Nutrients stimulating GLP-1 secretion include the metabolizable monosaccharides that include glucose, fructose, and galactose 239,, , , as well as non-metabolizable monosaccharides such as methyl-α-glucopyranoside , long-chain fatty acids 232,, , , proteins 228,250,, , , , and certain amino acids , , . In anesthetized pigs, baseline levels of total GLP-1 in the portal vein are in the range of ∼30 pmol/l and increase up to 150 pmol/l upon treatment with neuromedin C, which is a known stimulator of GLP-1 secretion . Like pancreatic α-cells, the intestinal L-cells secrete PGDPs simultaneously and in equimolar concentrations. Consistent with this, treatment of RYGB patients with exendin (9–39) increases the fMRI response to images of food in the caudate nucleus, and in the insula in the human brain in response to consuming palatable food . Thus, increased circulating GLP-1 is invariably reported after bariatric surgery , , , , , and after surgical repositioning of the distal gut (so-called ileal interposition), both of which rapidly expose the L-cells to incoming incompletely digested nutrients . GLP-1(7-36) can suppress glucagon secretion in α cells by increasing cAMP levels, activating PKA and EPAC, leading to a decrease in intracellular calcium concentration and reduced glucagon release. Additionally, GLP-1 promotes somatostatin secretion from δ cells, which inhibits glucagon secretion from α cells. GLP-1R expression is lower in α cells compared to β and δ cells, resulting in relatively less direct action of GLP-1 on α cells. In β cells, GLP-1(9–36) activates the GLP-1R, which increases cAMP levels, subsequently activating PKA and CREB, leading to the promotion of insulin secretion. Results showed that Teadenol A considerably increased GLP-1 production when administered to STC-1 cells. Berberine-activated stomach bitter taste receptors to increase GLP-1 secretion in a PLC-dependent manner . U73122, a PLC inhibitor, reduced berberine-induced GLP-1 release in NCI-H716 cells, whereas quinine, a TRPM5 blocker, did not. In this part of the review, we will explore natural products that modulate GLP-1 secretion and expression (Fig. 8 and Table 7). Other emerging indications are based on studies in participants with obesity-related comorbidities or preliminary trials in broader populations. Cardiovascular and renal outcomes are primarily derived from trials in participants with type 2 diabetes or established cardiovascular disease. Beyond obesity and type 2 diabetes, the therapeutic potential of GLP-1 RAs extends to a range of conditions such as cardiovascular disease, liver disease, neurodegenerative disease, and substance abuse disorders. In line with previous studies 40,41, only publicly available data from the selected social media were analysed; no access to any private or protected accounts was undertaken. In line with similar studies 49,50, for each keyword selected here, the most common resulting themes were then analysed manually. Consistent with the above, and in line with previous social media-based work 36,37,38,39,40,41, we aimed to assess the possible impact of GLP-1 agonists on mental health in general as being perceived and discussed in popular open web platforms . Treatment of primary neonatal mouse cardiomyocytes with liraglutide increases cAMP formation and reduces apoptosis, as indicated by inhibition of TNFa induction of caspase 3 activity . In the isolated perfused rat heart, acute GLP-1R agonism protects from ischemia/reperfusion injury 625,626, an effect that can be blocked by pretreatment with either exendin (9–39), the cAMP inhibitor Rp-cAMP, the PI3 Kinase inhibitor LY or the MAP Kinase inhibitor UO126 . In dogs with acute myocardial infarction, infusion of GLP-1 improves cardiac performance by increasing myocardial glucose uptake and by enhancing left ventricular function . GLP-1 improvement of endothelial function, assessed by flow-mediated vasodilation, was also demonstrated during a hyperglycemic clamp in patients with T2DM and normoglycemic controls . Using well-characterized antibodies, expression was noted in the non-human primate and human sinoatrial node , which would be consistent with the effect of GLP-1 on heart rate. 4. Comparison between GLP-1 RA and insulin therapy This figure summarize evidence from randomized controlled