Type 2 Diabetes Mellitus and the
Angiotensin-1 Converting Enzyme I/D Polymorphism

The Health Outcome

In type 2 diabetes, the body either does not properly respond to insulin (insulin resistance) or does not secrete enough insulin. Insulin, which is produced by the islet cells of pancreas, decreases blood glucose levels both by promoting storage of glucose as glycogen in the liver and by aiding cellular uptake and utilization of glucose. In type 2 diabetes, decreased insulin signaling causes higher blood glucose levels and decreased cellular glucose metabolism, which can inhibit cell function and lead to long term tissue damage (2,3).

Genetic susceptibility to type 2 diabetes is supported by evidence for the heritability of type 2 diabetes, including higher prevalence in monozygotic twins than in dizygotic twins and sibling recurrence rates that are higher than the prevalence in the general population (4). Also, diabetes is a major feature of certain monogenic and digenic disorders; subtler changes in the genes associated with these diseases may increase susceptibility to type 2 diabetes (4). Studies have suggested associations with such genes (e.g. PPAR g and KCNJ11), as well as hepatocyte nuclear factors 1 and 4, calpain-10, and the genes encoding insulin and the insulin receptor. The mitochondrial genome has also been implicated in type 2 diabetes and genome-wide linkage studies have identified susceptibility loci at 1q, 5q, 8p, 10q, 12q and 20q (4,5).

The Finding

The case-control study by Stephens et al. (6) looked for an association between type 2 diabetes and the Angiotensin-1 Converting Enzyme (ACE) Insertion (I)/Deletion (D) polymorphism (ACE I/D). This study compared the allele frequencies and genotype distributions of ACE I/D in Caucasians with type 2 diabetes (both men and women) and Caucasian men without diabetes. ACE cleaves angiotensin I to form angiotensin II and aldosterone-stimulating peptide. Angiotensin II increases vasoconstriction and sodium retention, and ACE also inactivates bradykinin, a potent vasodilator. Thus, ACE plays an important role in blood pressure regulation and electrolyte balance (7). Angiotensin II is also pro-inflammatory and chronic, low-grade, systemic inflammation may be a risk factor for type 2 diabetes (6).

Studies on the use of ACE inhibitors to lower coronary heart disease risk showed a reduction in progression of impaired glucose tolerance to type 2 diabetes by 25-30% (6). Thus, increased ACE activity may play a role in type 2 diabetes. In Caucasians, the I/D polymorphism accounts for about 50% of the phenotypic variance in serum ACE (8). The D allele leads to higher ACE expression and activity(9) and therefore might predispose individuals to type 2 diabetes.

Previous studies had suggested an association between the D allele and type 2 diabetes in non-Caucasians
(10-12), so Stephens et al. (6) focused on Caucasian populations in the UK . Cases were 605 men and women with type 2 diabetes who were recruited from a London diabetes clinic from 2001 to 2002. Controls were 3,012 healthy men recruited from nine general medical practices throughout the UK beginning in 1989. Those with symptoms or a previous diagnosis of diabetes were excluded. Cases were on average older than controls (mean age of 66.8 ± 10.9 compared to 56.0 ± 3.5). Using PCR amplification, the authors were able to determine the ACE I/D genotype for 95% of cases and 80% of controls.

The genotype studies suggested an association of the ACE I/D polymorphism with type 2 diabetes. The odds ratios (OR) were 1.46 [1.07 – 1.97] for ID and 1.47 [1.05– 2.05] for DD compared to II in case men (p = 0.03). The authors next grouped those with the ID and DD genotypes into one group of D allele carriers and found an odds ratio of 1.46 [1.10-2.32] for D carriers compared to II homozygotes in case men (p=0.01). The authors next looked at family history of diabetes among cases. The DD genotype was associated with a positive family history for diabetes when compared with either the II genotype (odds ratio of 1.52 [0.89-2.60], p = 0.03) or the II/ID group combined (odds ratio 1.63, p = 0.01).

