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.