DM with modern insulins is profitable from government position of payment due to decreasing expenditures for complications treatment.