Gut hormones and appetite regulation.

PURPOSE OF REVIEW: Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. RECENT FINDINGS: Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. SUMMARY: Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update.

Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions.

Synergistic Combinations of Gut- and Pancreas-Hormone-Based Therapies: Advancements in Treatments for Metabolic Diseases.

Metabolic diseases, such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, and liver disease, have become increasingly prevalent around the world. As an alternative to bariatric surgery, glucagon-like peptide 1 (GLP-1) receptor agonists have been at the forefront of weight loss medication to combat these metabolic complications. Recently, there has been an exciting rapid emergence of new weight loss medications that combine GLP-1 receptor (GLP-1R) agonists with other gut- and pancreatic-derived hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) receptor agonists. Dual-agonist (GLP-1/GIP and GLP-1/GCG) and tri-agonist (GLP-1/GIP/GCG) administration generally result in greater weight loss, reduction of blood sugar and lipid levels, restoration of tissue function, and improvement in whole-body substrate metabolism compared to when GLP-1R agonists are used alone. The aim of this review is to summarize the recent literature of both preclinical and clinical studies on how these emerging gut-peptide therapies further improve weight loss and metabolic health outcomes for various metabolic diseases.

Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods.

The incretin effect describes the insulin response to nutrient ingestion that exceeds the response to glycemia per se. It is mediated by gastrointestinal factors and is necessary to maintain postprandial glucose homeostasis. The incretin effect results in a more than twofold increase of the insulin response to a meal in healthy people and two different techniques have been used in the past to measure its magnitude. Most studies employ an OGTT on 1 day, followed by a matching glucose infusion on a separate day. Another study design employs a hyperglycemic glucose clamp that is maintained after oral ingestion of glucose. Both protocols allow quantification of the incretin effect by comparing the insulin response to an identical glycemic stimulus. Here we performed a within-subject comparison of both techniques to quantify the incretin effect and suggest different calculation methods to interpret the results derived from the clamp experiment in a cohort of healthy young adults (n = 10, age 33 ± 4 yr). All subjects participated on four different study days: 1) OGTT, 2) isoglycemic glucose infusion (Iso-IV), 3) hyperglycemic clamp with oral glucose ingestion (clamp-OGTT), and 4) hyperglycemic clamp (clamp). With the classic OGTT/Iso-IV method, the insulin response to glucose ingestion increased more than twofold and was 60 ± 6% and 49 ± 5% for insulin and c-peptide. Different estimates of the incretin effect based on the clamp method ranged from 58% to 79% for insulin and 38% to 61% for c-peptide, both significantly higher than values derived from the OGTT/isoglycemic infusion method. However, when the effect of continuous hyperglycemia on insulin secretion was accounted for, using extrapolation from early time points of the clamp, good agreement was noted between the two methods. Based on these results, both techniques seem to be equally suited to measure the incretin effect and should be employed according to the scientific questions, experimental contingencies, and investigator experience.NEW & NOTEWORTHY This proof-of-concept study shows that the incretin effect can be reliably assessed by two different methods with similar quantitative results. A single-day hyperglycemic clamp with oral glucose ingestion allows the determination of the incretin effect with fewer study days and less day-to-day variability.

The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide.

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

Incretin and Pancreatic ß-Cell Function in Patients with Type 2 Diabetes.

To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic ß-cells. However, if pancreatic ß-cells solely depended on the blood glucose level for insulin secretion, a surge in blood glucose levels would be inevitable after the ingestion of a large amount of carbohydrates. To avoid a deluge of glucose in the bloodstream after a large carbohydrate- rich meal, enteroendocrine cells detect the amount of nutrient absorption from the gut lumen and secrete incretin hormones at scale. Since insulin secretion in response to incretin hormones occurs only in a hyperglycemic milieu, pancreatic ß-cells can secrete a "Goldilocks" amount of insulin (i.e., not too much and not too little) to keep the blood glucose level in the normal range. In this regard, pancreatic ß-cell sensitivity to glucose and incretin hormones is crucial for maintaining normal glucose homeostasis. In this Namgok lecture 2022, we review the effects of current anti-diabetic medications on pancreatic ß-cell sensitivity to glucose and incretin hormones.

[The "other" incretin - the therapeutic rediscovery of the glucose-dependent insulinotropic polypeptide]. / A "másik" inkretin ­ a glükózdependens insulinotrop polipeptid terápiás újrafelfedezése.

Among the two incretins that strongly stimulate insulin secretion and are also involved in its physiological regulation in type 2 diabetes, glucagon-like peptide-1 (GLP1) has been the focus of interest for a long time, due to its retained - although reduced - secretagogue nature also in type 2 diabetes. Its receptor agonists were also included in the antidiabetic treatment toolkit. In the light of more recent studies, however, the "other" incretin, the glucose-dependent insulinotropic polypeptide (GIP) has also come into a different light. It turned out that by regulating glucagon and insulin production according to blood sugar levels, it acts as a bifunctional blood sugar stabilizing factor in type 2 diabetes as well. The article reviews new data on the physiology of GIP, its verifiable effects in type 2 diabetes and obesity, the so-called "twincretin" effect as well as the benefits of the double stimulation of the GIP and the GLP1 receptor. It describes the pharmacology of the first dual receptor agonist, tirzepatide, already incorporated in therapeutic recommendations, and the first clinical trials related to its use. In the light of the data so far, the molecule may open new horizons in the treatment of type 2 diabetes and obesity. Orv Hetil. 2023; 164(6): 210-218.

Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)-GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation.

Activation of GIPR Exerts Analgesic and Anxiolytic-Like Effects in the Anterior Cingulate Cortex of Mice.

