We examined the changes that occur in the adenosine receptor system during diabetes mellitus. Experimental diabetes mellitus was induced in male Lewis rats with streptozocin (65 mg/kg), and A(1) adenosine receptor binding was characterized with [(125)I]N (6)-2-(4-aminophenyl) ethyladenosine. In adipocytes, high-affinity A(1) adenosine receptor binding decreased from 1466±228 of protein to 312±123 fmol/mg of protein (p<0.01) following 14 d of untreated diabetes mellitus. 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 curve for the inhibition of adenylate cyclase byN (6)-R-phenylisopropyladenosine (R-PIA), however, did show a rightward shift, indicating that diabetic adipocyte membranes were less sensitive to the effects of adenosine than nondiabetic adipocyte membranes. In contrast, the A(1) adenosine receptor-binding characteristics and adenylate cyclase dose-response curve for cerebral cortical tissue were unchanged by diabetes. These 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 diabetes 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 by diabetes, but others are relatively spared. Understanding these alterations in adenosine receptor function may lead tonovel therapies of this common metabolic disease.