REVIEW ARTICLE Incretins: Beyond type 2 diabetes Paresh Dandona MD | Husam Ghanim PhD | Ajay Chaudhuri MD Diabetes-Endocrinology Center of Western NY, State University of New York at Buffalo, Buffalo, New York Correspondence Paresh Dandona BSc, MBBS, DPhil, FRCP, Director, Diabetes-Endocrinology Center of Western NY, Chief of Endocrinology, State University of New York at Buffalo 1000 Youngs Road, Williamsville, Buffalo, NY 14221. Email: pdandona@kaleidahealth.org While the use of incretins, including GLP-1 receptor agonists and PDD-IV inhibitors, is well established in the treatment of type 2 diabetes, many other aspects of these agents are yet to be discovered and utilized for their potential clinical benefit. These include the potential role of GLP-1 receptor agonists in the induction of weight loss, blood pressure reduction, anti- inflammatory and nephro- and cardio-protective actions. Their potential benefit in type 1 diabe- tes is also being investigated. This review will attempt to comprehensively describe novel dis- coveries in the field of incretin pathophysiology and pharmacology beyond their classical role in the treatment of type 2 diabetes. KEYWORDS cardiovascular disease, diabetic nephropathy, incretins, type 1 diabetes, weight control 1 | INTRODUCTION The initial discovery by McIntyre et al. 1,2 that the intake of glucose orally as compared to glucose given intravenously leads to a much greater insulin secretion, was important but it took two decades to fully appreciate its significance and another 2 decades to translate the discovery into pharmacological and clinical significance. 3 The arrival of GLP-1 receptor agonists (GLP-1RA) in 2005 revolutionized the field of type 2 diabetes and energized the commitment with which diabetologists devoted themselves to the treatment of diabe- tes. It was remarkable that a molecule could stimulate the beta cell to secrete insulin while suppressing glucagon from the alpha cell in the pancreatic islet. 4 Furthermore, insulin secretion induced by GLP-1 was glucose dependent, such that insulin secretion occurred only in the presence of hyperglycemia and thus did not induce hypoglyce- mia. 5,6 Insulin secretion and β cell stimulation by GLP-1 appears to last for as long as it is given: the stimulation of insulinogenesis by lira- glutide, a GLP-1RA, was found to be durable while the drug was administered but disappeared within 2 weeks of cessation of the drug. 7 GLP-1 and GLP-1RA also suppress appetite at the hypotha- lamic level facilitating weight loss while also reducing the rate of gas- tric emptying and thus reducing post prandial peaks of glucose. 6,8,9 Such observations related to their clinical effects led to further novel discoveries about their properties and actions at the cellular and molecular level, both in vivo and vitro. An understanding of the mode of secretion and transport of GLP-1, the natural incretin, from the ileum led to the discovery that GLP-1 is rapidly destroyed by the enzyme, dipeptidyl peptidase IV (DPP-IV), in plasma, leading to an extremely short half-life of 2 minutes. 10,11 This led to the develop- ment of another class of drugs, the DPP-IV inhibitors which protect GLP-1, increase the bio-availability of GLP-1 and hence improve insu- linogenesis and suppress glucagon. 11,12 DPP-IV is also responsible for destroying GIP, the other incretin secreted by the duodenum which also induces insulin secretion from the beta cell. 13 Furthermore, DPP- IV and its cellular precursor, CD-26, is an inflammatory signal media- tor and hence DPP-IV inhibitors may be expected to be anti- inflammatory. 14 This review will attempt to comprehensively describe novel dis- coveries in the field of incretin pathophysiology and pharmacology beyond their classical role in the treatment of type 2 diabetes. 2 | ANTI-INFLAMMATORY EFFECTS OF GLP-1RA The initial report showing such an effect was the first study demon- strating the safety and efficacy of the concomitant use of insulin with exenatide. 15 The study also demonstrated simultaneous reductions in plasma concentrations of CRP and systolic blood pressure. There was a reduction in plasma CRP concentration by >30%. This led to a more detailed investigation on the anti-inflammatory actions of exenatide at the cellular and molecular level. This detailed study was carried out in patients with type 2 diabetes on treatment with oral agents, met- formin, sulfonylureas and insulin. This study investigated both an Received: 4 October 2017 Revised: 1 November 2017 Accepted: 2 November 2017 DOI: 10.1111/dom.13153 Diabetes Obes Metab. 2018;20(Suppl. 1):59–67. wileyonlinelibrary.com/journal/dom © 2018 John Wiley & Sons Ltd 59