Variation in the α2A adrenoceptor gene and the effect of dexmedetomidine on plasma insulin and glucose

Abstract

Sympathetic activation inhibits insulin secretion through activation of pancreatic α(2)A adrenoreceptors (α(2A)ARs). A common genetic α(2A)AR variant (rs553668) is associated with impaired insulin secretion. α(2A)R agonists would be expected to decrease insulin secretion, but their effects on glucose homeostasis in humans are poorly characterized. We examined the hypotheses that the selective α(2A)R agonist, dexmedetomidine, decreases plasma insulin levels and increases plasma glucose levels in humans and that these effects are modified by genetic α(2A)AR variants. Healthy, fasting, White (n=31) and Black (n=33) participants aged between 18 and 45 years received three sequential infusions of placebo (normal saline) at 30-min intervals, followed by three infusions of dexmedetomidine (0.1, 0.15, and 0.15 mcg/kg). Plasma insulin and glucose concentrations were measured at baseline and after the administration of placebo and dexmedetomidine. We genotyped ADRA2A rs553668 and rs2484516, which characterize haplotypes 4 and 4b, respectively. Dexmedetomidine decreased fasting insulin concentrations by 37%, from a median value after placebo administration of 7.9 μU/ml (interquartile range: 6.0-12.6) to 4.9 μU/ml (interquartile range: 3.5-7.9; P<0.001). Plasma glucose concentrations increased from 76±6 to 79±7 mg/dl (P<0.001). The rs2484516 variant allele was associated with higher baseline insulin concentrations before (P=0.001) and after adjustment for potential confounders (P=0.014) and a greater decrease in insulin concentration after dexmedetomidine administration (P=0.016), which was no longer significant after adjustment for baseline concentrations and other confounders (P=0.58). Low-dose dexmedetomidine decreased plasma insulin concentration and mildly increased plasma glucose concentration in healthy fasting individuals. The ADRA2A genetic variation may affect baseline insulin concentrations and thus the insulin decrease after dexmedetomidine administration.