PPARα activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans
Open accessAbstract
Fibrates, activators of the nuclear receptor PPARα, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARα 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 PPARα activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.
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The hyperglycaemic effect of glucocorticoids is generally attributed to reduced insulin sensitivity in muscle, liver, and adipose tissue.
“This unwanted hyperglycaemic effect is generally attributed to the reduction in sensitivity to insulin action in muscle, liver and adipose tissue.5–7”
From Twenty‐four‐hour profiles of plasma glucose, insulin, C‐peptide and free fatty acid in subjects with varying degrees of glucose tolerance following short‐term, medium‐dose prednisone (20 mg/day) treatment: evidence for differing effects on insulin secretion and action (2012) · cites this paper as [7]
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- Authors
- Subramanian, S., DeRosa, M. A., Bernal-Mizrachi, C., Laffely, N., Cade, W. T., Yarasheski, K. E., Cryer, P. E., & Semenkovich, C. F.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2006-12
- Volume
- 291
- Issue
- 6
- Pages
- E1365-E1371
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC4303180
- OpenAlex
- W2129907414
- Cited by
- 34
- References
- 40
- Citations by year
- 2019: 1 · 2018: 1 · 2016: 2 · 2014: 1 · 2013: 1 · 2012: 3
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p41rr000954-34, 1f32dk066977-01)
- National Heart, Lung, and Blood Institute (P50HL083762)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32-DK-066977, P50-DK-20579, P30DK056341, P30DK020579)
- National Center for Research Resources (P41-RR000954, M01-RR00036, P41-RR-00095, M01RR000036)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- PPARα, fenofibrate, glucocorticoid-induced insulin resistance, dexamethasone, blood pressure, hyperinsulinemia, glucose disposal, hepatic glucose production, fibrates, dyslipidemia, vascular function
- MeSH terms
- Adult, Hypolipidemic Agents, Blood Pressure, Dexamethasone, Female, Forearm, Glucocorticoids, Humans, Insulin Resistance, Male, Fenofibrate, Regional Blood Flow, Glucose Clamp Technique, Blood Pressure Monitoring, Ambulatory, PPAR alpha
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