The glucagon-secreting alpha cells surround the insulin -secreting beta cells, which reflects the close relationship between the two hormones. To do this, it acts on the liver in several ways:.
Glucagon also acts on adipose tissue to stimulate the breakdown of fat stores into the bloodstream. Glucagon works along with the hormone insulin to control blood sugar levels and keep them within set levels. Glucagon is released to stop blood sugar levels dropping too low hypoglycaemia , while insulin is released to stop blood sugar levels rising too high hyperglycaemia.
The release of glucagon is stimulated by low blood glucose, protein -rich meals and adrenaline another important hormone for combating low glucose. The release of glucagon is prevented by raised blood glucose and carbohydrate in meals, detected by cells in the pancreas.
For example, it encourages the use of stored fat for energy in order to preserve the limited supply of glucose. A rare tumour of the pancreas called a glucagonoma can secrete excessive quantities of glucagon. Unusual cases of deficiency of glucagon secretion have been reported in babies. Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose.
In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release.
Another hormone well known to inhibit glucagon secretion is somatostatin. Diseases associated with excessively high or low secretion of glucagon are rare. Alternatively, DPP4 inhibitors like sitagliptin and vildagliptin increase the endogen effects of GLP1, reducing glucagon plasma concentrations in diabetic individuals Rosenstock et al. Since all these alternatives produce opposing actions on insulin and glucagon, they generate promising expectations for diabetes treatment.
Given that imidazoline compounds stimulate insulin release while inhibiting glucagon secretion, these drugs are potentially valuable in diabetes. In mice, the use of a highly SSTR2-selective non-peptide agonist inhibited glucagon release without affecting insulin release Strowski et al.
Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists. Essentially, they impair the ability of glucagon to stimulate adenylate cyclase activity in liver, thus reducing hepatic glucose output and improving plasma glucose levels. This is the case of [des-His 1 , des-Phe 6 , Glu 9 ] glucagon-NH 2 , which reduces glucose levels in streptozotocin-induced diabetic rats Van Tine et al.
Recent investigations have demonstrated that the antagonist des-His-glucagon binds preferentially to the hepatic glucagon receptor in vivo , and this correlates with the glucose lowering effects Dallas-Yang et al. For instance, a novel competitive antagonist N -[3-cyano 1, 1-dimethylpropyl -4, 5, 6, 7-tetrahydrobenzothienyl]ethylbutanamide was recently shown to inhibit glucagon-mediated glycogenolysis in primary human hepatocytes and to block the increase in glucose levels after the administration of exogenous glucagon in mice Qureshi et al.
The information about the effect of these antagonists on humans is, however, scarce. Despite the success of several approaches to modulate glucagon secretion or action and improve glucose control in animal models or in humans, more information is still required. Long-standing studies should address whether the utilization of these agents could lead to undesired hypoglycaemia in humans, accumulation of lipids or compensatory mechanisms that decrease the benefits of these therapies in the long term.
In this aspect, the results obtained in animal models are positive: although the glucagon receptor knock-out mouse develops hyperglucagonaemia, it is not hypoglycaemic and does not have an abnormal accumulation of lipids Gelling et al.
Additionally, recent long-term studies in mice further prove the viability of glucagon antagonism Winzell et al. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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