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Hubálek, Frantisek; Refsgaard, Hanne H F; Gram-Nielsen, Sanne; Madsen, Peter; Nishimura, Erica; Münzel, Martin; Brand, Christian Lehn; Stidsen, Carsten Enggaard; Claussen, Christian Hove; Wulff, Erik Max; Pridal, Lone; Ribel, Ulla; Kildegaard, Jonas; Porsgaard, Trine; Johansson, Eva; Steensgaard, Dorte Bjerre; Hovgaard, Lars; Glendorf, Tine; Hansen, Bo Falck; Jensen, Maja Kirkegaard; Nielsen, Peter Kresten; Ludvigsen, Svend; Rugh, Susanne; Garibay, Patrick W; Moore, Mary Courtney; Cherrington, Alan D; Kjeldsen, Thomas
Nature communications, 07/2020, Letnik: 11, Številka: 1Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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