Structural principles of insulin formulation and analog design: A century of innovation.

BACKGROUND: The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. SCOPE OF REVIEW: Pioneering crystallographic analyses-beginning with Hodgkin's solving of the 2-Zn insulin hexamer-elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous ß-cell secretion more closely, ideally with reduced risk of hypoglycemia. MAJOR CONCLUSIONS: Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.

[History of insulin production in Czechoslovakia]. / Historie výroby inzulinu v Ceskoslovensku.

The aim of the article is an effort to capture the history of insulin production in Czechoslovakia. Information has been obtained mainly from two Czech journals: "Casopis lékaru ceských" (published since 1862) and "Praktický lékar" (published since 1921). At first, imported insulin in the form of insulin injections or substances from which insulin was prepared appeared at the market in Czechoslovakia. During years 1923-1945, insulin was produced by five companies, since 1945 only by one company "Léciva".

Evolution of insulin development: focus on key parameters.

INTRODUCTION: Although insulin products and treatment strategies have improved significantly, clinical challenges still exist. Meeting glycemic goals while minimizing glucose variability and hypoglycemia is of utmost importance when considering existing insulin therapies and designing investigational insulin treatments. METHODS: A PubMed search identified relevant, peer-reviewed articles related to the evolution of insulin development for this nonsystematic review. Search terms included "animal insulin," "synthetic insulin," "regular human insulin," "insulin lispro," "insulin aspart," "insulin glulisine," "insulin glargine," "insulin detemir," "insulin degludec," "biphasic human insulin," "insulin premixes," "ultra-long acting," "oral insulin," and "inhaled insulin." RESULTS: While the discovery of animal insulin significantly decreased mortality rates from diabetes, issues with availability and large variability between batches led to difficulty in determining proper doses and, subsequently, challenges in achieving glycemic control and avoiding hypoglycemia. The development of synthetic insulin created a more readily available supply, but hypoglycemia still persisted. Recombinant DNA technology solved insulin production problems and allowed for the development of better retarding agents, but pharmacokinetic/pharmacodynamic profiles still did not mimic natural insulin. Insulin premixes offered improved glycemic control, decreased intrapatient variability versus self-mixing, and required fewer injections per day; however, patient adherence remained a problem due to the need to inject 30-60 minutes before a meal for optimal control. This prompted the development of rapid-acting insulin analogs that could be injected right before a meal and long-acting insulin analogs with flatter time-action profiles. CONCLUSION: Despite advances in insulin development, a need to provide more physiologic basal insulin coverage and reduce hypoglycemic risk in patients with diabetes remains. Newer insulin analogs and more convenient routes of insulin delivery have shown promising safety and efficacy results. Many patients with diabetes have not reached glycemic goals on currently available insulins. Additional studies are necessary to tailor optimal insulin delivery strategies to specific subsets of diabetes patients.