Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat.
Insulin resistance is of pathogenic importance in several common human disorders including type 2 diabetes, hypertension, obesity and hyperlipidemia, but the underlying mechanisms are unknown. The spontaneously hypertensive rat (SHR) is a model of these human insulin resistance syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridemia, and hypertension map to a single region on rat chromosome 4. Genetic analysis of an SHR derived from a National Institutes of Health colony led to the identification of a causative mutation in the SHR Cd36. We have investigated glucose and fatty acid metabolism in the stroke-prone SHR (SHRSP). We demonstrate defects in insulin action on 2-deoxy-D-glucose transport (SHRSP 3.3 +/- 1.5 vs. 21.0 +/- 7.4 pmol x min(-1) x [20 microl packed cells](-1), SHRSP vs. WKY, respectively, P = 0.01) and inhibition of catecholamine-stimulated lipolysis (P < 0.05 at all concentrations of insulin) in adipocytes isolated from SHRSP. In contrast, basal levels of catecholamine-stimulated nonesterified free fatty acid (NEFA) release and plasma levels of NEFA are similar in SHRSP and WKY. These results are in agreement with the data on the SHR.4 congenic strain, which suggested that the QTL containing Cd36 mutations accounted for the entire defect in basal catecholamine action but only for approximately 40% of the SHR defect in insulin action. In the SHR, both abnormalities appear consequent of defective Cd36 expression. Because Cd36 sequence and expression are apparently normal in SHRSP, it is likely that the molecular mechanism for defective insulin action in this strain is caused by a gene(s) different than Cd36.
Collison
M
M
Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Glasgow, UK.
Glazier
A M
AM
Graham
D
D
Morton
J J
JJ
Dominiczak
M H
MH
Aitman
T J
TJ
Connell
J M
JM
Gould
G W
GW
Dominiczak
A F
AF
D017667:Adipocytes; D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000235:genetics*; D002395:Catecholamines / Q000502:physiology; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D009154:Mutation / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR / Q000235:genetics*; D011921:Rats, Inbred WKY; D020521:Stroke / Q000235:genetics*
D018955:CD36 Antigens; D002395:Catecholamines; D005227:Fatty Acids; D007328:Insulin; D003847:Deoxyglucose; D005947:Glucose