Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats

Activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-c arboxamide-1-beta -D-ribofurano- side (AICAR) increases glucose transport i n skeletal muscle via an insulin-independent pathway. To examine the effect s of AMPK activation on skeletal muscle glucose transport activity and whol e-body carbohydrate and lipid metabolism in an insulin-resistant rat model, awake obese Zucker fa/fa rats (n = 26) and their lean (rt = 23) Littermate s mere infused for 90 min with AICAR, insulin, or saline. The insulin infus ion rate (4 mU kg-l min-l) was selected to match the glucose requirements d uring AICAR (bolus, 100 mg/kg; constant, 10 mg kg-l min-l) isoglycemic clam ps in the lean rats. The effects of these identical AICAR and insulin infus ion rates mere then examined in the obese Zucker rats. AICAR infusion incre ased muscle AMPK activity more than fivefold (P < 0.01 vs. control and insu lin) in both lean and obese rats. Plasma triglycerides, fatty acid concentr ations, and glycerol turnover, as assessed by [2-C-13]glycerol, mere all de creased in both lean and obese rats infused with AICAR (P < 0.05 vs. basal) , whereas insulin had no effect on these parameters in the obese rats. Endo genous glucose production rates, measured by [U-C-13]glucose, mere suppress ed by > 50% during AICAR and insulin infusions in both lean and obese rats (P < 0.05 vs. basal). In lean rats, rates of whole-body glucose disposal in creased by more than two-fold (P < 0.05 vs. basal) during both AICAR and in sulin infusion; [H-3]2-deoxy-D-glucose transport activity increased to a si milar extent, by >2.2-fold (both P < 0.05 vs, control), in both soleus and red gastrocnemius muscles of lean rats infused with either AICAR or insulin . In the obese Zucker rats, neither AICAR nor insulin stimulated whole-body glucose disposal or soleus muscle glucose transport activity. However, AIC AR increased glucose transport activity by similar to2.4-fold (P < 0.05 vs. control) in the red gastrocnemius from obese rats, whereas insulin had no effect. In summary, acute infusion of AICAR in an insulin-resistant rat mod el activates skeletal muscle AMPK and increases glucose transport activity in red bastrocnemius muscle while suppressing endogenous glucose production and lipolysis. Because type 2 diabetes is characterized by diminished rate s of insulin-stimulated glucose uptake as well as increased basal rates of endogenous glucose production and lipolysis, these results suggest that AIC AR-related compounds may represent a new class of antidiabetic agents.