This so-called ‘incretin effect’ explains why a greater amount of insulin is released in response to an oral glucose load compared with that elicited by an isoglycaemic intravenous glucose challenge,1 and in healthy subjects it accounts for up to 70% of glucose-induced insulin secretion.¹ The two incretin hormones have effects on the β-cell in addition to their ability to stimulate insulin secretion. They induce insulin gene expression and stimulate of all steps in insulin biosynthesis, thereby ensuring that continued supplies of insulin are available for secretion. They also upregulate the expression of other genes involved in β-cell function (e.g. GLUT 2 and glucokinase).² Additionally, in vitro and pre-clinical in vivo studies have demonstrated that they both stimulate β-cell proliferation and neogenesis and exert anti-apoptotic effects, leading to expansion of the β-cell mass. However, while both incretins share effects on the β-cell, GLP-1 also exhibits activity at sites other than the β-cell. Glucagon secretion is inhibited, thereby suppressing endogenous glucose production; gastric emptying is delayed, minimising post-prandial glucose excursions; there is a marked effect to reduce appetite and promote satiety, leading to reduced food intake and, in the longer-term, to bodyweight loss.3 More recent studies have indicated that GLP-1 may also have some beneficial cardiovascular effects.³

The Incretin Hormones and Type 2 Diabetes
The incretin effect is reduced in patients with type 2 diabetes, possibly explaining why the insulin response to an oral glucose challenge is blunted and delayed compared with healthy non-diabetic subjects.⁴ Subsequent studies revealed that the subjects with type 2 diabetes have impairments in incretin action. Thus, although GLP-1 retains its insulinotropic activity, its potency in this respect is reduced.⁵ In contrast, the insulinotropic effect of GIP is severely impaired, with the ability of GIP to stimulate second-phase insulin secretion being absent, although a first-phase response is present.⁶ Furthermore, additional studies indicated there were also disturbances in secretion of the incretin hormones. While levels of GIP are relatively normal in individuals with type 2 diabetes,⁷ these subjects may exhibit modest but significant deficits in meal-stimulated GLP-1 secretion compared with non-diabetic controls.⁷

These observations suggested that dysregulation of incretin activity may be involved in the impaired glucose regulation in type 2 diabetes. However, it appears that the incretin defect is a consequence rather than a cause of the diabetic state,⁸ although it may contribute to impairments in insulin secretion once glucose homeostasis begins to deteriorate. Such findings suggested that interventions to enhance incretin activity might correct underlying incretin deficits in individuals with impaired glucose regulation and lead to improvements in glucose control. Accordingly, a continuous infusion of GLP-1 resulted in a blood glucose profile in diabetic subjects that was very similar to that in non-diabetic controls, not only in the overnight (fasting) period, but also during the following day in response to meals.⁹ The proof-of-concept that it was possible to improve glucose homeostasis by augmenting GLP-1 activity on a chronic basis was shown in a study in which patients with type 2 diabetes received continuous subcutaneous infusions of GLP-1 over a six-week period. This was associated with a marked reduction in blood glucose levels at one week, with the reduction persisting for the duration of the study,¹⁰ demonstrating that tachyphylaxis to the continued presence of GLP-1 does not occur. In this study, GLP-1 was well tolerated and led to a significant reduction in glycolated haemoglobin (HbA1c) levels, which was accompanied by a small but significant weight loss.¹⁰