Hypoglycemia, S-ACE and ACE genotypes in a Danish nationwide population of children and adolescents with type 1 diabetes

Johannesen, Jesper; Svensson, Jannet; Bergholdt, Regine; Eising, Stefanie; Gramstrup, Hanne; Frandsen, Erik; Dick‐Nielsen, Jens; Hansen, Lars; Pociot, Flemming; Mortensen, Henrik B.

doi:10.1111/j.1399-5448.2010.00660.x

Cited by 10 publications

(11 citation statements)

References 25 publications

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“…Most association studies were performed on small sample sizes, without adjusting for insulin dose requirement or other non‐genetic predictors of HbA1c level, and should therefore be interpreted with caution. These candidate gene association studies have never been or have been poorly replicated, except for angiotensin I converting enzyme (ACE) gene . Five of the 13 selected studies reported significant or suggestive associations, which were however never replicated …”

Section: Resultsmentioning

confidence: 99%

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A systematic review of non‐genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis

Gloaguen

Bendelac

Nicolino

et al. 2018

Diabetes Metabolism Res

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Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic βcells. Although all T1D patients require daily administration of exogenous insulin, their insulin requirement to achieve good glycaemic control may vary significantly. Glycated haemoglobin (HbA1c) level represents a stable indicator of glycaemic control and is a reliable predictor of long-term complications of T1D. The purpose of this article is to systematically review the role of non-genetic predictors and genetic factors of HbA1c level in T1D patients after the first year of T1D, to exclude the honeymoon period. A total of 1974 articles published since January 2011 were identified and 78 were finally included in the analysis of non-genetic predictors. For genetic factors, a total of 277 articles were identified and 14 were included. The most significantly associated factors with HbA1c level are demographic (age, ethnicity, and socioeconomic status), personal (family characteristics, parental care, psychological traits...) and features related to T1D (duration of T1D, adherence to treatment …). Only a few studies have searched for genetic factors influencing HbA1c level, most of which focused on candidate genes using classical genetic statistical methods, with generally limited power and incomplete adjustment for confounding factors and multiple testing. Our review shows the complexity of explaining HbA1c level variations, which involves numerous correlated predictors. Overall, our review underlines the lack of studies investigating jointly genetic and non-genetic factors and their interactions to better understand factors influencing glycaemic control for T1D patients.

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Section: Resultsmentioning

confidence: 99%

“…Three other loci were tested: (1) HLA‐DRB1 and ‐DQB1 haplotypes, conferring the highest risk for T1D; (2) the ACE, for its possible role in diabetic nephropathy and hypoglycaemia and (3) apolipoprotein E (APOE) . None of these genes was significantly associated with HbA1c in T1D patients.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of non‐genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis

Gloaguen

Bendelac

Nicolino

et al. 2018

Diabetes Metabolism Res

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“…This has consistently been shown in seven studies in five different cohorts by four independent research groups. [1][2][3][4][5][6][7] One study reported an additive effect of presence of three RAS components -high serum ACE activity, high plasma angiotensinogen concentration and homo-or heterozygosity for the A-allele of the X chromosome-located angiotensin-II receptor subtype 2 1675G/A polymorphism -on the risk of severe hypoglycaemia in type 1 diabetes. 8 This finding suggests that increased angiotensin II receptor subtype 1 activation that is not counterbalanced by subtype 2 activation is detrimental during hypoglycaemia in subjects with type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Færch

Thorsteinsson

Tarnow

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Introduction: High spontaneous activity of the renin–angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function during hypoglycaemia. Methods: Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps. Results: Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan was observed. Conclusion: In conclusion candesartan has no effect on cerebral function during mild experimental hypoglycaemia in subjects with type 1 diabetes and high RAS activity. Candesartan may reduce glucose utilisation or increase endogenous glucose production during hypoglycaemia.

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“…We previously speculated whether genetic factors are implicated and reported a high rate of severe hypoglycaemia in type 1 diabetic subjects carrying the common deletion-allele of the angiotensin-converting enzyme (ACE) gene that confers high enzyme activity in blood and tissues (9). This finding has been reproduced in six studies in five different populations by four independent research groups (10, 11, 12, 13, 14, 15). Schouwenberg and coworkers showed in healthy adults that possessing the Arg Arg (vs the Gly Gly) polymorphism of the β2-adrenergic receptor may to some extent protect against the development of hypoglycaemia unawareness (16, 17), a major risk indicator of severe hypoglycaemia.…”

Section: Introductionmentioning

confidence: 55%

“…The only hitherto consistently reported biomarkers of severe hypoglycaemia in type 1 diabetes are undetectable C-peptide levels (9, 4), low HbA1c (40, 41, 42) and high serum ACE activity (10, 11, 12, 13, 14, 15). However, these markers only explain a minor proportion of the risk variation between subjects.…”

Section: Discussionmentioning

confidence: 99%

Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia

Kristensen

Pedersen‐Bjergaard

Due-Andersen

et al. 2016

Endocrine Connections

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IntroductionIn healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM).Material and methodsThis is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined.ResultsIncidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion.DiscussionPatients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.

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Hypoglycemia, S-ACE and ACE genotypes in a Danish nationwide population of children and adolescents with type 1 diabetes

Abstract: This large nationwide cohort has identified an increased risk for hypoglycemia associated with higher S-ACE level, however only in girls. A strong association was found between ACE genotype and S-ACE levels, but ACE genotype was not related to risk of hypoglycemia.

Cited by 10 publications

References 25 publications

A systematic review of non‐genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis

A systematic review of non‐genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia

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