Effects of glucose-dependent insulinotropic polypeptide on glucagon

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion. It is well known that GIP exerts a strong, glucose-dependent (during elevated blood glucose levels) insulinotropic effect. In recent years, it has become clear that GIP also exerts effects on glucagon secretion. The regulation of glucagon secretion is interesting as the combination of inadequate insulin secretion and excessive glucagon secretion represents an essential contributor towards the hyperglycaemia in patients with type 2 diabetes. Moreover, the absence of a well-timed counterregulatory glucagon response contributes towards an increased risk of hypoglycaemia in patients with type 1 diabetes. Here, we review several studies investigating the effect of GIP on glucagon secretion and discuss the current evidence for a glucose-dependent glucagonotropic effect of GIP in healthy individuals and in patients with diabetes, respectively. We conclude that at fasting glycaemia and lower levels of glycaemia, GIP seems to increase glucagon secretion, with little effect on insulin release, which points towards a bifunctional blood glucose-stabilizing role of GIP in healthy humans. In patients with type 2 diabetes, GIP may contribute to inappropriate glucagon secretion and in patients with type 1 diabetes, GIP augments glucagon responses to hypoglycaemia.