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Abstract

Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. Incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to that of natural incretin hormone, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 enzyme (DPP-4) to increase plasma concentration of incretins and their biologic effects. Since Glucagon like peptide-1 (GLP-1) is an incretin hormone with various antidiabetic actions including stimulation of glucose induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Since DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, antidiabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin based therapeutic agents as means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors raised substantial concerns due to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in the manuscript.

Figure 1 Processing of proglucagon and proGIP by PC1/3 generates incretins with insulinotropic effect in intestine. For this to happen, proglucagon is first processed to produce glicentin, GLP1(1-37) or GLP-1(1-36) amide, IP2 and GLP-2. Glicentin and GLP-1 can further be cleaved by PC1/3 to yield oxyntomodulin and GLP-1(7-37) or GLP-1(7-36) amide, respectively. Similarly, proGIP is modified by PC1/3 to generate GIP(1-42) in intestine. Abbreviations: GRPP, glicentin-related pancreatic polypeptide; GLP-2, glucagon-like peptide-2; PC, prohormone convertase; IP, intervening peptide.

Figure 2 Molecular signaling mechanism responsible for the insulinotropic effects of GLP-1 and GIP. Interaction of GLP-1 and GIP with their cognate receptors, GLP-1R and GIPR, results in the activation of Adenylate Cyclase (AC) by way of G proteins (G) leading to increase in intracellular cAMP levels. Activation of PKA and EPAC2 (cAMP-GEFII) closes KATP channels (K Ch) facilitating membrane depolarization resulting in the opening of the voltage gated Ca2+ channels (Ca Ch) and influx of Ca2+ into pancreatic beta cells. Increase in cytoplasmic Ca2+ not only stimulates fusion of insulin-containing cytoplasmic granules leading to insulin secretion from pancreatic beta cells but also promotes transcription of proinsulin gene refreshing insulin depots. Key players of glucose-mediated insulin secretion are also depicted in the figure. In this scenario, glucose enters into the cell through Glucose Transporter 2 (GLUT2) and gets phosphorylated to glucose 6 phosphate (G6P) by glucokinase (GK). Glycolysis increases the ATP/ADP ratio leading to closure of K channels (K Ch) inducing membrane depolarization. Other abbreviations: Nu, Nucleus; ER, Endoplasmic Reticulum, Mt, Mitochondria.

Figure 3 Molecular structures of GLP-1, GLP-1 analogues and DPP-4 inhibitors. GLP-1(7-37) is an incretin hormone synthesized from the transcription product of proglucagon gene. Liraglutide (Victoza) developed by Nova Nordisk is a long acting GLP-1 agonist with addition of a fatty acid chain (FA) designed to bind to serum albumin. Exenatide (BYETTA®) isolated from the saliva of the gila monster is a GLP-1R agonist and an insulin secretagogue with glucoregulatory functions. Vildagliptin (Galvus) approved by European Medicines Agency (EMEA) but not by the US FDA, is an oral antihyperglycemic drug acting as an DPP-4 inhibitor. Sitagliptin (Januvia) developed and marketed by Merck & Co. is an oral antidiabetic agent with DPP-4 inhibiting activity.

Conclusions: The first incretin mimetic (exenatide) was approved by the U.S. FDA in April 2005. Soon after that, in October 2006, the U.S. FDA approved the first oral incretin effect amplifier, DPP-4 inhibitor (sitagliptin). So far, several other incretin mimetics have reached to market and there are even more incretin based drugs under development awaiting marketing approval. Clinical trials of incretin-based therapies demonstrated that incretins are as effective as other antidiabetic drugs (sulphonylureas, thiazolidinediones, and long-acting insulin therapies) if not superior for improving blood glucose control and achieving weight loss. Although, some concerns were raised against incretin based therapies regarding pancreatitis or pancreatic cancer, U.S. FDA review of preclinical and some limited clinical data from all currently available incretin therapies revealed no concern for pancreatic disease. The fact that no clinical incretin-based treatment study has been suspended for safety concerns further supported this notion. Consequently, regulatory agencies advised no change to current treatment protocols of patients with diabetes treated with incretin-based therapies. The fact that 80,000 subjects are currently enrolled in ongoing cardiovascular disease (CVD) outcome trials required by the U.S. FDA, the long-term effects of incretin based therapies concerning cardiovascular morbidity and mortality will hopefully be available soon in patients with T2DM. Among CVD outcome trials, specifically LEADER (liraglutide), EXSCEL (exenatide once-weekly), ELIXA (lixisenatide), and REWIND (dulaglutide) are expected to be completed between 2016 and 2019.