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A beta3-adrenergic agonist increases muscle GLUT1/GLUT4 ratio, and regulates liver glucose utilization in diabetic
F I Milagro1, J Gómez-Ambrosi, L Forga
1Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain.
Aim:
Previous studies have reported that beta3-adrenergic agonists reduce plasma glucose levels in situations of hyperglycaemia and diabetes in rodents. Nevertheless, the mechanisms still remain unclear. In this context Trecadrine, a novel compound with affinity for beta3-adrenergic receptors, has been tested in alloxan-diabetic rats for its potential use as an anti-diabetic drug, but also to elucidate the role of muscle/liver glucose utilization in the process.
Methods And Results:
Daily oral administration (1 mg/kg) to alloxan-diabetic Wistar rats (n = 10) for 4 days caused a significant reduction in plasma glucose levels (from 15.0 to 8.3 mmol/l) with no apparent effects on insulin secretion. Furthermore, Trecadrine administration tended to normalize glucose storage (estimated by measuring glucokinase activity) and output (by measuring glucose-6-phosphatase activity) in the liver of diabetic animals. On the other hand, Trecadrine administration for 4 days resulted in an increase in GLUT1 gene expression in gastrocnemius muscle as compared to insulin-dependent glucose transporter GLUT4. Furthermore, a significant stimulation of 2-deoxy-D-glucose uptake in extensor digitorum longus muscle and, in a lesser degree, in gastrocnemius, but not in soleus muscle and in white adipose tissue, occurs.
Conclusions:
Trecadrine reduces glucose output from the liver, thus thus contributing to the reduction of plasma glucose levels to achieve the values of control rats. Furthermore, Trecadrine administration stimulates glucose uptake in skeletal muscle, especially in those muscles with predominant glycolytic fast-twitched fibres, apparently by a direct non-insulin-dependent mechanism, involving a relative increase in the content of GLUT1 in the plasma membrane as compared with GLUT4. In conclusion, Trecadrine shows a potent hypoglycaemic effect in the alloxan-induced model of diabetes in rats by decreasing hepatic glucose output and improving muscle glucose uptake.