Question

How does adenylate cyclase inhibitor affect glucose export? Why is the level of glucose export reduced but not eliminated?

Answer 1

The classical potentiating effect of exogenously applied glucagon on insulin release results from binding to Gαs‐coupled receptors raising cAMP in the β‐cells. Although the closest source of glucagon is islet α‐cells the importance of this glucagon for normal insulin secretion is not immediately obvious. Glucagon secretion is preferentially stimulated in response to hypoglycaemia, which does not provide the insulin secretion‐triggering Ca2+ elevation in the β‐cells that is required for a potentiating effect of glucagon. However, glucagon release is significant even when maximally inhibited by 5 to 7 mM glucose and tends to increase at higher glucose concentrations, indicating that islet glucagon may help to reduce blood glucose by stimulating insulin release under conditions when insulin and glucagon should have opposite actions on glucose mobilization from the liver. In diabetes, the glucose‐mobilizing effect apparently dominates because glucagon hypersecretion plays a key role in the clinical manifestations of the disease. The importance of islet glucagon may also depend on species since hormone from the peripheral α‐cells in rodent islets does not necessarily reach the bulk of centrally located β‐cells whereas the more even distribution of the different cell types in human islets should favour paracrine interactions. However, one should be aware that islet α‐cells are not the only source of glucagon, which is also secreted from the stomach and intestine.

The observation that the plasma insulin response to an oral glucose load is much more pronounced than after intravenous glucose administration was originally attributed to additional stimulation by gastrointestinal or liver factors forming the basis for the incretin concept. The most important incretin hormones are glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), which are secreted from gastrointestinal L‐ and K‐cells, respectively, in response to nutrients. GLP‐1 in particular has several beneficial properties for treatment of type 2 diabetes as it not only promotes insulin release but also inhibits that of glucagon, whereas GIP stimulates secretion of both hormones and may contribute to glucagon‐dependent hyperglycaemia in diabetes. Like glucagon, GLP‐1 and GIP bind to Gαs‐coupled receptors to increase cAMP in β‐cells. However, cAMP elevation is not the only mechanism involved. The GLP‐1 receptor also appears to couple via Gαq to stimulate phospholipase C, which generates Ca2+‐mobilizing inositol‐1,4,5 trisphosphate (IP3) and protein kinase C (PKC)‐activating diacylglycerol. PKC in turn depolarizes the β‐cells by activating Na+ influx through TRPM4 and TRPM5 channels to promote voltage‐dependent Ca2+ influx and insulin release.

Some inhibitors of insulin secretion induce Gαi‐coupled inhibition of adenylate cyclase with reduction of cAMP in β‐cells. Adrenalin and noradrenalin act in this manner on α2‐adrenoceptors, somatostatin on type 1, 2 and 5 receptors, melatonin on MTNR1B receptors46 and galanin on its receptor(s). However, ghrelin, which was previously thought to act on Gαi‐coupled β‐cell receptors was recently found to activate Gαi‐signalling indirectly by stimulating somatostatin secretion. Like the case for cAMP‐elevating agonists, also those with lowering effect act by additional mechanisms. Adrenaline, noradrenaline, somatostatin and galanin are thus known to activate K+ channels to hyperpolarise β‐cells and inhibit L‐type Ca2+ channels, and to inhibit exocytosis at a distal site mediated by acylation of essential exocytosis proteins or by activation of the Ca2+‐dependent serine/threonine protein phosphatase calcineurin.