Incretin-based therapies: where will we be 50 years from now?

Abstract

The development of incretin-based therapies (glucagon-like peptide 1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors) has changed the landscape of type 2 diabetes management over the past decade. Current developments include longer-acting GLP-1 receptor agonists, fixed-ratio combinations of GLP-1 analogues and basal insulin, as well as implantable osmotic minipumps for long-term delivery of GLP-1 receptor agonists. In longer terms, oral or inhaled GLP-1 analogues may become a reality. In addition, oral enhancers of GLP-1 secretion (e.g. via G-protein-coupled receptors, nuclear farnesoid-receptor X and the G-proteincoupled bile acid-activated receptor [TGR5]) are currently being explored in experimental studies. Combination of GLP-1 with other gut hormones (e.g. peptide YY, glucagon, gastrin, glucose-dependent insulinotropic polypeptide [GIP], secretin, cholecystokinin, vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide) may enhance the glucose-and weight-lowering effect of GLP-1 alone, and dual or triple hormone receptor agonists may even exploit the properties of different peptides with just one molecule. There is also an increasing interest in employing incretin-based therapies in other areas, such as type 1 diabetes, impaired glucose metabolism, obesity, polycystic ovary syndrome, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), psoriasis or even neurodegeneration. Thus, incretin-based therapies may continue to broaden the therapeutic spectrum for type 2 diabetes and for various other indications in the coming years. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965Diabetologia ( -2015.Keywords GIP . GLP-1 . Gut hormones . Type 2 diabetes Where are we today and where have we come from?The development of incretin-based therapies is a splendid and unique example of the successful development of novel glucose-lowering medications based on basic research findings from academic researchers. Physiological experiments in human volunteers revealed different increments in insulin secretion after oral and intravenous glucose administration, which were subsequently attributed to the actions of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [1]. These peptide hormones were later synthesised and prepared for intravenous infusion in patients with type 2 diabetes. On this basis, the glucose-lowering activity of GLP-1 was first discovered by academic researchers. Later on, dipeptidyl peptidase-4 (DPP-4) inhibition was identified as an effective way of raising endogenous GLP-1 levels [2]. These clinical research findings have prompted the development of GLP-1 receptor

Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes

“…A variant in CYP7A1 decreasing LDL-cholesterol has previously been linked to lower fasting glucose [28]. The direction of effects, with higher levels of bile acids in the circulation linked to increased risk of diabetes, seems however counterintuitive, as bile acids are increasingly being recognised as hormones that regulate various metabolic processes in beneficial ways, including increasing incretin secretion in the gut [29], although different classes of bile acids affect downstream receptor signalling in different ways, not all of which may promote glucose homeostasis [30]. However, with regards to pharmaceutical applications, bile acid sequestrants such as colesevelam (approved for lipid-lowering purposes) bind to bile acids in the gut and thus increase CYP7A1 expression through feedback systems.…”

Impact of postprandial glucose control on diabetes-related complications: How is the evidence evolving?

“…GLP-1 "enhancers") [14,79] or act as antagonists of glucagon action or inhibition of the paradoxical increase in glucagon secretion [80,81] (Table 3). Emerging strategies also include the modification of short-acting GLP-1 receptor agonists to potentially offer even shorter half-lives with the aim of delaying gastric emptying [82]. Short-acting GLP-1 agonists are also under study in combination therapy with basal insulin for improving PPG control in intensive insulin therapy for type 2 diabetes [83,84].…”

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research

“…In addition to already approved and widely applied compounds, such as metformin and sulfonylureas, it would be a great step forward in diabetes therapy to provide insulin and glucagon-like peptide 1 receptor agonists as oral formulations [147]. In this respect, the appropriate coating of compounds to direct their absorption in the gastrointestinal tract (GIT) is of major importance.…”