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Association of the ACE gene I/D polymorphism with insulin sensitivity depends on the presence of additional macroangiopathic risk factors

      In the July issue of Atherosclerosis, Viitanen et al. reported an association of the I/D-polymorphism in intron 16 of the angiotensin converting enzyme (ACE) gene with features of the insulin resistance syndrome in subjects with a history of myocardial infarction [
      • Viitanen L.
      • Pihlajamaki J.
      • Halonen P.
      • Lehtonen M.
      • Kareinen A.
      • Lehto S.
      • Laakso M.
      Association of angiotensin converting enzyme and plasminogen activator inhibitor-1 promoter gene polymorphisms with features of the insulin resistance syndrome in patients with premature coronary heart disease.
      ]. During an oral glucose tolerance test (oGTT), the glucose concentration at 1 h and the free fatty acid concentration at 2 h were significantly higher in DD compared to ID and II. These findings were interpreted to be in accordance with those of Zingone et al., who found that the D allele of the ACE polymorphism was associated with impaired glucose tolerance [
      • Zingone A.
      • Dominijanni A.
      • Mele E.
      • et al.
      Deletion polymorphism in the gene for angiotensin converting enzyme is associated with elevated fasting blood glucose levels.
      ]. They are in contrast, however, with two other studies reporting that carriers of the I allele are more insulin resistant [
      • Katsuya T.
      • Horiuchi M.
      • Chen Y.D.
      • Koike G.
      • Pratt R.E.
      • Dzau V.J.
      • Reaven G.M.
      Relations between deletion polymorphism of the angiotensin-converting enzyme gene and insulin resistance, glucose intolerance, hyperinsulinemia, and dyslipidemia.
      ,
      • Panahloo A.
      • Andres C.
      • Mohamed-Ali V.
      • Gould M.M.
      • Talmud P.
      • Humphries S.E.
      • Yudkin J.S.
      The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance?.
      ]. Moreover, an association of the ACE gene polymorphism with insulin resistance was recently reported for hypertensive but not for normotensive subjects [
      • Perticone F.
      • Ceravolo R.
      • Iacopino S.
      • et al.
      Relationship between angiotensin-converting enzyme gene polymorphism and insulin resistance in never-treated hypertensive patients.
      ]. In the above studies, only estimates (e.g. HOMA, oGTT) but not measurements (euglycemic clamp) of insulin sensitivity were used. We had analyzed insulin sensitivity determined by the euglycemic hyperinsulinemic clamp in (n=216) in our Tübingen family (TÜF) study database [
      • Stumvoll M.
      • Wahl H.G.
      • Loblein K.
      • Becker R.
      • Machicao F.
      • Jacob S.
      • Haring H.
      Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity.
      ] and did not find an association with the I/D polymorphism in the ACE gene. Our study population consisted of unrelated healthy, normal glucose tolerant and normotensive subjects who were characterized by the presence or absence of a family history of type 2 diabetes. To substantially increase the power, we additionally assessed insulin sensitivity using a validated index [
      • Matsuda M.
      • DeFronzo R.A.
      Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.
      ] from the oGTT (n=386, NGT).
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