trials and observational studies conducted in individuals with overweight or obesity, with and without diabetes. Overview of emerging therapeutic roles for glucagon-like peptide-1 receptor agonists. Additionally, the higher risk of surgical and long-term complications necessitates careful patient selection.20,21 As such, bariatric surgery is typically reserved for individuals with severe obesity (body mass index BMI ≥ 40 kg/m2 or BMI ≥ 35 kg/m2 with obesity-related comorbidities) who have not achieved sufficient weight loss with other interventions.22 In contrast, GLP-1 RAs are generally recommended for those with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 with obesity-related comorbidities. While GLP-1 RAs have demonstrated substantial efficacy in promoting weight loss, it is useful to first examine other treatment modalities in obesity management. Long-term safety concerns, particularly regarding potential risks to the thyroid and gallbladder, are still being explored.2,3 Additionally, weight regain after treatment discontinuation and reductions in lean mass have raised new clinical concerns, while issues surrounding cost and accessibility present barriers to the widespread adoption of these drugs.4, 5, 6, 7 This review explores the evolving role of GLP-1 RAs, highlighting their benefits beyond weight loss, key safety and policy considerations, and future directions for optimizing their use. In a recent meta-analysis comparing short- and long-acting GLP-1 RAs on a basal insulin background, post-prandial glucose increases were not significantly different . The effect on gastric emptying relates only to meals, before which the short-acting GLP-1 RA has been administered (once daily with lixisenatide and twice daily with exenatide b.i.d.), with minor effects at most for other meals . A comparison of the reported coefficients of variation for reducing HbA1c and body weight is displayed in panel E. Thus, the time–action profile changes between periods (lasting a few hours) during which patients are exposed to effective circulating drug concentrations, and “resting” periods, during which GLP-1 receptors are not activated. Nausea and vomiting were noticed as common side effects, mainly occurring after the initiation of injection treatment or after increasing the dose. GPR40, the other long chain FFA receptor, is also highly expressed and the most enriched GPCR in L-cells 266,293. Treatment of NCI-H716 or STC-1 cells with the Ca2+ ionophore ionomycin or with phorbol myristate acetate (PMA) increases cytosolic Ca2+ levels and stimulates GLP-1 secretion in a dose-dependent manner 251,253. The FFA-induced rise in intracellular Ca2+ is substantially reduced when cells are cultured in a Ca2+ free medium, and is abolished upon treatment of cells with the Ca2+ channel inhibitor nicardipine or when using BSA (which binds fatty acids) . GLP-1RAs in the cardiovascular system Isolated cinnamon components enhance insulin-dependent glucose metabolism, according to in vitro research . The study examined GLP-1 release from mouse STC-1 cells, a primary source of this anti-diabetic hormone, after curcumin application. The authors evaluated the effects of degradation-resistant and sensitive curcumin analogues on GLP-1 secretion. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. (However, it’s perfectly normal if your weight hasn’t dropped yet.) Energy levels should also continue to improve as your body adapts. Oral semaglutide is also available as a once daily option, and several small molecule GLP-1R agonists, exemplified by orforglipron are in late stage clinical development (Figure 1). There are currently multiple once-weekly GLP-1RAs used to treat T2D, and two, liraglutide and semaglutide, are approved for therapy of people with obesity. The reduction in fasting plasma glucose was systematically more pronounced with long-acting compounds.The AWARD-6 showed no difference in reported GI AEs between dulaglutide and liraglutide.20 The frequency of nausea in both groups peaked at week one and gradually declined thereafter.Most first-time drug users experienced mild to moderate gastrointestinal adverse effects .GLP-1 agonists are only prescribed when someone has a Body Mass Index, or BMI, of 35kg/m2 or higher, and has additional psychological or other medical conditions