Association between the ACE gene I/D polymorphism and insulin sensitivity in healthy subjects

Background

Recent studies suggested that the blockade of the renin-angiotensin system (RAS) may be associated with

metabolic benefits. The ACE gene has an insertion/deletion (I/D) polymorphism, with the D allele being

associated with higher ACE levels. Data about the potential influence of the ACE I/D genotype on insulin

resistance have been contrasting.

Objectives

To investigate the relationship between the ACE gene I/D polymorphism and both insulin sensitivity and glucose

intolerance in a large cohort of healthy subjects.

Design

Relationship Between Insulin Sensitivity and Cardiovascular Disease Risk: (RISC) Study

Over 1 500 subjects were recruited at 19 centres in 13 European countries. In this report, cross-sectional data

are presented from the 1,286 men and women whose clamp study passed the quality control check and for

whom genomic DNA was available.

At baseline: lifestyle and medical history questionnaire. Anthropometry; Biological samples;

oral glucose tolerance test. Euglycaemic hyperinsulinaemic (240 pmol.min-1.m-2) clamp.

Fabrice Bonnet1,2, Sheila Patel3, Ibrahim M Ibrahim4, Martine Laville2, Beverley Balkau5, Mark Walker4 on behalf of the EGIR-RISC Study group

1Dept of Endocrinology, University hospital of Rennes, France; 2Centre for Research In Human Nutrition, CRNH Rhône-Alpes, INSERM U 870-INRA 1235, Lyon, France;3Cardiovascular Endocrine Group, University of Melbourne, Australia, 4School of Clinical Medical Sciences, Diabetes, University of Newcastle, UK; 5INSERM U780, Villejuif, France

RISC is supported by the European Union (QLG1-CT-2001-01252) and by AstraZeneca

EGIR-RISC Study GroupProject Management Board:B Balkau (Villejuif, France); SW Coppack (London, England); JM Dekker(Amsterdam, The Netherlands);E Ferrannini (Pisa, Italy) A Mari (Padova, Italy); A Natali (Pisa, Italy); M Walker (Newcastle, England).RISC recruitment centres:Amsterdam, The Netherlands: R.J. Heine, J Dekker, G Nijpels, W Boorsma.Athens Greece: A Mitrakou, S Tournis, K KyriakopoulouBelgrade, Serbia and Montenegro: N Lalic, K Lalic, A Jotic, L Lukic, M CivcicDublin, Ireland: J Nolan, TP Yeow, M Murphy, C DeLong, G Neary, MP ColganFrankfurt, Germany: T Konrad, H Böhles, S Fuellert, F Baer, H ZuchholdGeneva, Switzerland: A Golay, V. Barthassat, V. Makoundou, TNO Lehmann, E. Harsch Bobbioni, T MerminodGlasgow, Scotland: J Petrie, C Perry, F Neary, C MacDougall, K Shields, L MalcolmKuopio, Finland: M Laakso, U Salmenniemi, A Aura, R Raisanen, U Ruotsalainen, T Sistonen, M LaitinenLondon, England: SW Coppack, N McIntosh, P KhadobakshLyon, France: M Laville, F. Bonnet, A Brac de la Perriere, C Louche-Pelissier, C Maitrepierre, J Peyrat, A SerusclatMadrid, Spain: R. Gabriel, EM Sánchez, R. Carraro, A Friera, B. NovellaMalmö, Sweden (1): P Nilsson, M Persson, G Östling, (2): O Melander, P BurriMilan, Italy: PM Piatti, LD Monti, E Setola, F Minicucci, A ColleluoriNewcastle-upon-Tyne, England: M Walker, IM Ibrahim, M Jayapaul, D Carman, Y McGrady, D RichardsonOdense, Denmark: H Beck-Nielsen, P Staehr, K Hojlund, V Jensen, C OlsenPerugia, Italy: GB Bolli, F Porcellati, C Fanelli, M Romolini, F Calcinaro, A SaturniPisa, Italy: E Ferrannini, A Natali, E Muscelli, S Pinnola, M Kozakova, L LanducciRome, Italy: G Mingrone, P Di Rocco, C Guidone, A FavuzziVienna, Austria: W Waldhäusl, M Roden, C Anderwald, A HoferCore laboratories and reading centres:Lipids – Dublin, Ireland: P Gaffney, J Nolan, G Boran. Hormones – Odense, Denmark: C Olsen, L Hansen,H Beck-Nielsen. Urine Albumin:creatinine – Amsterdam, The Netherlands: A Kok, J Dekker.Genetics – Newcastle-upon-Tyne, England: S Patel, M Walker. Stable isotope analysis – Pisa, Italy: A Gastaldelli,D Ciociaro. Ultrasound reading centre – Pisa, Italy: M Kozakova, E Ferrannini. Data Management – Villejuif, France:B Balkau, L Mhamdi. Mathematical modelling and website management – Padova, Italy: A Mari, G Pacini,C Cavaggion. Coordinating office – Pisa, Italy: SA Hills, L Mota, L Landucci.Further information on the RISC project and participating centres can be found on www.egir.org.

