Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

Abstract

Aims/hypothesis. We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACE gene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. Methods. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.Results. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACE gene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. To avoid progression of these frequent episodes into severe hypoglycaemia patients rely on maintenance of performance capacity [3] until hypoglycaemic symptoms are recognised and self-treated or until the next pre-scheduled meal is ingested.Risk of severe hypoglycaemia is a major limiting factor for the achievement of good metabolic control [4] rendering prediction of individual risk of severe hypoglycaemia increasingly important. Loss of hypoglycaemic warning symptoms and blunted hormonal counterregulatory response are the most important known predictors of severe hypoglycaemia [4,5]. However, even patients at high risk according to these paFollowing the Diabetes Control and Complications Trial [1] a growing demand for strict glycaemic control has emerged to avoid late diabetic complications in Type 1 diabetes. As a consequence the majority of patients with Type 1 diabetes experience mild hypoglycaemia on a regular basis and recent studies applying continuous glucose monitoring indicate that pa-

The relationship between ACE genotype and risk of severe hypoglycaemia in a large population-based cohort of children and adolescents with type 1 diabetes

“…Our findings are contrary to those reported recently in adult (sample size of 171 and 207 outpatients) [8,21] and paediatric populations (sample size of 86 patients) [20]. In light of this several questions arise.…”

“…Herings et al [9] and Morris et al [10] have shown that the use of ACE inhibitors increased the risk of having a severe hypoglycaemic event in adults, but these studies were retrospective in design and the findings remain controversial [11][12][13][14]. The fact that a small proportion of patients experiences severe hypoglycaemia whereas other patients with similar glycaemic control remain spared indicates that genetic factors may contribute to an increased risk, and studies conducted in Denmark and Sweden have supported this notion [8,20,21]. This study was of a large population-based cohort of type 1 diabetic children followed prospectively for 12 years and in whom the phenotype of hypoglycaemic frequency has been carefully documented.…”

“…It has been shown that the incidence of severe hypoglycaemia within a cohort is highly skewed [6] with variable inter-individual susceptibility. The Diabetes Control and Complications Trial demonstrated familial clustering of diabetes complications [7] suggesting that genetic factors may account for some of this variability [8]. The cause of severe hypoglycaemia remains multifactorial.…”

“…The D allele has also been associated with increased risk of hypertension, diabetic renal complications and cardiovascular complications. Some studies have shown an association between ACE and physical performance [17][18][19], and it has been proposed that there may be a similarity in metabolic features between hypoglycaemia and exercise [8,20,21], such that patients with type 1 diabetes and the DD genotype are at increased risk of severe hypoglycaemia compared with those with the II genotype [21].…”

Predicting risk of severe hypoglycaemia in type 2 diabetes

“…Intriguingly, there have been reports of severe hypoglycaemia risk being associated with a polymorphism (D/D deletion) in the gene encoding angiotensin-converting enzyme (ACE) in both type 2 and type 1 diabetes [12,13]. The postulated mechanism here is different from those described above, with molecular differences in the renin-angiotensin system determining how sensitive cognitive functioning is to a fall in glucose.…”