Background: Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. Methods: The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala2-GIP) and antagonist (Pro3-GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR. Results: In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala2-GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro3-GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice. Conclusions: GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.

The Role of Incretins on Insulin Function and Glucose Homeostasis.

The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.

GIP(3-30)NH2 - a tool for the study of GIP physiology.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone impacting glucose, lipid and bone metabolism through the GIP receptor (GIPR). The GIP system has key species differences complicating the translation of findings from rodent to human physiology. Furthermore, the effects of endogenous GIP in humans have been difficult to tease out due to the lack of a suitable GIPR antagonist. The naturally occurring GIP(3-30)NH2 has turned out to constitute a safe and efficacious GIPR antagonist for rodent and human use. To study GIP physiology, it is recommended to use the species-specific GIP(3-30)NH2 peptide sequence, and for human intravenous infusions, an antagonist:agonist ratio of a minimum of 600 with a 20min infusion time before the intervention of interest is recommended. Several studies using GIP(3-30)NH2 are coming, hopefully providing new insights into the physiology of GIP, the pathophysiologic involvement of GIP in several diseases and the therapeutic potential of the GIPR.

Primary, Secondary, and Tertiary Effects of Carbohydrate Ingestion During Exercise.

The purpose of this current opinion paper is to describe the journey of ingested carbohydrate from 'mouth to mitochondria' culminating in energy production in skeletal muscles during exercise. This journey is conveniently described as primary, secondary, and tertiary events. The primary stage is detection of ingested carbohydrate by receptors in the oral cavity and on the tongue that activate reward and other centers in the brain leading to insulin secretion. After digestion, the secondary stage is the transport of monosaccharides from the small intestine into the systemic circulation. The passage of these monosaccharides is facilitated by the presence of various transport proteins. The intestinal mucosa has carbohydrate sensors that stimulate the release of two 'incretin' hormones (GIP and GLP-1) whose actions range from the secretion of insulin to appetite regulation. Most of the ingested carbohydrate is taken up by the liver resulting in a transient inhibition of hepatic glucose release in a dose-dependent manner. Nonetheless, the subsequent increased hepatic glucose (and lactate) output can increase exogenous carbohydrate oxidation rates by 40-50%. The recognition and successful distribution of carbohydrate to the brain and skeletal muscles to maintain carbohydrate oxidation as well as prevent hypoglycaemia underpins the mechanisms to improve exercise performance.

Rational design of a GLP-1/GIP/Gcg receptor triagonist to correct hyperglycemia, obesity and diabetic nephropathy in rodent animals.

AIMS: To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. MAIN METHODS: First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. KEY FINDINGS: We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. SIGNIFICANCE: XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.

Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus.

The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of IκB kinase-ß inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3ß in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.

Can dipeptidyl peptidase-4 inhibitors treat cognitive disorders?

The linkage of neurodegenerative diseases with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), including oxidative stress, mitochondrial dysfunction, excessive inflammatory responses and abnormal protein processing, and the correlation between cerebrovascular diseases and hyperglycemia has opened a new window for novel therapeutics for these cognitive disorders. Various antidiabetic agents have been studied for their potential treatment of cognitive disorders, among which the dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated more recently. So far, DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models, and cognitive benefits in diabetic patients with or without cognitive impairments. This review aims to summarize the potential mechanisms, advantages and limitations, and currently available evidence for developing DPP-4 inhibitors as a treatment of cognitive disorders.

The role of dietary sugars in health: molecular composition or just calories?

This review will focus on the question of whether dietary sugars are a relevant determinant in the global rise of overweight and obesity in adults, adolescents, and children. Initially, the review describes the current definitions for sugars in the diet and makes reference to them while analyzing their role in overweight and obesity as well as diet-related diseases, including type 2 diabetes, cardiovascular diseases, non-alcoholic fatty liver disease and cancer. Second, it will focus particularly on sucrose and the question of whether it is the molecular composition of sucrose (glucose and fructose) or its energy content that promotes body weight gain and diet-related diseases. Finally, the review will clarify the molecular characteristics of sucrose regarding the release of the gastrointestinal glucose-dependent insulinotropic peptide (GIP) compared to other energy-providing nutrients and its relevance in metabolic diseases. Current data indicates that dietary sugars are only associated with an increase in obesity when consumed as an excess source of calories and with that an increase in the risk of diet-related diseases. Furthermore, it was shown that a diet rich in fat will stimulate GIP secretion more than a diet rich in sucrose. Taken together, current scientific evidence does not support the conclusion that dietary sugars per se are detrimental to human health.

[Internalized receptor for glucose-dependent insulinotropic peptide stimulates adenylyl cyclase on early endosomes]. / Signalisation endosomale du récepteur du peptide insulinotrope dépendant du glucose (GIP).

G-protein coupled receptors represent the largest family of membrane receptors. G-protein dependent signal of GPCR is classically thought to originate exclusively from the plasma membrane and, until very recently, internalized GPCRs were considered silent. At present, experimental proofs exist showing that GPCR can continue to signal via G proteins after internalization. We demonstrated that, once internalized in early endosomes, Glucose-dependent Insulinotropic Peptide Receptor (GIPR) continues to stimulate production of cAMP and activate PKA. In addition to indirect proofs showing that kinetics of cAMP production and PKA activation depend on internalization and GIPR trafficking, we identified the active form of Gαs on early endosomes containing GIPR and detected a distinct FRET signal accounting for cAMP production at the surface of endosomes containing GIP, relative to endosomes without GIP.

Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain.

Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.

Incretin hormones: Their role in health and disease.

Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin-based glucose-lowering medications (GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 or DPP-4). GLP-1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP-1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP-1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux-en-Y gastric bypass). GIP and GLP-1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP-1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high-risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well-characterized physiological effects.