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Molecular engineering of safe and efficacious oral basal insulin.

ABSTRACT: Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.

SUBMITTER: Hubalek F

PROVIDER: S-EPMC7385171 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Molecular engineering of safe and efficacious oral basal insulin.

Hubálek Frantisek F Refsgaard Hanne H F HHF Gram-Nielsen Sanne S Madsen Peter P Nishimura Erica E Münzel Martin M Brand Christian Lehn CL Stidsen Carsten Enggaard CE Claussen Christian Hove CH Wulff Erik Max EM Pridal Lone L Ribel Ulla U Kildegaard Jonas J Porsgaard Trine T Johansson Eva E Steensgaard Dorte Bjerre DB Hovgaard Lars L Glendorf Tine T Hansen Bo Falck BF Jensen Maja Kirkegaard MK Nielsen Peter Kresten PK Ludvigsen Svend S Rugh Susanne S Garibay Patrick W PW Moore Mary Courtney MC Cherrington Alan D AD Kjeldsen Thomas T

Nature communications 20200727 1

Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong al ...[more]

PMID: 32719315

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Molecular engineering of safe and efficacious oral basal insulin.

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Molecular engineering of safe and efficacious oral basal insulin.

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