Genetic variation and activity of the renin-angiotensin system and severe hypoglycemia in type 1 diabetes.
BACKGROUND
The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated.


METHODS
Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity.


RESULTS
Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia.


CONCLUSIONS
High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.
Pedersen-Bjergaard
Ulrik
U
Endocrinology Section, Division of Internal Medicine I, Hillerød Hospital, Hillerød, Denmark. ulpebj@noh.regionh.dk
Dhamrait
Sukhbir S
SS
Sethi
Amar A
AA
Frandsen
Erik
E
Nordestgaard
Børge G
BG
Montgomery
Hugh E
HE
Pramming
Stig
S
Hougaard
Philip
P
Thorsteinsson
Birger
B
D000328:Adult; D000808:Angiotensinogen / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007003:Hypoglycemia / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011446:Prospective Studies; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics* / Q000502:physiology*; D012307:Risk Factors
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A