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  • cAMP is a key secondary messenger which transduces

    2021-10-16

    cAMP is a key secondary messenger which transduces extracellular signals at glucagon receptors to intracellular effector molecules. cAMP-protein kinase A (PKA) pathway increases the gene expression of enzymes including phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) which are involved in gluconeogenesis (Altarejos and Montminy, 2011). Metformin, a biguanide class of drug is still a gold standard therapy for T2DM. Its exact mechanism of actions is not yet known. Miller et al. (2013) recently showed that metformin attenuates glucagon signalling by reducing cAMP formation and that this effect is not because of the direct inhibition of the glucagon receptor. Thus reducing glucagon mediated cAMP formation directly or indirectly could be a potential therapeutic approach in clinical management of T2DM. The glucagon receptor also couples to the calcium signalling pathway upon stimulation with glucagon. But the physiological importance of calcium in glucagon signaling has not yet been fully explored. The water extract of L. coromandelica SAR 405 is reported to be useful for the treatment of diabetes when administered to patients on an empty stomach (Rahmatullah et al., 2012). This suggests that the hypoglycemic effect of L. coromandelica bark seen in human subjects may be due to its inhibitory effect on liver glucose output. With this hypothesis the authors tested L. coromandelica bark for its effect on the glucagon response in recombinant system. It attenuated glucagon-mediated cAMP formation. In the presence of the extract, the glucagon response curve shifted towards the right without a change in the maximal response of glucagon, suggesting a competitive nature of the inhibitor. In the recombinant system, reduction in cAMP levels could be due to antagonism of glucagon receptor or direct inhibition of adenylate cyclase. L. coromandelica bark did not inhibit forskolin mediated cAMP formation. Forskolin is a direct activator of adenylate cyclase. These observations support that the inhibitory effect of L. coromandelica bark could be specific for the glucagon receptor. Receptor binding studies would help in further characterization. L. coromandelica bark did not show cytotoxicity at the concentrations which were used in the cAMP accumulation assay. Additionally, in the accumulation assays the cells were treated with the plant extract for a short duration (1h) as opposed to chronic incubation (48h) in the cytotoxicity assay. These results suggest that the inhibitory effect of L. coromandelica bark on the glucagon receptor is not due to cytotoxicity. Similar to glucagon, L. coromandelica bark also attenuated an oxyntomodulin cAMP response. A change in EC50 of oxyntomodulin in the presence of L. coromandelica bark was less than that of glucagon. It can be ascribed to ligand biasness or low potency of oxyntomodulin. Further studies need to be carried out to evaluate the effect of L. coromandelica bark on the expression of genes which are involved in gluconeogenesis and its hypoglycemic potential in animal models. The authors are in the process of isolating the active principles of the aqueous extract of L. coromandelica bark by activity-guided fractionation.
    Conclusion L. coromandelica bark has been reported to have therapeutic potential for the treatment of diabetes. However the molecular mechanism of its action is not known. This paper reports glucagon receptor antagonizing action of L. coromandelica bark. In Type 2 diabetic subjects the levels of glucagon are elevated and correlated well with hyperglycemia. Increased liver glucose output through glucagon mediated glycogenolysis and gluconeogenesis contributes to elevated blood glucose. Glucagon mediates its effect through the glucagon receptors. Hence antagonizing the glucagon receptor will help to curb hyperglycemia. Since L. coromandelica bark extract showed antagonism of glucagon mediated cAMP formation, a second messenger of glucagon receptor, it could be used for the treatment of hyperglycemia in Type 2 diabetes.