that are related to obesity.Taken as a whole, it appears that changes in overall patient satisfaction may be related to transitioning away from twice daily GLP-1 RA treatment to a longer dosing-interval GLP-1 RA therapy.The fact that some GLP-1 RAs have particularly weak effects with respect to body weight (e.g., albiglutide), whereas other compounds seem to have more pronounced effects (e.g., semaglutide) even if their glucose-lowering effects are similar, has sparked interest in characterizing the mechanism of action.However, as atherogenesis progresses, larger necrotic areas form, endothelial cells (EC) undergo apoptosis, and matrix metalloproteinases (MMP) proteolytically destroy the fibrous cap.Injected low-dose liraglutide and exendin-4 were also attenuated by subdiaphragmatic vagal deafferentation 687,691, but longer-term effects of these compounds on food intake did not depend on intact vagal afferents .Recent studies have raised concerns about a potential association between GLP-1 RAs and non-arteritic anterior ischemic optic neuropathy. These medications stimulate insulin secretion from the pancreas while inhibiting the release of glucagon, leading to lower blood sugar levels. GLP-1 receptor agonists mimic the action of a natural hormone called glucagon-like peptide-1, which is released in response to food intake. These medications work by stimulating insulin secretion and suppressing glucagon release, leading to improved blood sugar control. In β-cells, binding of GLP-1 to its receptor leads to activation of adenylate cyclase (AC) and subsequently to an increase in cAMP (Figure 5) . In summary, the most obvious metabolic phenotype of the global germline GLP-1R KO mice is diminished insulin secretion in response to oral glucose, and a paradoxical protection from diet-induced obesity despite impaired glycemic control. The molecular mechanism underlying the diminished insulinotropic response of the GLP-1R KO mice to orally administered glucose likely reflects loss of GLP-1R-dependent augmentation of insulin secretion. Once-weekly injections of semaglutide dose-dependently induces body weight loss of up to 7% and reduces HbA1c by 1.8% after 40 wk of treatment in T2DM patients . GLP-1 also lowers blood glucose in patients with type 1 diabetes, e.g. via its ability to slow down gastric emptying, indicating that not all of GLP-1s glycemic effects derive from its action on the β-cell or insulin action 516,517. Nevertheless, intra-islet glucagon levels are much higher than circulating levels, and studies in mice highlight the importance of glucagon, acting through the GLP-1 receptor in the control of glucose-stimulated insulin secretion 173,365. Consistent with this, adenoviral overexpression of PCSK1 in α-cells increases islet GLP-1 production and secretion, ultimately leading to enhanced glucose-stimulation of insulin secretion and improved survival of the islets . Indeed, GLP-1 RA-related “rapid” lifestyle changes due to significant/dramatic weight loss may have a positive effect on the individual. Managing type 2 diabetes, including taking medicines, maintaining a healthy lifestyle, and monitoring blood glucose levels can be stressful, and this can be a factor in the development of depression and thoughts of suicide. Some seemed to consider weight reduction as a more important goal than health effects. In the isolated perfused porcine ileum, GLP-1 secretion is inhibited by electrical nerve stimulation or by administration of norepinephrine, effects that can be blocked by co-infusion of the nonselective α-adrenergic receptor antagonist phentolamine . Together, these data suggest that M1 and M2 muscarinic receptors are implicated in human L-cell GLP-1 secretion. Receptors for acetylcholine, including the muscarinic receptors M1, M2, and M3, are expressed in rat L-cells and human NCI-H716 cells . Secretion of preproglucagon-derived peptides is stimulated in rats and in primary rat L-cell cultures upon treatment with GIP 289,323,327. Natural products may modulate GLP-1 expression and secretion, according to some data. Because of how annoying these side effects are, patients may not take their medication as prescribed . To simulate the effects of synthetic medicines, some, such as curcumin and berberine, may directly activate GLP-1 receptors . Impressively, this incretin hormone promotes fullness, inhibits GCG secretion, and increases insulin secretion. High quantities of PGC-1α mRNA and protein were seen after inhibiting miR-23a expression through cell transfection. 