nutrients Review Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective Joanna Michałowska * , Ewa Miller-Kasprzak and Paweł Bogda ´nski Department of Obesity and Metabolic Disorders Treatment and Clinical Dietetics, Pozna´nUniversity of Medical Sciences, Szamarzewskiego St. 82/84, 60-569 Pozna´n,Poland; [email protected] (E.M.-K.); [email protected] (P.B.) * Correspondence: [email protected] Abstract: The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non- alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions. Keywords: obesity; GLP-1; GIP; incretins; incretin-based therapy; type 2 diabetes mellitus; non- alcoholic fatty liver disease; cardiovascular disease Citation: Michałowska, J.; Miller-Kasprzak, E.; Bogda´nski,P. Incretin Hormones in Obesity and Related Cardiometabolic Disorders: 1. Introduction The Clinical Perspective. Nutrients The prevalence of obesity is rapidly growing worldwide, posing serious consequences 2021 13 , , 351. https://doi.org/ to individuals, society and the economy [1,2]. This disease is associated with many comor- 10.3390/nu13020351 bidities, being one of the leading causes of mortality and morbidity. Obese adults are at higher risk of developing type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), Received: 31 December 2020 non-alcoholic fatty liver disease (NAFLD) and other health problems [3–5]. Therefore, Accepted: 22 January 2021 Published: 25 January 2021 understanding the key mechanisms involved in the pathogenesis of obesity is needed for the development of prevention and therapeutic strategies. Research evidence shows that Publisher’s Note: MDPI stays neutral gastrointestinal (GI) tract hormones incretins may play a vital role in the pathogenesis and with regard to jurisdictional claims in treatment of obesity and its comorbidities, as they are responsible for the regulation of published maps and institutional affil- body weight, maintenance of energy balance, and glucose homeostasis [6–9]. iations. Incretin hormones are released from the intestine after nutrient intake. They play a crucial role in stimulating insulin and glucagon secretion by the pancreas [10,11]. There are two known incretins: glucose-dependent insulinotropic polypeptide (GIP) produced by the K cells of an upper gut and glucagon-like peptide-1 (GLP-1) produced by the L cells of a lower gut. Together, they are responsible for an “incretin effect”, which refers to Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the observation of two- to three-fold higher insulin secretion after oral glucose intake, This article is an open access article in comparison to an equivalent intravenous glucose administration [8,9]. Fasting healthy distributed under the terms and subjects have low basal plasma concentrations of GIP and GLP-1. They start to rise conditions of the Creative Commons few minutes after nutrient ingestion, reaching a peak approximately after 1 h, with GIP Attribution (CC BY) license (https:// concentrations being usually higher than GLP-1 concentrations. In patients with T2DM, creativecommons.org/licenses/by/ the incretin effect is diminished or absent. This is due to the fact that the pancreas is 4.0/). no longer responsive to GIP; however, it does remain sensitive to GLP-1 [12]. Thus, Nutrients 2021, 13, 351. https://doi.org/10.3390/nu13020351 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 32 Nutrients 2021, 13, 351 2 of 32 responsive to GIP; however, it does remain sensitive to GLP-1 [12]. Thus, incretin-based glucoseincretin-based-lowering glucose-lowering medications, in medications, particular GLP in particular-1 receptor GLP-1 agonists receptor (GLP agonists-1RAs), (GLP-have 1RAs),proven haveto be effective proven toan bed are effective currently and used are in currently T2DM treatment used in T2DM [13–18]. treatment A similar [13 obser-–18]. Avation similar of decreased observation incretin of decreased effect was incretin made effect in obese was individuals made in obese with individuals normal glucose with tolerance.normal glucose Several tolerance. studies reported Several a studies reduction reported in the a incretin reduction effect in thein nondiabetic incretin effect indi- in vidualsnondiabetic with individuals