AICAR Administration Causes an Apparent Enhancement of Muscle and Liver Insulin Action in Insulin-Resistant High-Fat-Fed Rats
- Miguel A. Iglesias1,
- Ji-Ming Ye1,
- Georgia Frangioudakis1,
- Asish K. Saha2,
- Eva Tomas1,
- Neil B. Ruderman2,
- Gregory J. Cooney1 and
- Edward W. Kraegen1
- 1Garvan Institute of Medical Research, Sydney, New South Wales, Australia
- 2Boston University School of Medicine, Boston, Massachusetts
Exercise improves insulin sensitivity. As AMP-activated protein kinase (AMPK) plays an important role in muscle metabolism during exercise, we investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) on insulin action in insulin-resistant high-fat-fed (HF) rats. Rats received a subcutaneous injection of 250 mg/kg AICAR (HF-AIC) or saline (HF-Con). The next day, euglycemic-hyperinsulinemic clamp studies were performed. Glucose infusion rate during the clamp was enhanced (50%) in HF-AIC compared with HF-Con rats. Insulin-stimulated glucose uptake was improved in white but not in red quadriceps, whereas glycogen synthesis was improved in both red and white quadriceps of HF-AIC rats. HF-AIC rats also showed increased insulin suppressibility of hepatic glucose output (HGO). AICAR-induced responses in both liver and muscle were accompanied by reduced malonyl-CoA content. Clamp HGO correlated closely with hepatic triglyceride content (r = 0.67, P < 0.01). Thus, a single dose of AICAR leads to an apparent enhancement in whole-body, muscle, and liver insulin action in HF rats that extends beyond the expected time of AMPK activation. Whether altered tissue lipid metabolism mediates AICAR effects on insulin action remains to be determined. Follow-up studies suggest that at least some of the post-AICAR insulin-enhancing effects also occur in normal rats. Independent of this, the results suggest that pharmacological activation of AMPK may have potential in treating insulin-resistant states and type 2 diabetes.
Address correspondence and reprint requests to Dr. Ji-Ming Ye, Diabetes and Metabolism Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, New South Wales 2010, Australia. E-mail:.
Received for publication 9 January 2002 and accepted in revised form 17 June 2002.
N.B.R. is on the Diabetes Advisory Panel for Merck and has received honoraria from Millennium Pharmaceuticals.
ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; AMPK, AMP-activated protein kinase; FFA, free fatty acid; GIR, glucose infusion rate; GLUT, glucose transporter; HF, high-fat fed; HGO, hepatic glucose output; LCACoA, long-chain acyl-CoA; Rd, glucose disappearance rate; Rg′, glucose uptake.