1. The Complex Interrelation between Weight and Overall Levels of Psychological Wellbeing By using a hybrid of outpatient treatment and controlled lab testing, researchers were able to assess measures of alcohol consumption and cravings in both settings.Collectively, these data suggest that FFAs increase intracellular Ca2+ by stimulating the influx of Ca2+ via the cell-surface (most likely L-type) Ca2+ channels .A large study published in January this year attempted to assess the scope of off-target effects of GLP-1RAs by looking at 175 different health outcomes.While such a proximal-distal loop might indeed exist, it cannot be ruled out that while fewer in number, L-cells in the upper intestine are sufficient for the rapid induction of GLP-1 secretion following nutrient intake , , .Soluble fibre forms a gel-like texture in the gut that slows digestion and glucose absorption, providing a more gradual stimulus for appetite-regulating hormones like GLP-1 and PYY.Low levels of adipocyte markers such peroxisome proliferator-activated receptor (PPARγ), TNF-receptor superfamily member 6, GLUT4, and fatty acid-binding protein 4 were observed , .In type-1 diabetic models, although liraglutide is less effective than GIP analogues in promoting osteoblast differentiation, it improves tissue material biomechanics by reducing collagen degradation . The association between WFS1 variants and impaired incretin action may result from alterations of endoplasmic reticulum homeostasis and, consequently, β-cell dysfunction . Collectively, these data suggest that the sensitivity of β-cell proliferative mechanisms to respond to GLP-1R agonism declines with increasing age . However, in juvenile but not adult human islets, exendin-4 stimulated calcineurin/NFAT signaling and enhanced expression of proliferation-promoting factors such as NFATC1, FOXM1, and CCNA1 . Using this model, exendin-4 was found to enhance β-cell proliferation in juvenile but not adult human islets . An innovative approach to assess human β-cell replication in vivo was recently established by the group of Alvin Powers . It should be mentioned, nevertheless, that when taken with insulin, it can cause hypoglycemia . These individuals lost at least 5 % of their baseline weight on a low-calorie diet for 4–12 weeks before the experiment. In the 56-week research, 422 non-diabetic patients with BMIs of 30 or 27 kg/m2 and dyslipidemia or hypertension were recruited. Patients with obesity and prediabetes can benefit from taking Liraglutide 3 mg for three years since it reduces their risk of diabetes . Those who had nausea or vomiting while using Liraglutide 3.0 mg lost 9.2 kg per year, compared to 6.3 kg for those who did not. 1. Long-acting release formulation of exenatide (EX-LAR) Activation of these GCG neurons in HFD-fed mice revealed a persistent reduction of food intake and body weight, without changes in glucose homeostasis or stress responses. Notably, GLP-1 but not GIP, is able to activate both Gq and Gs, while GIP seems only to activate Gs, suggesting a possible mechanism for the diminished insulinotropic response to GIP in diabetic β cells. Oduori and colleagues probed this anomaly in studies of mice and both murine and human islets exposed to hyperglycemia, and determined that a Gs/Gq signaling switch in β cells arises following exposure to sustained hyperglycemia (7). Exendin-4 stimulated glucose-dependent insulin secretion in both juvenile and older adult human islets. Importantly, infusion of exendin(9-39) alone increased levels of plasma glucagon under conditions of both euglycemia and hyperglycemia, and decreased levels of plasma insulin when the glucose was elevated. Most recently, Wegovy® was approved for weight loss in adults in June 2021 and adolescents ≥12 years old in December 2022 . In fact, the study also found that patients who discontinued the medication had a 30–33% increased risk of cardiac disorders compared to patients who continued to take the medication 14, 15. Although it is important to note the side effect of hypoglycemia impacts patients with diabetes on other