CLINICAL RESEARCH: ENDOTHELIAL FUNCTION
Family History of Diabetes Is a Major Determinant of Endothelial Function
Allison B. Goldfine, MD*, ,*,
Joshua A. Beckman, MD,
Rebecca A. Betensky, PhD ,
Heather Devlin*,
Shauna Hurley,
Nerea Varo, PhD,
Uwe Schonbeck, PhD,
Mary Elizabeth Patti, MD* and
Mark A. Creager, MD
* Joslin Diabetes Center, Boston, Massachusetts
Brigham and Women's Hospital, Boston, Massachusetts
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
Manuscript received October 18, 2005;
revised manuscript received February 1, 2006,
accepted February 14, 2006.
* Reprint requests and correspondence: Dr. Allison B. Goldfine, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215 (Email: allison.goldfine{at}joslin.harvard.edu).
OBJECTIVES: We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors.
BACKGROUND: Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis.
METHODS: Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FH+) or with no first-degree relative with diabetes (FH–).
RESULTS: Although fasting glucose was higher in FH+ than FH– (5.3 ± 0.1 mmol/l vs. 4.9 ± 0.1 mmol/l, p < 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FH+ (7.1 ± 0.9% vs. 11.7 ± 1.6%, p < 0.02), with no difference in nitroglycerin-induced endothelium-independent vasodilatation. In the combined cohort, only FH+ (r2 = 0.12, p < 0.02) and HbA1c (r2 = 0.14, p < 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FH– (p < 0.03, analysis of variance), but not in FH+, as even the most insulin-sensitive FH+ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p = 0.04).
CONCLUSIONS: Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes.
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Abbreviations and Acronyms
| | EDV = endothelium-dependent vasodilation | | EIV = endothelium-independent vasodilation | | FH = family history | | FH+ = subjects with both parents having type 2 diabetes | | FH– = subjects with no first-degree relative with diabetes or coronary artery disease | | HbA1c = glycosylated hemoglobin | | HOMA-IR = homeostasis model assessment of insulin resistance | | T2D = type 2 diabetes |
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