title: Family history of diabetes is a major determinant of endothelial function.
abstract: OBJECTIVE
  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.
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts 02215, USA. allison.goldfine@joslin.harvard.edu
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Beckman
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.forename: Heather
authors.initials: H
authors.lastname: Devlin
authors.forename: Shauna
authors.initials: S
authors.lastname: Hurley
authors.forename: Nerea
authors.initials: N
authors.lastname: Varo
authors.forename: Uwe
authors.initials: U
authors.lastname: Schonbeck
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Patti
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006331:Heart Diseases / Q000209:etiology; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D012307:Risk Factors; D014664:Vasodilation