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

Design of "first-generation" insulin analogues over the past 3 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-h...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2022-03, Vol.107 (4), p.909-928
Main Authors: Jarosinski, Mark A, Chen, Yen-Shan, Varas, Nicolás, Dhayalan, Balamurugan, Chatterjee, Deepak, Weiss, Michael A
Format: Article
Language:English
Subjects:
Animals
Blood Glucose
Dextrose
Diabetes Mellitus, Type 2 - drug therapy
Diabetes therapy
Glucose
Goals
Humans
Hypoglycemic agents
Hypoglycemic Agents - pharmacokinetics
Hypoglycemic Agents - therapeutic use
Innovations
Insulin - pharmacology
Insulin - therapeutic use
Insulins - therapeutic use
International marketing
Mini-Review
Type 2 diabetes
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Summary:Design of "first-generation" insulin analogues over the past 3 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 ultrarapid and ultrabasal analogue formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogues seek to exploit therapeutic mechanisms: glucose-responsive ("smart") analogues, pathway-specific ("biased") analogues, and organ-targeted analogues. Smart insulin analogues and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogues may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will affect use and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale, and potential clinical applications.
ISSN:0021-972X
1945-7197
1945-7197
DOI:10.1210/clinem/dgab849