Fig. 1: Selected covalent insulin dimers function as partial agonists and induce biased signaling. | Nature Communications

Fig. 1: Selected covalent insulin dimers function as partial agonists and induce biased signaling.

From: Functionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists

Fig. 1: Selected covalent insulin dimers function as partial agonists and induce biased signaling.

IRPA-1 functions as an IR partial agonist and is also a partial antagonist (a, b). Human IRb agonist activity (IRPA alone) or partial agonist activity (in the presence of 1 nM of RHI) of IRPA-1 in vitro in CHO-hIRb cells as measured by pAkt (a). RHI was also titrated alone or in the presence of fixed dose of IRPA-1 and the pAkt readouts are shown in b. IRPAs function as IR partial agonists in human myotube (c) and mouse hepatocyte (d). All titrations in a-d were conducted in duplicate (mean ± SD). IRPAs show reduced stimulation of IR internalization relative to RHI (e). The study was conducted using PathHunter Enzyme Fragment Complementation Assay (in quadruplicate, (mean ± SD)) to measure IR internalization (Endosome Translocation; DiscoverX). IRPA-1 induces differential pAkt vs. pERK signaling in HEK 293 cells expressing human IGF-1R (f, g) and has minimal stimulation of cellular proliferation (h). All titrations in f-h were conducted in triplicate (mean ± SD). Source data are provided as a Source Data file.

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