antihypoglycemic agents, the overall risk for hypoglycemia in those without diabetes and not on antihypoglycemic medications is low. Past research also suggests that long-term use of such medications may result in more severe side effects such as hypoglycemia (low blood sugar), pancreatitis, and C-cell hyperplasia, a potential precursor to medullary thyroid carcinoma 7, 11. In fact, GLP-1 receptor agonists have been linked to improved cardiac function (i.e., decreased blood pressure and lower risk of stroke or heart attack) and kidney function . Notably, while GLP-1 can potentially affect glucagon secretion via its stimulatory effect on the β-cells in normal physiological conditions, GLP-1 also inhibits glucagon release in type 1 diabetes, thus demonstrating that GLP-1 inhibition of glucagon secretion does not fully depend on the β-cell secretome . Consistent with this role of Irs2, increased expression of Irs2 in β-cells improves insulin secretion in obese mice and protects against STZ-induced β-cell destruction (as reviewed in ). Pharmacological inhibition of GLP-1R endocytosis by dynasor attenuates cAMP formation in BRIN BD11 pancreatic β-cells and lowers PKA substrate phosphorylation, resulting in a lesser magnitude of glucose-stimulated insulin secretion . I need something to help with binge eating and food noise and to help my body know how to work correctly.Incretin action may also be reduced during hyperglycemia and in some individuals with diabetes, prediabetes and insulin resistance .In the SUSTAIN-10 trial, safety profiles were generally similar between semaglutide 1 mg and liraglutide 1.2 mg, except GI AEs were higher in the semaglutide group (43.9% versus 38.3%).23 In addition, there was a higher proportion of AEs leading to treatment discontinuation with semaglutide compared with liraglutide (11.4% versus 6.6%).In 1982, they published a paper in the Proceedings of the National Academy of Sciences (PNAS), revealing that the glucagon precursor gene actually encodes three peptides-glucagon and two new hormones expressed in the intestine.20 A year later, a research team led by Graeme Bell from Chiron Corporation published two papers in the journal Nature.21,22 They cloned and sequenced the preproglucagon gene, discovering GLP-1 and GLP-2 hormones.Parkinson's disease is another neurodegenerative disease for which GLP-1 RAs are being explored as treatment options 221,228.By leveraging the high specificity of the antibodies and employing meta-stable covalent linkages of a cytotoxic payload, this effector molecule is targeted specifically to the antigen-producing cells. Day 1: The first dose Low concentrations of glucose or methyl-α-glucopyranoside stimulate L-cell electrical activity and promote GLP-1 secretion via sodium-glucose cotransporter (SGLT1)-dependent induction of small inward currents (Figure 3) .One specific subgroup within the MAPK family, the p38 MAPK pathway, is activated by cellular stress factors and demonstrably linked to inflammatory processes.A linear regression analysis relating reductions in fasting plasma glucose to reductions in HbA1c is shown in panel D.Peak plasma concentrations may determine the time when nausea and vomiting are observed with GLP-1 RA treatment.Clinical trials show that Lixisenatide is well-tolerated and can help overweight people lose weight.Pharmacological inhibition of either PI3-Kinase or ERK blocks the stimulatory effect GLP-1 and exendin-4 on neurite outgrowth in PC12 cells . Adipocytes from BAT and iWAT indicated that GLP-1R knockdown restored WAT-derived exosomes' inhibitory influence on thermogenic gene expression and mitochondrial respiration, although miR-23b silencing had the reverse effect. UCP2 mRNA expression increased after 24 hours of GLP-1 incubation . After 24 hours of incubation with GLP-1 amide, miR-23a RNA expression decreased and PGC-1α mRNA and protein expression increased. This HepG2 cell line study tested cell viability with glucotoxicity and GLP-1. GLP-1 increased the expression of the mitochondrial protective gene (PGC-1α). Samad et al. examined how 6-Gingerol reduces hyperglycemia in Leprdb/db diabetic mice and whether it effects insulin secretion via the endocrine route. Endocrine L cells in the small intestine are the primary sites of GPR-120 expression; these cells are responsible