PPARalpha activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans.
Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARalpha activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARalpha activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.
Subramanian
Savitha
S
Endocrinology, Metabolism, and Lipid Research, Dept. of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
DeRosa
Michael A
MA
Bernal-Mizrachi
Carlos
C
Laffely
Nicholas
N
Cade
William T
WT
Yarasheski
Kevin E
KE
Cryer
Philip E
PE
Semenkovich
Clay F
CF
D000328:Adult; D001794:Blood Pressure / Q000502:physiology*; D018660:Blood Pressure Monitoring, Ambulatory; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply; D005938:Glucocorticoids / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D047493:PPAR alpha / Q000378:metabolism*; D012039:Regional Blood Flow / Q000502:physiology
D005938:Glucocorticoids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D003907:Dexamethasone; D011345:Fenofibrate