Modeling the metabolic effects of terbutaline in beta2-adrenergic receptor diplotypes.
OBJECTIVE
Our objective was to determine whether beta(2)-adrenergic receptor polymorphisms influence terbutaline-stimulated changes in glucose, insulin, and potassium concentrations in healthy adults.


METHODS
Seven healthy adults homozygous for the Arg-19/Gly16/Glu27 haplotype (RGE) and seven homozygous for the Cys-19/Arg16/Gln27 haplotype (CRQ) volunteered to receive a 1-hour infusion of terbutaline (0.01 mg/kg). A 2-compartment pharmacokinetic model was fitted to the terbutaline concentrations. Concentrations of glucose and insulin were fitted simultaneously by use of a coupled feedback indirect response model. An indirect response model was also fitted to the plasma potassium concentration versus time data. The -2 log-likelihood ratio test was used to determine whether estimates of the covariates of diplotype and sex improved the model fittings.


RESULTS
Demographic variables, anthropometric characteristics, and pharmacokinetics did not differ by diplotype. The coupled feedback model fitted the glucose and insulin concentration data well with excellent precision. Terbutaline stimulated production of glucose (S(1)) to a greater extent in RGE compared with CRQ diplotypes, as follows: S(1) = 0.039 +/- 0.007 (mean +/- SD) versus 0.0276 +/- 0.01, respectively (P <.05, -2 log-likelihood criterion). The baseline values, disposition rate constants for glucose (k(out1)) and insulin (k(out2)), production rate of insulin (S(2)), feedback effect of insulin on glucose (S(3)), and pharmacodynamic parameters for potassium did not differ by diplotype or sex.


CONCLUSIONS
The beta(2) receptor diplotype influences receptor-stimulated glucose production in healthy, nonobese individuals, which is consistent with beta(2) receptor-mediated hepatic glycogenolysis. Future metabolic studies of this system should consider beta(2) receptor genetic variants.
Lima
John J
JJ
Nemours Children's Clinic, Center for Clinical Pediatric Pharmacology Jacksonville, FL 32207, USA. jlima@nemours.org
Matsushima
Nobuko
N
Kissoon
Niranjan
N
Wang
Jianwei
J
Sylvester
James E
JE
Jusko
William J
WJ
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006239:Haplotypes; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D013726:Terbutaline / Q000493:pharmacokinetics / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D018343:Receptors, Adrenergic, beta-2; D013726:Terbutaline