Non-insulin receptor-mediated insulin degradation via insulin degrading enzyme has been proposed to play a role in insulin resistance (IR). Recently, chain-splitting (CS) via a disulfide bond exchange process has been shown to occur for insulin icodec dosed to humans. As insulin icodec contains disulfide bond stabilizing substitutions, the present aim was to estimate the degree of CS of human insulin (HI) from A-chain (Ach) levels during infusion of HI to rats combined with kinetics of Ach in rats.

Ach was injected IV into male Sprague-Dawley (SprD) rats (1, 7 and 50 nmol/kg), and Ach in plasma sampled from the carotid artery was measured by LC/MS. Ach clearance (CL) and t½ (geometric mean) were estimated by regression analysis. A euglycemic clamp during IV HI infusion (2 nmol/kg/min) into SprD rats (n=2) allowed plasma HI and Ach from in vivo CS to be measured. The rate of CS was estimated as the 180 min clamp Ach level multiplied by Ach CL.

Ach was measured in all rats. The estimated CS rate in the clamp experiment was 0.37 nmol/kg/min or 19% of the HI infusion.

We have estimated that a substantial proportion of HI was degraded by CS in rats during HI infusion. Further studies are warranted to substantiate our findings and to investigate 1) if CS of HI during transport to the interstitial fluid may limit the access of HI to target tissues and 2) to what extent increased CS and reduced access of endogenous insulin may be a mechanism for compensatory insulin secretion, hyperinsulinemia and IR.

Disclosure

J. Sturis: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. C. Cramer: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. C.L. Brand: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. H. Helleberg: Stock/Shareholder; Novo Nordisk A/S. P. Kurtzhals: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. F. Hubalek: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S.

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