Our objective is to study the regulation of prostacyclin (PGI2) production in the isolated adipocyte of the normal and diabetic organism. We recently demonstrated (a) that isolated rat adipocytes produce PGI2, a potent vasodilator and inhibitor of platelet aggregation, in large quantities-sufficient to produce local and systemic effects- and (b) that insulin inhibits this production. This is the first direct demonstration in any cell that insulin regulates arachidonic acid metabolism and prostaglandin production. We also observed that elevated levels of PGI2 and thromboxane A2 may circulate in rats with diabetic ketoacidosis and that the adipocyte may be a major source of the high plasma levels of PGI2. An imbalance between PGI2 produced by vascular endothelium and thromboxane A2 (a potent vasoconstrictor and inducer of platelet aggregation) produced by platelets may result in a situation that favors platelet aggregation and contributes to the genesis of diabetic vascular disease. Understanding the mechanism of PGI2 production in the adipocyte is important because a) the adipocyte appears to be one of the major sources of this potent substance in the body, (b) any valid model of the pathogenesis of diabetic vascular disease must consider PGI2 production by the adipocyte, (c) these studies can provide a model for the effects of insulin on prostaglandin synthesis in other target cells such as endothelium and platelets, and (d) this work can thereby elucidate the molecular basis of diabetic vascular disease.
Our specific aims are as follows: 1) to explore the mechanism of hormone-induced production of PGI2 (and PGE2 where appropriate) in the isolated rat adipocyte, with emphasis on (a) the site of origin of the arachidonic acid that is the precursor of PGI2 synthesis, (b) the identity of the adrenergic receptor that mediates norepinephrine-induced PGI2 production, (c) the possible role of cAMP, (d) the effect of calcium, (e) the possible role of the phospholipase inhibitory protein, and (f) the mechanism by which insulin inhibits this production; 2) to define the hormonal regulation of PGI2 production in the adipocyte, with emphasis on (a) lipolytic hormones, and on (b) vasoactive hormones; 3) to explore these questions in adipocytes from normal and diabetic rats; and 4) to pursue these questions in adipocytes from normal and diabetic subjects.
