New therapies for diabetes: incretin mimetics and gliptins

Diabetes and Primary Care, Summer, 2007 by Neil Munro, Jonathan Levy, Heba El-Gayar, Michael Feher

Incretin hormones are peptides that are released from the intestinal tract in response to mixed meals and contribute to glucose homeostasis by promoting glucose-dependent insulin secretion. The incretin effect is observed experimentally when insulin responses to oral and intravenous glucose loads are compared. An enhanced response is seen with oral, as opposed to parenteral, glucose (Elrick et al, 1964; Perley and Kipnis, 1967). In this article the authors review the mechanisms and pathways by which these therapies work.

Key words

- DPP-IV inhibitors

- GLP-1

- Gliptins

- Incretin mimetics

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Two hormones secreted from the gastrointestinal tract--glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)--account for more than 50% of the incretin effect of a mixed meal. They rapidly stimulate insulin release in the presence of hyperglycaemia. GLP-1 has 30 amino acids and GIP has 42 amino acids (McIntyre et al, 1964; Nauck et al, 1986). GIP is derived from K cells located in the jejunum and responds more to dietary fat than glucose. GLP-1 is secreted by L cells in the ileum, predominantly in the presence of glucose. This occurs in association with neural signalling arising from a food stimulus. These mechanisms induce insulin secretion through direct activation of G-protein coupled receptors expressed on pancreatic [beta]-cells (Vilsboll and Holst, 2004). In type 2 diabetes the [beta]-cell response to GIP is largely lost, but GLP-1 receptor sensitivity remains. The reasons for reduced GIP responsiveness remain unclear, but may be associated with reduced GIP receptor expression in people with significant insulin resistance (Rudovich et al, 2005). Current developments have therefore focused on the role of GLP-1 in glucose homeostasis.

Signalling mechanisms of incretin hormones

Insulin secretion in response to glucose is triggered by [beta]-cell depolarisation: an influx of calcium, in conjunction with calmodulin, causes insulin granules to fuse with the cell membrane, releasing their contents. When GLP-1 binds to receptors on the [beta]-cell membrane, signalling pathways are activated, this results in 3',5'-cyclic adenosine monophosphate-dependant protein kinase A activation. GLP-1 cannot trigger insulin release by itself as its insulinotropic effect is dependent on ambient glucose. At glucose levels close to the threshold for triggering insulin secretion, GLP-1 has very little effect (Triplitt et al, 2006).

Therapeutic potential

From the therapeutic point of view, this means that incretin mimetics possess the potential to achieve glucose homeostasis with minimal risk of iatrogenic hypoglycaemia. In contrast, sulphonylureas and meglitinides trigger insulin release irrespective of ambient glucose and can produce hypoglycaemia. As the site of action of the incretins is separate from those activated by secretagogues, they have the further advantage of providing an additive, rather than competitive, effect (Zander et al, 2002).

In addition to its glucose-dependent action on insulin secretion, GLP-1 has been shown to suppress glucagon secretion, delay gastric emptying and induce satiety, with a resultant reduction in food intake (Levy, 2006) which offers the potential for weight reduction. Elevated glucagon levels are found in people with type 2 diabetes and contribute to background and postprandial hyperglycaemia. By its direct action on islet [alpha]-cells, GLP-1 reduces excess glucagon secretion without having an impact on its protective effect in hypoglycaemia. In rodents, suppression of apoptosis and proliferation of [beta]-cells have been demonstrated. Should this preserving effect be demonstrated in humans it would represent a very significant milestone in treatments aimed at reversing the inexorable decline of [beta]-cells seen in type 2 diabetes.

The key properties of GLP-1 are summarised in Box 1.

Long-acting GLP-1 agonists/analogues and DPP-IV inhibition

The potential for incretin action to be applied in a clinical setting has been recognised for many years. However, in its native form there are a number of drawbacks. In vivo GLP-1 only remains active for 1-2 minutes owing to proteolytic inactivation by the enzyme dipeptidyl peptidase IV (DPP-IV), therefore, as it will be destroyed in the intestine it needs to be given parenterally.

Long-acting GLP-1 analogues that are resistant to DPP-IV inactivation and mimic the action of the native hormone have been under development. The peptides exendin-3 and exendin-4, were isolated from the saliva of the lizard species Heloderma; H. horridum--the Mexican beaded lizard, and H. suspectum--the Gila monster (Eng et al, 1990; Eng et al, 1992; respectively). Exendin-4 has a 50 % homology with human GLP-1, binds to pancreatic GLP-1 receptors in vitro and resists deactivation by DPP-IV. This GLP-1 agonist has a therapeutic action of about 6 hours, reaching a peak plasma concentration after 2 hours.

Incretin mimetics

Exenatide

The first incretin mimetic to become commercially available is exenatide (Byetta; Amylin Pharmaceuticals, San Diego and Eli Lilly & Company, Basingstoke). Exenatide is synthetically produced exendin-4. It was granted approval for clinical use by the US Food and Drug Administration in April 2005 and gained a European licence in 2006.