obesity, suggesting with obesity, that incretin suggesting hormones that incretin may play hormones a role mayin the play pathophys- a role in iologythe pathophysiology of obesity [9,19,20] of obesity. Moreover, [9,19,20 incretins]. Moreover, present incretins pleiotropic present actions pleiotropic and effect actionss in variousand effects organ in varioussystems. organ GLP- systems.1 is responsible GLP-1 isfor responsible the reduction for thein food reduction intake in and food appetite, intake inandcreased appetite, satiety, increased and decreased satiety, and gastric decreased emptying. gastric It affects emptying. adipose It affects cells, bone adipose metabo- cells, lismbone and metabolism the cardiovascular and the cardiovascular system. GIPsystem. addresses GIP fewer addresses organs fewer and organsfunctions and compared functions tocompared GLP-1; however, to GLP-1; research however, suggests research that suggests it may that also it influence may also influenceadipose tissue adipose by tissuepromot- by promotinging fat storage fatstorage in subcutaneous in subcutaneous adipose adipose tissue tissueand bone and metabolism bone metabolism by promoting by promoting bone formationbone formation and limiting and limiting bone boneresorption resorption [8,9].[ The8,9]. summary The summary of the of biological the biological effects effects of GIP of andGIP GLP and GLP-1-1 on various on various organs organs is presented is presented in Figure in Figure 1. 1. FigureFigure 1. 1.The The summary summary of of biologicalbiological effectseffects of glucose-dependentglucose-dependent insulinotropic insulinotropic polypeptide polypeptide (GIP (GIP)) and and glucagon glucagon-like-like ↑ ↓ peptide-1 (GLP-1) on variouspeptide organs.-1" :(GLP increase;-1) on# various: decrease. organs. : increase; : decrease. Nutrients 2021, 13, 351 3 of 32 Incretin hormones play an important role in human physiology, presenting differ- ent actions by peripheral and central mechanisms. The aim of this review is to describe and summarize the current knowledge regarding the role of incretin hormones in the pathophysiology of obesity and associated cardiometabolic disorders; and their therapeu- tic potential. 2. Biology of Incretins The term incretin was introduced in 1932 to describe compounds produced by in- testinal mucosa in response to nutrient ingestion, which were capable of reducing blood glucose [21]. GIP was discovered in 1970 by John C. Brown in dogs. This hormone was initially named “gastric inhibitory polypeptide”, due to its inhibitory effect on gastric acid secretion [22,23]. The insulinotropic action of GIP in humans was presented three years later, and the acronym GIP was proposed to be changed to its current name—glucose- dependent insulinotropic polypeptide [24,25]. The work in the next several years was focusing on the role of GIP in the pathogenesis of T2DM and its potential for the treatment of this disease, and the evidence that this peptide is not the only incretin emerged [25]. Fi- nally, in 1980s glucagon-like peptides (called GLP-1 and GLP-2) were identified by cloning of the preproglucagon gene, which exhibited insulin-releasing activity. Further investiga- tion demonstrated that truncated GLP-1 (7–36) shows not only insulinotropic effect but also inhibits the secretion of glucagon [21,25]. GIP is a peptide, which is synthesized and secreted mainly from K cells located in the duodenum and proximal jejunum; however, expression of this incretin by the central nervous system (CNS) has also been observed [26]. GIP expression has been detected in the brain, including hippocampus, thalamus, cerebellum, brainstem, and cortex in rats [27], and hypothalamus in humans [28]. This incretin derives from a precursor pro-peptide (pro-GIP), which is posttranslationally processed at residue 65 by proprotein convertase subtilisin/kexin type 1 to 42 amino acid (aa) form of GIP(1–42). Another amidated isoform of GIP(1–30) has also been detected as the pro-GIP peptide sequence contains a consensus cleavage site for prohormone convertase 2 (PC2) at residues 52–55 [29]. Both isoforms bind to GIP receptor (GIPR) and present intrinsic activity; however, it was speculated that they