Characterization of insulin-resistance: role of receptor alteration in insulin-dependent diabetes mellitus, essential hypertension and cardiac hypertrophy.
Insulin-resistance is associated with a number of disease states such as diabetes, syndrome X, and hypertension. These situations may be coupled to insulin-resistance through the insulin signaling system as a common pathway. The purpose of this study was to investigate the receptor binding alterations in streptozotocin-induced diabetic rats, spontaneously hypertensive rats and aortocaval shunted rats (eccentric cardiac hypertrophy). A physical model describing a 1:1 stoichiometry of ligand binding with its receptor is proposed describing reversible binding of [(125)I]insulin or [(125)I]IGF-1 at the microvascular endothelial as well as with the cardiac myocytes after CHAPS-treatment. Analysis of the collected effluents are curve-fitted with a conservation equation and a first-order Bessel function which allowed the calculation of the forward binding constants (k(n)), the reversible constants (k(-n)), the dissociation constants (k(d)) and the residency time constants (tau). The results showed that streptozotocin-induced diabetic rats showed insulin-resistance through alterations in the kinetics of insulin receptor binding. The normotensive controls of the spontaneously hypertension rats (SHR) carry themselves insulin-resistant receptors whose binding to insulin worsens in the hypertensive SHR. Negative cooperativity between insulin-like growth factor IGF-1 and insulin receptors could be a causative factor predisposing for insulin-resistance in the aortocaval shunted rats to insulin resistance. The defects may be occurring at the receptor level in insulin-dependent diabetes mellitus, Wistar-Kyoto rats and spontaneously hypertensive rats. In conclusion, alterations in the kinetics of insulin binding to its receptor seem to play a central role for the initiation of insulin-resistance during the various pathophysiological states.
Bikhazi
A B
AB
Department of Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. ab04@aub.edu.lb
Azar
S T
ST
Birbari
A E
AE
El-Zein
G N
GN
Haddad
G E
GE
Haddad
R E
RE
Bitar
K M
KM
D000818:Animals; D000900:Anti-Bacterial Agents; D006332:Cardiomegaly / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013045:Species Specificity; D013311:Streptozocin
D000900:Anti-Bacterial Agents; D007328:Insulin; D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1