TISSUE-SPECIFIC EFFECTS OF IN-VIVO ADENOSINE RECEPTOR BLOCKADE ON GLUCOSE-UPTAKE IN ZUCKER RATS

Previous studies have shown that treatment of obese Zucker rats with t he adenosine receptor antagonist 1,3-dipropyl-8-(p-acrylic) phenyl xan thine (BWA1433) improves intraperitoneal glucose tolerance, In this st udy, a euglycemic hyperinsulinemic clamp was performed on obese (fa/fa ) and lean (Fa/fa) Zucker rats that had been treated orally with BWA14 33 or vehicle for 1 wk, A constant infusion of [H-3]glucose was initia ted in fasted animals to measure basal whole body glucose kinetics. No differences in glucose concentration or rates of glucose production/d isappearance were observed between lean or obese animals with or witho ut BWA1433, During the euglycemic hyperinsulinemic clamp, whole body g lucose disposal in obese Zucker rats was only 22% of that observed in lean animals. BWA1433 treatment increased glucose disposal by 88% in o bese Zucker rats. At the end of the clamp, [C-14]-2-deoxyglucose was i njected to determine tissue-specific differences in glucose uptake, Ga strocnemius, soleus, heart, and liver of untreated obese animals had s ignificantly lower glucose uptake than lean controls under hyperinsuli nemic conditions. BWA1433 treatment of obese animals increased glucose uptake in gastrocnemius and soleus muscles by 44 and 47%, respectivel y. Conversely, BWA1433 treatment decreased glucose uptake in adipose t issue by 54 and 49% in obese and lean Zucker rats, respectively. In su mmary, BWA1433 improves glucose tolerance by increasing glucose uptake in skeletal muscle while decreasing glucose uptake by adipose tissue. This study suggests that insulin resistance in obese Zucker rats is t issue specific and that signaling from adenosine receptors may be a fa ctor contributing to tissue-specific insulin resistance.