Clinical characteristics of the study participants according to

ACE genotype

ACE genotype

II ID DD No. of participants 243 662 381

Age (years) 43 8 44 8 44 8

Sex (% of men) 47 44 44

BMI (kg/m2) 25.6 4.1 25.4 4.0 25.7 4.1

Waist circumference (cm) 87.4 11.8 86.1 12.5 87.1 13.6

Hip circumference (cm) 101.0 9.3 100.1 9.1 100.3 9.3

Family history of diabetes (%) 24.1 28.8 27.3

Fat mass (kg) 21.1 9.0 20.8 8.7 21.2 9.2

Fat free mass (kg) 54.1 10.9 53.6 11.6 54.2 11.6

ACE genotype

II ID DD p for trend Fasting glycaemia (mmol/l) 5.1 1.1 5.1 0.6 5.1 0.6 0.70

Glucose at 120 min (mmol/l) 5.6 1.5 5.7 1.5 5.9 1.7 0.004

Fasting insulin* (pmol/l) 31 (19-42) 31 (19-43) 31 (20-42) 0.37

Fasting proinsulin* (pmol/l) 6 (4-8) 6 (4-8) 6 (4-8) 0.58

Insulinogenic index* (pmol/mmol) 78 (43-112) 77 (43-111) 71 (40-102) 0.16

Impaired fasting glucose (%) 17.0 17.0 19.9 0.44

Impaired glucose tolerance (%) 7.5 9.2 13.1 0.017

Adiponectin* (mg/l) 7.3 (5.0-9.5) 7.9 (5.6-10.2) 7.6 (5.1-10.1) 0.62

HOMA-IR* 0.95 (0.5-1.3) 0.97 (0.6-1.4) 0.95 (0.6-1.3) 0.41

M/I value* 145 (99-190) 128 (85-171) 124 (85-163) 0.02

M/I is expressed as (µmol/min/kgFFM)/(nmol/l). P values are adjusted for sex, age, centre and waist circumference. *Expressed as the median (interquartile range).

Indices of insulin sensitivity and glucose tolerance according to ACE genotype

Genotype OR (95% CI) p value

DD vs (ID and II) 1.52 (1.01-2.28) 0.04

DD vs II 2.02 (1.09-3.74) 0.02

DD vs ID 1.38 (0.90-2.13) 0.14

ID vs II 1.47 (0.81-2.65) 0.20

Odds ratio of having impaired glucose tolerance according to the ACE genotype

This association between the ACE I/D genotype and insulin sensitivity persisted in multiple regression after correction for age, sex, centre, physical activity and waist circumference (p=0.02).

Conclusion

In our large population of healthy subjects, the deletion polymorphism of the

ACE gene, a marker of higher ACE activity, was significantly associated with

impaired glucose tolerance and reduced glucose utilization in the clamp.

These findings therefore suggest a role for local RAS in glucose metabolism.

Intervention studies are needed to determine whether metabolic effects of the

blockers of the RAS may differ according to the ACE I/D genotype.