for sensing dietary fatty acids and activating GLP-1 release. In addition, Teadenol A increased GLP-1 secretion by intestinal endocrine STC-1 cells. Authors showed that human enteroendocrine NCI-H716 cells exhibited bitter taste receptor subtype TAS2R38. Because of these effects, GLP-1RAs are a foundational treatment for diabetes and obesity. Recently, new drugs belonging to the GLP-1 receptor agonists (GLP-1 RA) class to treat metabolic diseases such as obesity and type 2 diabetes 8,9,10,11 have been made available. This prevents the liver from releasing stored glucose when it’s not needed and improves how your body responds to insulin. It works by increasing insulin levels in your body, which decreases your blood sugar (glucose). Typically, the initial effects of GLP-1 agonists on blood sugar control become apparent within the first week of treatment. Through these molecular mechanisms, GLP-1 not only plays a crucial role in the treatment of diabetes by enhancing the function and protecting pancreatic β-cells from apoptosis, but it may also offer potential therapeutic benefits in fields such as cardiovascular and neural protection.198,205,206 GLP-1 can also enhance the uptake and utilization of glucose in muscle and adipose tissues.207,208,209 And GLP-1’s action in the brain reduces appetite and may influence energy expenditure.176,210,211 These effects involve interactions with other satiety and hunger signals, such as PYY, CCK, insulin, and leptin.212,213 Various GLP-1 and GIP receptor agonist-based weight loss drugs such as Ozempic, Wegovy, Mounjaro, and Victoza are the latest blockbuster treatments for obesity and, because they lower blood glucose, type II diabetes as well. These studies collectively highlight the roles of glucagon-like peptide-1 receptor agonists in promoting weight loss and reducing appetite through central and peripheral mechanisms. These restrictions and warnings demonstrate the FDA’s stringent consideration of patient safety in the drug approval process.108 In March 2015, the FDA required a black box warning on Tanzeum due to the observed risk of thyroid C-cell tumors in animals, although it is unclear if this effect also occurs in humans.108 Later, the FDA added a warning about the risk of anaphylactic shock to the medication’s label. Liraglutide shares 97% sequence homology with human GLP-1 and can bind to and activate GLP-1R.78 The elimination half-life of liraglutide is 13 h, and only one injection per day is required.62 The second position of its N-terminus is glycine (alanine in GLP-1), which is not easily degraded by the DPP-4 enzyme.77 Compared with GLP-1, the C-terminus of its amino acid sequence contains 9 additional amino acid residues (PSSGAPPPS), which are not easily degraded by peptide chain endonucleases; thus, it has a long half-life and strong biological activity.78 The average half-life of exenatide is 2.4 h, 2 to 3 times per day.78 These side effects are often mild and tend to improve over time.72,73,74 Rare but serious side effects may include pancreatitis and allergic reactions.75 The GLP-1 RA head-to-head clinical studies have demonstrated that all GLP-1 RA agents are effective therapeutic options at reducing A1C. Deciphering the interplay between GLP-1, miRNAs, and other regulatory pathways holds immense potential for personalized medicine, tailoring treatment to individual patient needs. By elucidating how specific miRNAs influence GLP-1 receptor function, we can pave the way for even more precise therapeutic strategies. However, the true magic of GLP-1RAs lies in their multifaceted effects. Do you think GLP-1RAs have the potential to delay or perhaps reverse the onset of diabetes in the future? Some argue that GLP-1Rs are present in adipose tissue, skeletal muscle, the liver, and other tissues that insulin is thought to target . GLP-1's influence extends beyond metabolism to potential roles in brain diseases and certain cancers due to its ability to inhibit cell proliferation and promote apoptosis , . The secret of GLP-1RAs' medicinal efficacy is their complex interplay with several cellular signaling pathways. Clinical trials have consistently shown their benefits, including significant reductions in body fat and improvements in metabolic rate for obese individuals . The therapeutic potential of GLP-1 