Covalently-linked insulin dimers: their metabolism and biological effects in vivo as partial competitive antagonists of insulin clearance

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Abstract
The biological properties of three covalently-linked insulin dimers were studied in greyhounds. Constant infusions showed that the plasma distribution kinetics were slower for the dimers than for insulin. The metabolic clearance rates of the three dimers (10.3±0.4, 8.8±0.5, 8.2±0.5 ml· min-1· kg-1; mean ± SEM) were significantly lower than that of insulin (19±0.8 ml · min-1 · kg-1), and their hypoglycaemic effects (11.2%, 3% and 0.3%) were markedly reduced compared with their lipogenic potencies in vitro (80%, 30% and 13%, respectively). A low dose infusion of insulin or an equipotent dose of one of the dimers significantly prolonged the effects of an insulin bolus on plasma glucose but not on non-esterified fatty acids. The apparent distribution space (106.4±11.9 ml/kg) and clearance rate (14.7±0.5 ml · min-1 · kg-1) of an insulin bolus were significantly reduced by one dimer (44.5±8.4 ml/ kg and 10.7±2.8ml·min-1·kg-1) but not by the equipotent insulin infusion (102.7±8.2ml/kg and 16.4±0.07ml· min-1 · kg-1). The apparent partial competitive antagonism of insulin by the dimers that has been reported in vitro can be observed in vivo, in that antagonism of insulin metabolism was directly demonstrated with one of the dimers.