DESENSITIZATION OF THE ADIPOCYTE A(1) ADENOSINE RECEPTOR DURING UNTREATED EXPERIMENTAL DIABETES-MELLITUS

We examined the changes that occur in the adenosine receptor system du ring diabetes mellitus. Experimental diabetes mellitus was induced in male Lewis rats with streptozocin (65 mg/kg), and A(1) adenosine recep tor binding was characterized with [I-125]N-6-2-(4-aminophenyl) aminop henyl) ethyladenosine. In adipocytes, high-affinity A(1) adenosine rec eptor binding decreased from 1466 +/- 228 of protein to 312 +/- 123 fm ol/mg of protein (p < 0.01) following 14 d of untreated diabetes melli tus. Neither the dissociation constant (K-d = 1.3 +/- 0.2 nM) nor the basal level of adenylate cyclase activity (2.8 +/- 1.1 pmol cAMP/mg of protein/min) was altered by diabetes mellitus, The dose-response curv e for the inhibition of adenylate cyclase by N-6-R-phenylisopropyladen osine (R-PIA), however, did show a rightward shift, indicating that di abetic adipocyte membranes were less sensitive to the effects of adeno sine than nondiabetic adipocyte membranes. In contrast, the A(1) adeno sine receptor-binding characteristics and adenylate cyclase dose-respo nse curve for cerebral cortical tissue were unchanged by diabetes, The se findings suggest that diabetes has tissue-specific effects on the A (1) adenosine receptor system, Furthermore, the decreased sensitivity to adenosine potentially worsens the hyperlipidemia associated with di abetes mellitus. Such alterations in the adenosine receptor system may play a previously undescribed role in the pathophysiology of diabetes mellitus and may help explain why some organs are severely affected b y diabetes, but others are relatively spared. Understanding these alte rations in adenosine receptor function may lead to novel therapies of this common metabolic disease.