systematic evaluation of the metabolic to mitogenic potency ratio for b10-substituted insulin analogues系统评估代谢的促有丝分裂的力量比b10-substituted胰岛素类似物.pdfVIP

Systematic Evaluation of the Metabolic to Mitogenic Potency Ratio for B10-Substituted Insulin Analogues 1 2 1 1 1 Tine Glendorf *, Louise Knudsen , Carsten E. Stidsen , Bo F. Hansen , Anne Charlotte Hegelund , 1 1 1 Anders R. Sørensen , Erica Nishimura , Thomas Kjeldsen 1 Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark, 2 Diabetes Research Unit, Novo Nordisk A/S, Gentofte, Denmark Abstract Background: Insulin analogues comprising acidic amino acid substitutions at position B10 have previously been shown to display increased mitogenic potencies compared to human insulin and the underlying molecular mechanisms have been subject to much scrutiny and debate. However, B10 is still an attractive position for amino acid substitutions given its important role in hexamer formation. The aim of this study was to investigate the relationships between the receptor binding properties as well as the metabolic and mitogenic potencies of a series of insulin analogues with different amino acid substitutions at position B10 and to identify a B10-substituted insulin analogue without an increased mitogenic to metabolic potency ratio. Methodology/Principal Findings: A panel of ten singly-substituted B10 insulin analogues with different amino acid side chain characteristics were prepared and insulin receptor (both isoforms) and IGF-I receptor binding affinities using purified receptors, insulin receptor dissociation rates using BHK cells over-expressing the human insulin receptor, metabolic potencies by lipogenesis in isolated rat adipocytes, and mitogenic potencies using two diffe