ORIGINAL INVESTIGATION Hum Genet (1998) 102:372-378 © Springer-Verlag 1998 Abstract The deletion (D) allele of the angiotensin-con- verting enzyme (ACE) gene insertion/deletion (I/D) poly- morphism has been shown to be associated with cardiovas- cular and renal diseases in diabetes mellitus, but the mech- anism underlying this association is not known. In addi- tion, recent studies of the effect of the ACE gene on blood pressure have yielded conflicting results. Therefore, we studied the association of the ACE gene I/D polymorphism with glucose intolerance and insulin resistance, and the contribution of this locus to genetic susceptibility to hy- pertension in non-insulin-dependent diabetic mellitus (NIDDM). We analysed the ACE genotype in 84 unrelated NIDDM patients with a known disease duration of less than 1 year and in 115 age- and sex-matched controls. The I/D polymorphism was determined by the polymerase chain reaction. There were no differences in ACE geno- type distribution and allele frequencies between patients with NIDDM and nondiabetic controls. The frequencies of the D and I alleles in both groups were identical, viz., 0.65 and 0.35, respectively. The NIDDM patients with the DD genotype had significantly higher blood glucose levels in the oral glucose tolerance test than those with the other genotypes; the incremental glucose area under the curve in the order of II, ID, and DD was 7.2 ± 2.4, 9.2 ± 4.0, and 10.7 ± 2.7 mmol/l ⋅ h (II vs ID vs DD, P=0.0066 by ANO- VA). No significant difference was found between the ACE genotype and serum insulin values. Similarly, there were no differences in body mass index, blood pressure, or serum lipids between the three genotypes. Among the non- diabetic controls, there was no statistically significant as- sociation of the I/D polymorphism with serum lipids, blood glucose levels, serum insulin concentrations, or blood pressure values. In conclusion, NIDDM patients with the DD genotype have higher blood glucose levels and are more glucose intolerant; this may help to explain the reported association between the D allele and vascular complications in NIDDM. X.-H. Huang · T. Koivula · T. Hiltunen · T. Lehtimäki ( ✉ ) Department of Clinical Chemistry, Research Laboratory for Atherosclerosis, Tampere University Hospital, P.O. Box 2000, FIN-33521, Tampere, Finland Tel.: +358-3-247-5091, Fax: +358-3-247-5554 e-mail: tjlehtimaki@tays.fi V. Rantalaiho · O. Wirta · A. Pasternack Department of Internal Medicine, Tampere University Hospital, Tampere, Finland T. Hiltunen · T. Nikkari · T. Lehtimäki Department of Medical Biochemistry, Tampere University Medical School, Tampere, Finland Xiao-Hong Huang · Vappu Rantalaiho · Ole Wirta Amos Pasternack · Timo Koivula · Timo Hiltunen Tapio Nikkari · Terho Lehtimäki Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM Received: 15 September 1997 / Accepted: 13 November 1997 Introduction Angiotensin-converting enzyme (ACE; kininase II, di- peptidyl carboxypeptidase I, EC 3.4. 15–1) plays an im- portant role in the maintenance of vascular tone in that it activates angiotensin I into the vasoconstrictory peptide angiotensin II and inactivates the vasodilatory peptide bradykinin (Erdös 1990). The ACE gene is known to ex- hibit a polymorphism caused by either the presence (inser- tion, I) or absence (deletion, D) of a 287-bp sequence within intron 16, resulting in three genotypes: II, ID, and DD. These genotypes are strongly related to serum ACE levels, with the highest values in DD and the lowest values in II homozygotes (Rigat et al. 1990; Tiret et al. 1992). Plasma ACE activity is elevated in some patients with diabetes (Lieberman and Sastre 1980; Van Dyk et al. 1994), particularly in subjects with microvascular compli- cations (Migdalis et al. 1990; Hallab et al. 1992). More- over, pharmacological inhibitors of ACE have been shown to improve glucose metabolism in some diabetic patients (Jauch et al. 1987; Kodama et al. 1990; Herings et al. 1995). These findings imply that the ACE gene is related to a predisposition to insulin resistance and/or glucose in- tolerance; this is further supported by the observation that the D polymorphism of the ACE gene is associated with raised fasting blood glucose levels (Zingone et al. 1994). In addition, allele D of the ACE gene is, according to