The effect of antecedent hypoglycaemia on β₂-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the β₂-adrenergic receptor

B J J W Schouwenberg, P Smits, C J Tack, B E de Galan, B J J W Schouwenberg, P Smits, C J Tack, B E de Galan

Abstract

Aims/hypothesis: Homozygosity for glycine at codon 16 (GlyGly) of the β(2)-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on β(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the β(2)-adrenergic receptor.

Methods: We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the β(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)).

Results: The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased β(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in β(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047).

Conclusion/interpretation: Antecedent hypoglycaemia did not affect β(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in β(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants.

Trial registration: ClinicalTrials.gov NCT00160056.

Figures

Fig. 1
Fig. 1
Plasma glucose values during the clamps on day 1 (a) and hypoglycaemic symptom scores during morning and afternoon clamps (b) in the whole group (n = 16). White circles, hypoglycaemia; black circles, euglycaemia
Fig. 2
Fig. 2
Response of FBF to salbutamol following antecedent hypoglycaemia and antecedent euglycaemia in (a) ArgArg participants (n = 8, p = 0.019) and (b) GlyGly participants (n = 8, p = NS). White squares, hypoglycaemia; black squares, euglycaemia
Fig. 3
Fig. 3
IC25 following antecedent hypoglycaemia and antecedent euglycaemia in ArgArg participants (n = 6, p = 0.109) and GlyGly participants (n = 6, p = 0,193). The difference in IC25 between ArgArg and GlyGly participants (IC25 following antecedent euglycaemia minus antecedent hypoglycaemia for each subgroup): p = 0.047

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