TY - JOUR
T1 - Genotype-based treatment of type 2 diabetes with an α2A-adrenergic receptor antagonist.
AU - Tang, Yunzhao
AU - Axelsson, Annika
AU - Spégel, Peter
AU - Andersson, Lotta
AU - Mulder, Hindrik
AU - Groop, Leif
AU - Renström, Erik
AU - Rosengren, Anders
PY - 2014
Y1 - 2014
N2 - The feasibility of exploiting genomic information for individualized treatment of polygenic diseases remains uncertain. A genetic variant in ADRA2A, which encodes the α2A-adrenergic receptor (α2AAR), was recently associated with type 2 diabetes. This variant causes receptor overexpression and impaired insulin secretion; thus, we hypothesized that blocking α2AAR pharmacologically could improve insulin secretion in patients with the risk genotype. A total of 50 type 2 diabetes patients were recruited on the basis of ADRA2A genotype for a randomized placebo-controlled intervention study with the α2AAR antagonist yohimbine. The patients received 0, 10, or 20 mg of yohimbine at three separate visits. The primary endpoint was insulin secretion at 30 min (Ins30) during an oral glucose tolerance test (OGTT). Patients with the risk variant had 25% lower Ins30 than those without risk genotype. After administration of 20 mg of yohimbine, Ins30 was enhanced by 29% in the risk group, making secretion similar to patients carrying the low-risk allele. The corrected insulin response and disposition index in individuals with the high-risk (but not low-risk) allele were improved by 59 ± 18% and 43 ± 14%, respectively. The beneficial effect of yohimbine was not a consequence of improved insulin sensitivity. In summary, the data show that the insulin secretion defect in patients carrying the ADRA2A risk genotype can be corrected by α2AAR antagonism. The findings show that knowledge of genetic risk variants can be used to guide therapeutic interventions that directly target the underlying pathophysiology and demonstrate the potential of individualized genotype-specific treatment of type 2 diabetes.
AB - The feasibility of exploiting genomic information for individualized treatment of polygenic diseases remains uncertain. A genetic variant in ADRA2A, which encodes the α2A-adrenergic receptor (α2AAR), was recently associated with type 2 diabetes. This variant causes receptor overexpression and impaired insulin secretion; thus, we hypothesized that blocking α2AAR pharmacologically could improve insulin secretion in patients with the risk genotype. A total of 50 type 2 diabetes patients were recruited on the basis of ADRA2A genotype for a randomized placebo-controlled intervention study with the α2AAR antagonist yohimbine. The patients received 0, 10, or 20 mg of yohimbine at three separate visits. The primary endpoint was insulin secretion at 30 min (Ins30) during an oral glucose tolerance test (OGTT). Patients with the risk variant had 25% lower Ins30 than those without risk genotype. After administration of 20 mg of yohimbine, Ins30 was enhanced by 29% in the risk group, making secretion similar to patients carrying the low-risk allele. The corrected insulin response and disposition index in individuals with the high-risk (but not low-risk) allele were improved by 59 ± 18% and 43 ± 14%, respectively. The beneficial effect of yohimbine was not a consequence of improved insulin sensitivity. In summary, the data show that the insulin secretion defect in patients carrying the ADRA2A risk genotype can be corrected by α2AAR antagonism. The findings show that knowledge of genetic risk variants can be used to guide therapeutic interventions that directly target the underlying pathophysiology and demonstrate the potential of individualized genotype-specific treatment of type 2 diabetes.
U2 - 10.1126/scitranslmed.3009934
DO - 10.1126/scitranslmed.3009934
M3 - Article
C2 - 25298321
SN - 1946-6242
VL - 6
SP - 257ra139
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 257
ER -