Coronary Vasomotor Abnormalities in Insulin-Resistant Individuals

4 May 2004 | Volume 140 Issue 9 | Pages 700-708

Background: Insulin resistance is a metabolic spectrum that progresses from hyperinsulinemia to the metabolic syndrome, impaired glucose tolerance, and finally type 2 diabetes mellitus. It is unclear when vascular abnormalities begin in this spectrum of metabolic effects.

Objective: To evaluate the association of insulin resistance with the presence and reversibility of coronary vasomotor abnormalities in young adults at low cardiovascular risk.

Design: Cross-sectional study followed by prospective, open-label treatment study.

Setting: University hospital.

Patients: 50 insulin-resistant and 22 insulin-sensitive, age-matched Mexican-American participants without glucose intolerance or traditional risk factors for or evidence of coronary artery disease.

Intervention: 3 months of thiazolidinedione therapy for 25 insulin-resistant patients.

Measurements: Glucose infusion rate in response to insulin infusion was used to define insulin resistance (glucose infusion rate 4.00 mg/kg of body weight per minute [range, 0.90 to 3.96 mg/kg per minute]) and insulin sensitivity (glucose infusion rate 7.50 mg/kg per minute [range, 7.52 to 13.92 mg/kg per minute]). Myocardial blood flow was measured by using positron emission tomography at rest, during cold pressor test (largely endothelium-dependent), and after dipyridamole administration (largely vascular smooth muscle–dependent).

Results: Myocardial blood flow responses to dipyridamole were similar in the insulin-sensitive and insulin-resistant groups. However, myocardial blood flow response to cold pressor test increased by 47.6% from resting values in insulin-sensitive patients and by 14.4% in insulin-resistant patients. During thiazolidinedione therapy in a subgroup of insulin-resistant patients, insulin sensitivity improved, fasting plasma insulin levels decreased, and myocardial blood flow responses to cold pressor test normalized.

Limitations: The study was not randomized, and it included only 1 ethnic group.

Conclusions: Insulin-resistant patients who do not have hypercholesterolemia or hypertension and do not smoke manifest coronary vasomotor abnormalities. Insulin-sensitizing thiazolidinedione therapy normalized these abnormalities. These results suggest an association between insulin resistance and abnormal coronary vasomotor function, a relationship that requires confirmation in larger studies.

Editors' Notes Context Cardiovascular abnormalities are not known to be present in early-stage insulin resistance. Contribution The authors tested endothelial and vascular smooth-muscle function in 22 insulin-sensitive controls and 50 young, insulin-resistant adults with no glucose intolerance or other cardiac risk factors. Insulin-resistant patients had normal vascular smooth-muscle function but had abnormal endothelial function. Administering thiazolidinediones to a sample of the insulin-resistant patients normalized endothelial function. Cautions These observations must be confirmed. Furthermore, the results do not indicate that pharmacologic intervention improves the long-term cardiovascular health of insulin-resistant but otherwise healthy patients. –The Editors

 

Author and Article Information

From University of California, Los Angeles, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; and Olive View–University of California, Los Angeles Medical Center, Sylmar, California.

Acknowledgments: The authors thank Drs. Alan Fogelman and Jerome Rotter for their critical review of this manuscript.

Grant Support: By National Institutes of Health grants HL33177 and 5PO1HL6003.

Potential Financial Conflicts of Interest:Consultancies: M.J. Quiñones (GlaxoSmithKline), W.A. Hsueh (Merck, GlaxoSmithKline, Novartis); Honoraria: M.J. Quiñones (GlaxoSmithKline), K. Van Herle (Novartis, GlaxoSmithKline, Takeda-Lilly); Grants received: M.J. Quiñones (GlaxoSmithKline), W.A. Hsueh (Merck, GlaxoSmithKline, Novartis, Takeda).

Requests for Single Reprints: Willa A. Hsueh, MD, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at University of California, Los Angeles, 900 Veteran Avenue, Suite 24-130, Los Angeles, CA 90095; e-mail, whsueh{at}mednet.ucla.edu.

Current Author Addresses: Drs. Quiñones, Bulnes-Enriquez, Jimenez, Van Herle, and Hsueh and Ms. De La Rosa: Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at University of California, Los Angeles, 900 Veteran Avenue, Suite 24-130, Los Angeles, CA 90095.

Dr. Hernandez-Pampaloni: Department of Radiology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.

Dr. Schelbert: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, B2-085J, CHS Box 95648, 650 Charles E. Young Drive South, Los Angeles, CA 90095-6948.

Drs. Hernandez, Modilevsky, and Yu: Department of Medicine, Olive View–University of California, Los Angeles Medical Center, Room 2B182, 14445 Olive View Drive, Sylmar, CA 91342.

Drs. Chon and Elashoff: Department of Biomathematics, David Geffen School of Medicine at University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1766.

Dr. Yang: Division of Medical Genetics, Departments of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.

Dr. Nicholas: Division of Nephrology and Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at University of California, Los Angeles, 900 Veteran Avenue, Suite 24-130, Los Angeles, CA 90095.

Dr. Castellani: Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles, 10833 Le Conte Avenue, 547-123 CHS, Los Angeles, CA 90095.

Author Contributions: Conception and design: M.J. Quiñones, W.A. Hsueh.

Analysis and interpretation of the data: M.J. Quiñones, M. Hernandez-Pampaloni, H. Schelbert, Y. Chon, H. Yang, R. Elashoff, W.A. Hsueh.

Drafting of the article: M.J. Quiñones, W.A. Hsueh.

Critical revision of the article for important intellectual content: M.J. Quiñones, M. Hernandez-Pampaloni, H. Schelbert, Y. Chon, S.B. Nicholas, R. Elashoff, W.A. Hsueh.

Final approval of the article: M.J. Quiñones, M. Hernandez-Pampaloni, H. Schelbert, W.A. Hsueh.

Provision of study materials or patients: M.J. Quiñones, I. Bulnes-Enriquez, X. Jimenez, G. Hernandez, R. De La Rosa, T. Modilevsky, K. Yu, K. Van Herle, W.A. Hsueh.

Statistical expertise: M.J. Quiñones, Y. Chon, H. Yang, R. Elashoff, W.A. Hsueh.

Obtaining of funding: W.A. Hsueh.

Administrative, technical, or logistic support: M.J. Quiñones, M. Hernandez-Pampaloni, I. Bulnes-Enriquez, X. Jimenez, G. Hernandez, R. De La Rosa, S.B. Nicholas, K. Van Herle, L.W. Castellani, W.A. Hsueh.

Collection and assembly of data: M.J. Quiñones, M. Hernandez-Pampaloni, I. Bulnes-Enriquez, X. Jimenez, G. Hernandez, R. De La Rosa, Y. Chon, H. Yang, L.W. Castellani, W.A. Hsueh.