Yliopistologo

Lääkäri Xiaohong Huangin väitöskirja

Angiotensin-converting enzyme gene and its association with macro- and microangiopathies in non-insulin-dependent diabetes mellitus (Angiotensiini konvertaasi entsyymin geeni ja sen yhteys makro- ja mikroangiopatiamuutoksiin tyypin 2 diabetespotilailla)

tarkastetaan torstaina 17.12.1998 klo 12 Tampereen yliopiston lääketieteen laitoksen B-rakennuksen pienessä luentosalissa, osoitteessa Medisiinarinkatu 3.

Vastaväittäjänä toimii professori Kimmo Kontula Helsingin yliopistosta ja kustoksena on professori Amos Pasternack.

Xiaohong Huang on syntynyt Kiinassa 15.5.1966. Hän on suorittanut M.D. -tutkinnon 1989 (West China University of Medical Sciences) ja Ph.D. -opintoja 1993-1996 (Peking Union Medical College). Huang on toiminut apulaislääkärinä 1989-1993 (Peking Union Medical College Hospital).

Huangin väitöskirja ilmestyy sarjassa Acta Universitatis Tamperensis, Vammalan Kirjapaino Oy, Vammala 1998.

ISBN 951-44-4465-5. ISSN 1455-1616

Väitöskirjan tilausosoite: Tampereen yliopiston julkaisujen myynti, PL 617, 33101 Tampere, puh. (03) 215 6055, e-mail: taju@uta.fi.

Lisätietoja: Xiaohong Huang, puh. (03) 215 6654 (työ), 050 351 6498 (koti).

TIIVISTELMÄ

Non-insulin-dependent diabetes mellitus (NIDDM) is a common chronic disorder characterized by hyperglycemia, a relative or absolute lack of insulin, and the development of diabetes-induced vascular changes. Evidence suggests that some genetic factors not only seem to play a role in the development of NIDDM but also might contribute to its vascular complications. Angiotensin Iconverting enzyme (ACE) catalyses the step which generates angiotensin II, and also inactivates bradykinin, peptides which play a key role in modulating vascular tone. Plasma ACE levels are under genetic control and are correlated with a deletion (D)/insertion (I) polymorphism at the ACE gene locus with highest levels found in DD homozygotes. Recent studies have shown an association of myocardial infarction and coronary heart disease with the ACE polymorphism in nondiabetic and diabetic subjects. The D allele has also been reported to be associated with diabetic nephropathy, but results remain inconclusive.

The present study was undertaken to assess the relationships of the I/D polymorphism with the development of hypertension, coronary heart disease and nephropathy in NIDDM patients, and to examine whether the association of the D allele with these vascular diseases is mediated through an effect on insulin resistance and/or glucose intolerance. One hundred and fifty NIDDM patients with disease duration less than one year, aged 40-65 years were recruited from the city of Tampere, Finland, between 1985 and 1988. Among them 84 were eligible for re-evaluation in the spring of 1996.

NIDDM patients with the DD genotype were more glucose intolerant and had higher blood glucose levels than patients with the other genotypes. The I/D polymorphism was not associated with insulin resistance or hypertension in the study. The DD genotype was the most common genotype in patients with CHD and the frequency of the D allele was significantly higher than that in subjects without CHD in both followup and cross-sectional settings. Thus our results support the hypothesis that the ACE gene is associated with the development of CHD in NIDDM patients. The ACE I/D polymorphism was not a genetic marker for diabetic nephropathy, but the decline of glomerular filtration rate tended to be steeper in patients with the DD genotype than in patients with the other genotypes. It is possible that the ACE genotype is not involved in the development of diabetic nephropathy but may influence the progression of renal function in diabetes.

The clinical consequences of the study could be significant. The incidence of both fatal and nonfatal CHD events is two to three times higher in diabetic than in nondiabetic subjects. The ACE gene polymorphism may not account for all of the genetic susceptibility to CHD, but it may provide a useful marker in identifying high risk subjects. The subgroup of diabetic patients with the DD genotype who are more glucose intolerant and seem to be much more susceptible to CHD therefore warrants close follow-up.


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