Effect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats
Effect of 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats Raynald Bergeron 1 , Stephen F. Previs 1 , Gary W. Cline 1 , Pascale Perret 1 , Raymond R. Russell III 1 , Lawrence H. Young 1 and Gerald I. Shulman 1 2 3 1...
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Published in | Diabetes (New York, N.Y.) Vol. 50; no. 5; pp. 1076 - 1082 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.05.2001
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Subjects | |
Online Access | Get full text |
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Summary: | Effect of 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats
Raynald Bergeron 1 ,
Stephen F. Previs 1 ,
Gary W. Cline 1 ,
Pascale Perret 1 ,
Raymond R. Russell III 1 ,
Lawrence H. Young 1 and
Gerald I. Shulman 1 2 3
1 Internal Medicine and
2 Cellular and Molecular Physiology, and the
3 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut. Current address for S.F.P. is
the Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4951.
Abstract
Activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside (AICAR) increases glucose transport in skeletal muscle via an insulin-independent pathway. To examine the
effects of AMPK activation on skeletal muscle glucose transport activity and whole-body carbohydrate and lipid metabolism
in an insulin-resistant rat model, awake obese Zucker fa/fa rats ( n = 26) and their lean ( n = 23) littermates were infused for 90 min with AICAR, insulin, or saline. The insulin infusion rate (4 mU · kg − 1 · min − 1 ) was selected to match the glucose requirements during AICAR (bolus, 100 mg/kg; constant, 10 mg · kg − 1 · min − 1 ) isoglycemic clamps in the lean rats. The effects of these identical AICAR and insulin infusion rates were then examined
in the obese Zucker rats. AICAR infusion increased muscle AMPK activity more than fivefold ( P < 0.01 vs. control and insulin) in both lean and obese rats. Plasma triglycerides, fatty acid concentrations, and glycerol
turnover, as assessed by [2- 13 C]glycerol, were all decreased 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. Endogenous glucose production rates,
measured by [U- 13 C]glucose, were suppressed 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 increased by more than twofold ( P < 0.05 vs. basal) during both AICAR and insulin infusion; [ 3 H]2-deoxy- d -glucose transport activity increased to a similar 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, AICAR increased glucose transport activity by ∼2.4-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 model activates skeletal muscle AMPK and increases glucose transport activity in red gastrocnemius
muscle while suppressing endogenous glucose production and lipolysis. Because type 2 diabetes is characterized by diminished
rates of insulin-stimulated glucose uptake as well as increased basal rates of endogenous glucose production and lipolysis,
these results suggest that AICAR-related compounds may represent a new class of antidiabetic agents.
Footnotes
Address correspondence and reprint requests to Dr. Gerald I. Shulman, Howard Hughes Medical Institute, Yale University School
of Medicine, 295 Congress Ave., BCMM 254, New Haven, CT 06510. E-mail: gerald.shulman{at}yale.edu .
Received for publication 27 June 2000 and accepted in revised form 23 January 2001.
AICAR, 5-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside; AMPK,AMP-activated protein kinase; ANOVA, analysis of variance; 2-DG, 2-deoxy- d -glucose; EGP, endogenous glucose production; GIR, glucose infusion rate; ZMP, monophosphorylated AICAR. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.50.5.1076 |