Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats.
We investigated the chronic in vivo effect of resistin on insulin sensitivity and glucose metabolism by overexpressing resistin protein in male Wistar rats using intravenous administration of an adenovirus encoding mouse resistin. After 7 days of elevated resistin levels at a supraphysiological concentration, the animals displayed glucose intolerance and hyperinsulinemia during glucose tolerance tests, and insulin tolerance tests demonstrated an impaired glucose-lowering effect of insulin. The glucose clamp studies were performed at submaximal (4 mU/kg/min) and maximal (25 mU/kg/min) insulin infusion rates and demonstrated the presence of insulin resistance induced by elevated resistin levels. Indeed, the insulin-stimulated glucose infusion rate was decreased by 12-31%; suppression of hepatic glucose output was attenuated by 28-55%; and insulin suppression of circulating FFA levels was inhibited by 7%. Insulin receptor substrate-1 and -2 phosphorylation and Akt activation were impaired in muscle and adipose tissue. Interestingly, activation of AMP-activated protein kinase in skeletal muscle, liver, and adipose tissue was also significantly downregulated. Together, these results indicate that chronic "hyper-resistinemia" leads to whole-body insulin resistance involving impaired insulin signaling in skeletal muscle, liver, and adipose tissue, resulting in glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. Thus elevated resistin levels in normal rats fed a regular chow diet produce many of the features of human syndrome X.
Satoh
Hiroaki
H
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla 92093-0673, USA.
Nguyen
M T Audrey
MT
Miles
Philip D G
PD
Imamura
Takeshi
T
Usui
Isao
I
Olefsky
Jerrold M
JM
D055372:AMP-Activated Protein Kinases; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D004032:Diet; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D006729:Hormones, Ectopic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology / Q000502:physiology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D052243:Resistin; D015398:Signal Transduction / Q000502:physiology
D005230:Fatty Acids, Nonesterified; D006729:Hormones, Ectopic; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C499624:RETN protein, human; D052243:Resistin; C499623:Retn protein, mouse; C499622:Retn protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose