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Impact of Polymorphism in the β2-Receptor Gene on Metabolic Responses to Repeated Hypoglycemia in Healthy Humans

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CONTEXT: The Arg16 variant in the β2-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus.

OBJECTIVE: We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia.

METHODS: Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n = 13) or Gly16 (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3.

RESULTS: During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± standard error of the mean of area under the curve) of glycerol (-13.1 ± 3.8 μmol L-1 hours; P = .0052), FFA (-30.2 ± 11.1 μmol L-1 hours; P = .021), and β-hydroxybutyrate (-0.008 ± 0.003 mmol L-1 hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 ± 20.6 μmol L-1 hour; P = .024).

CONCLUSION: There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and β-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume107
Issue number8
Pages (from-to)e3194-e3205
ISSN0021-972X
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

    Research areas

  • 3-Hydroxybutyric Acid, Epinephrine, Fatty Acids, Nonesterified, Glucose Clamp Technique, Glycerol, Humans, Hypoglycemia, Lactates, Male

ID: 78009174