Stephens et al. (6) also searched for an association between ACE I/D and plasma C-reactive protein (CRP), which is a measure of inflammation. An association between plasma CRP levels and the ACE DD genotype was only seen among cases not on ACE inhibitors (1.90 ± 1.66 mg/L vs. 1.56 ± 1.29 mg/L, p = 0.03 adjusted).

The authors conclude that their study “clearly shows an association” between ACE I/D and type 2 diabetes.

Public Health Implications

The authors' results support a weak association between the ACE I/D polymorphism and type 2 diabetes in Caucasian men, which is similar to previous findings in non-Caucasians (odds ratios from 1.1 to 1.5) (10-12). The decision to include both men and women as cases but only men as controls was potentially confounding; however, limiting the analysis to male cases obtained similar results. Also, cases were older than controls and the risk of type 2 diabetes increases with age. Therefore, the control population might include those who would develop type 2 diabetes by the time they reached the age of the case participants. This occurrence would act to weaken the observed association between ACE I/D and type 2 diabetes.

Further calculations can be performed to investigate the public health implications of Stephens et al. (6) findings, with the caveats that the samples in this study were not population-based and the causal relationship has not been established between D allele carrier status and type 2 diabetes. The attributable fraction of type 2 diabetes for ACE D carriers is about 35%, while that for the general population is approximately 29%. (Note that in this calculation, OR was substituted for RR, which is less accurate since neither D carriers nor type 2 diabetes are rare, so that OR differs significantly from RR.) In terms of population screening, the high prevalence of the DD genotype, seen in around 25% of controls, argues against using the ACE genotype as a screening test for type 2 diabetes given the weak association. Thus, neither population screening nor testing family members of those with type 2 diabetes is warranted, as most individuals who carry the D allele will not develop type 2 diabetes.

The authors also report a correlation between the DD genotype and a family history of diabetes (both type I and type II) among the case individuals, with an odds ratio of 1.52. This association is consistent with an increased susceptibility to type 2 diabetes in D carriers, as DD homozygotes will be more likely to have a greater number of D carriers in their family than II homozygotes. Furthermore, as family history may also include shared environmental factors, this connection between family history and DD homozygotes may also reflect an interaction between the D allele and a shared environmental factor.

Although ACE inhibitors may prove to be beneficial in reducing diabetes progression for some patients who carry the D allele, further research is needed. The association between ACE I/D and certain complications of diabetes may be stronger than that between ACE I/D and type 2 diabetes in general. For example, Marre et al. (13) found that the ACE D allele predisposed individuals to diabetic nephropathy and progression to kidney failure. The ACE I/D polymorphism may also be more informative when examined in combination with lifestyle factors such as BMI, diet, and physical activity. In fact, the ACE DD genotype has been associated with lower physical activity and endurance (14,15). Also, other genes may show stronger associations with type 2 diabetes, and examining genes in combination may prove to be the most instructive. For now, o ther factors such as health behaviors (BMI, diet, physical activity) and family history offer much more utility than genotypes for predicting onset of type 2 diabetes.

References

1. http://www.cdc.gov/diabetes/pubs/estimates.htm#prev (last accessed 04/2007)
2. http://www.emedicine.com/emerg/topic134.htm (last accessed 04/2007)
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7. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=106180 (last accessed 04/2007)
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11. Feng Y, Niu T, Xu X, Chen C, Li Q, Qian R, Wang G, Xu X. Insertion/deletion polymorphism of the ACE gene is associated with type 2 diabetes. Diabetes. 2002; 51:1986-8.
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14. Winnicki M. Physical activity and angiotensin-converting enzyme gene polymorphism in mild hypertensives. Am J Med Genet A. 2004;125:38-44.
15. Jones A, Montgomery HE, Woods DR. Human performance: a role for the ACE genotype? Exerc Sport Sci Rev. 2002;30:184-90.

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