TISSUE-RELATED CHANGES IN INSULIN-RECEPTOR NUMBER AND AUTOPHOSPHORYLATION INDUCED BY STARVATION AND DIABETES IN RATS

Insulin action is subject to regulation at the level of the insulin re ceptor and at postreceptor levels. Starvation and diabetes are often a ssociated with insulin resistance for glucose metabolism in various ti ssues. In muscle, fat, and liver, we examined whether changes in the f unctionality of the insulin receptor correlated with changes in insuli n action in the starved and diabetic state. Insulin-stimulated recepto r autophosphorylation reflects an early physiologic step in transmissi on of the insulin signal, and for that reason, changes in autophosphor ylation activity of the insulin receptor were used as a marker to dete rmine the functionality of the insulin receptor. Glycoprotein fraction s prepared from skeletal muscle, diaphragm, epididymal fat, and liver of control, 3-day starved, short-term 3-day (S) diabetic (streptozotoc in, 70 mg/kg intravenously), and long-term 6-month (L) diabetic (neona tal streptozotocin 100 mu g/g intraperitoneally) rats were used in thi s study. Receptor activity was monitored by measuring insulin-stimulat ed [gamma-P-32]adenosine triphosphate (ATP) receptor autophosphorylati on. In addition, to obtain information about whether changes in recept or autophosphorylation are related to changes in receptor number, rela tive numbers of high-affinity insulin receptors were determined by aff inity cross-linking of [I-125]insulin to the receptor cu chain and qua ntitation of the yield of labeled receptor alpha-chain. Control, starv ed, S diabetic, and L diabetic rats had plasma insulin and glucose lev els of 294 +/- 42, 90 +/- 24, 48 +/- 12, and 216 +/- 30 pmol/L and 6.7 +/- 0.2, 4.1 +/- 0.2, 23.3 +/- 0.7, and 21.6 +/- 2.9 mmol/L, respecti vely. In all tissues, insulin-stimulated receptor autophosphorylation was normal to increased (skeletal muscle > liver > diaphragm > fat), a nd these changes in receptor functionality did not correlate with chan ges in insulin action on glucose metabolism in muscle, fat, and liver of starved and diabetic rats. This indicates that insulin resistance f or glucose metabolism, when present in starved and diabetic rats, is d ue to postreceptor defects rather than to a decreased functionality of the receptor. Copyright (C) 1995 by W.B. Saunders Company