Relationship between negative cooperativity and insulin action

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Abstract
The respective abilities of porcine insulin and [LeuB25]insulin to enhance the rate of dissociation of receptor-bound [125I]insulin from human IM-9 lymphocytes and isolated rat adipocytes and to increase the rate of adipocyte glucose transport and oxidation were compared. Although porcine insulin (100 ng/ml) greatly enhanced the dissociation rate of previously bound [125I]insulin, [LeuB25]insulin (at a concentration yielding equivalent receptor occupancy) had no effect. Nevertheless, the analog fully stimulated adipocyte glucose transport and oxidation at concentrations consistent with its reduced (1.7% of normal) intrinsic binding affinity. Activation of glucose transport by the analog was rapid, and the corresponding rate of activation was indistinguishable from that produced by native insulin. The increased dissociation rate observed with increasing receptor occupancy by native porcine insulin was interpreted as evidence for negative cooperative site-site interactions between occupied receptors. According to this formulation, [LeuB25]insulin is a noncooperative insulin analog. Since this [LeuB25]insulin retains full biologic activity, the enhancement of the insulin dissociation rate at high levels of receptor occupancy does not reflect a phenomenon inherent in insulin''s action to augment glucose metabolism.