Abstract 19393: Decreased Insulin Secretion and Insulin Reistance in Beta 2 Adrenergic Receptor Knock-out Mice
Introduction: The reciprocal regulation of Sympathetic Nervous System and insulin relays on not fully understood mechanisms. β2 adrenergic receptors (β2ARs), in particular, are known to be involved in insulin production and in peripheral glucose uptake, but their role in development of diabetes is not yet clear.
Methods and Results: We characterized the metabolic phenotype of mice (age: 6 months) with deletion of β2AR gene (KO; n=22), performing tolerance tests to glucose (GTT, 2 mg/Kg), insulin (ITT, 0.75 IU/Kg) and sodium pyruvate (PTT, 2g/Kg) and hyperinsulinemic euglicemic clamps. As control we used wildtype littermates (WT; n=19). GTT showed higher glucose levels in KO mice than WT. Moreover, KO mice had a blunted production of insulin (RIA; time 0:0.38±0.001 vs 0.54±0.01, 30’:0.39±0.03 vs 0.85±0.02, 60’:0.36±0.023 vs 0.66±0.021, 120’:0.40±0.025 vs 0.56±0.023 ng/ml; p<0.05, KO vs WT, repeated measures ANOVA). PTT confirmed the higher glucose levels in KO mice. Clamp studies revealed a lower Glucose Infusion Rate (KO vs WT:14.6±8 vs 30±9 mg/Kg/min), with increased Endogenous Glucose Production (79.8±4 vs 36.1±3 mg/Kg/min) and Rate of disappearance (96.6±5 vs 63.2±3.4 mg/Kg/min; p<0.05), suggesting that insulin resistance developed at the hepatic level. Consistently, ITT showed a more rapid decrease of glucose levels in KO mice respect to WT. Immunohistochemical analysis of pancreatic tissue displayed a normal insular architecture. Ex vivo insulin secretion from pancreatic islets of KO mice was very low both in basal conditions (Glucose 2mM; KO:0.27±0.013 vs WT:0.89±0.022 ng/ml; p<0.05) and after stimulation (Glucose 20mM; KO:0.272±0.02 vs WT:1.03±0.021 ng/ml; p<0.05) while glucagon production was not different from WT. Adenoviral infection of β2AR in KO islets restored the ability to release insulin (Glucose 20mM:0.573±0.01). Finally, in rat insulinoma β cells we depleted β2AR density by means of siRNA (-91.4±5.2% vs siRNA-negative-control; p<0.01;Radioligand assay). Also in this in vitro model, glucose-induced (20mM) insulin secretion was impaired (KO:+38.02±6.3% vs WT:+107.1±21.4% of basal; p<0.05).
Conclusions: β2AR plays a critical role in glucose metabolism by affecting both insulin secretion and peripheral action.
- © 2010 by American Heart Association, Inc.