It is suggested that insulin in blood circulates in two forms : a biologically active free form and a biologically inactive form which we called bound insulin or insulin complex. The properties of free insulin appear to be similar to those of crystalline insulin extracted from pancreas. Bound insulin, on the other hand, exhibits different physicochemical characteristics and is unreactive with anti-insulin antisera. Partially purified preparations of bound insulin have been obtained from human or animal sera by resin adsorption and elution. These preparations exhibit about a 300-fold protein purification. Further purification about 3,000-fold) can be achieved by Sephadex chromatography of these preparations.
Bound insulin preparations produced
in vivo and
in vivo biologic effects similar to those of crystalline insulin. The biologic effects of bound insulin have been studied on practically all the
in vivo and
in vivo systems available for the detection of small amounts of insulin. Since there is no evidence that substances other than insulin can produce the sum of these
in vivo and
in vivo effects of bound insulin we assumed that bound insulin activity represent true insulin activity.
Bound insulin may represent a metabolite of free insulin which is produced
in vivo by the action of extrapancreatic tissues. Bound insulin is
not generated
in vitro by the addition of crystalline insulin in sera. Recent studies suggest that liver perfusion with crystalline insulin results in the production of bound insulin-like substances with properties similar to those of serum bound insulin. This is consistent with the suggestion that the liver may play an important role in the transformation of free to bound insulin. Total pancreatectomy in rats produced a significant decline in bound insulin concentrations.
Studies in nondiabetics suggest the possibility that insulin activity may be regulated through a dynamic balance between active, free and inactive, bound insulin. A malfunction of the biochemical mechanisms which regulate this balance at the tissue level may represent one of the primary lesions in the pathogenesis of some types of diabetes. Such a malfunction may cause increased transformation of free to bound insulin by extrapancreatic tissues and/or a decline in the rates of activation of bound insulin by the tissues of these patients. Inactive bound insulin, therefore, accumulates in the blood of these diabetics. This high concentration of bound insulin, in turn, may interfere with the normal clearance and utilization of the endogenous free or exogenous crystalline insulin.
In vivo studies indicate that adipose tissue extracts (ATE) can produce a significant decline in the blood glucose concentrations of adrenalectomized and hypophysectomized rats. Similar effects with ATE were produced in intact, spontaneously diabetic mice of the KK strain. The effect of ATE in these diabetic animals lasted 24 to 30 hours. The KK mice are considered to represent an inbred diabetic strain with features characterizing human diabetes of the maturity-onset type. It is suggested that the effect of ATE in these animals may result from the
In vivo activation by ATE of their circulating inactive bound insulin.
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