has led to the development of GLP-1RAs, which mimic its effects . Research has demonstrated that GLP-1 enhances the release of insulin in response to glucose via binding to the GLP-1R on pancreatic β cells. Reduced plasma glucose, weight loss, and immune function modulation are only a few of the many pleiotropic effects of GLP-1RAs. In addition to promoting hypoglycemic effects, they can increase the number of β cells in the pancreas, block cell death, and boost insulin production , . However, synthetically produced GLP-1 agonists are able to evade the effect of DPP-4 (as they are administered with a DPP-4 inhibitor), thereby increasing insulin production and lowering blood glucose levels over longer periods of time . In the same way, GLP-1 agonists bind to GLP-1 receptor sites and trigger the same effects even in the absence of intrinsic GLP-1 molecules. GLP-1 reduces glucose levels by stimulating insulin secretion upon glucose intake, also known as the incretin effect . These approvals are based on clinical trials showing safety and effectiveness in this age group, but treatment is typically considered after lifestyle interventions haven’t worked.GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability.Receptors for acetylcholine, including the muscarinic receptors M1, M2, and M3, are expressed in rat L-cells and human NCI-H716 cells .When chronically fed a high-fat diet (HFD), GLP-1R KO mice are paradoxically leaner than their wild-type controls yet are more glucose intolerant .They highlighted the need to consider potential tradeoffs between efficacy and side effects, finding that higher doses can have stronger efficacy but also induce more severe side effects.As depicted in Figure 5, not only HbA1c was lowered significantly more and HbA1c targets were achieved in a higher proportion of patients, but also fasting plasma glucose concentrations and body weight were controlled better with long-acting GLP-1 RAs .A comprehensive review of all head-to-head data indicates that subcutaneous semaglutide appears to offer the best A1C and weight reduction but also has higher rates of GI AEs. While many have popularized both Wegovy® and Ozempic®, fewer have discussed Rybelsus® and other GLP-1 agonists. Furthermore, there are very tangible side effects including hypoglycemia, gastrointestinal effects, cardiovascular risks, and drug interactions . Many have voiced concerns about the availability and continuity of care interruptions inevitable for individuals with diabetes as Ozempic® continues to see growing demand. Wegovy® intended utilization is for adults with obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 27 kg/m2) who also have additional weight-related problems and adolescents with an initial BMI at or above the 95th percentile for age and sex . Indeed, the prescription weight-loss drug market grew 72% more than initially forecasted in 2023, ballooning to a 2.3 billion dollar industry . Accordingly, as described in recent review articles 4,574, GLP-1 stimulates both the δ-cells to secrete somatostatin and the β-cells to secrete insulin, amylin, zinc, and GABA, all of which suppress the release of glucagon. In intact murine islets, blockade of N-type Ca2+ channels with ω-conotoxin, but not L-type Ca2+ channels using nifedipine, abolishes low glucose (1 mM) stimulation of glucagon secretion and blunts the GLP-1-mediated inhibitor effects. Diminished insulin secretion in response to treatment with GLP-1 has been replicated in other studies , , . Notably, the age-dependent decline in the exendin-4 induced β-cell proliferation was not related to changes of GLP-1R expression, as also indicated by preservation of exendin-4-induced insulin secretion in the adult islets . Solid clinical proof of slowed diabetes progression or enhanced β-cell mass has not been provided in type-2 diabetic patients treated with any GLP-1 receptor agonist . Randomised controlled trials have shown that high-fibre, oat-based meals can increase GLP-1 and PYY levels, enhance fullness, and reduce subsequent energy intake compared with low-fibre cereals. Soluble fibre forms a gel-like texture in the gut that slows digestion and glucose absorption, providing a more gradual stimulus for appetite-regulating hormones like GLP-1 and PYY. Evidence suggests that nut-based snacks can enhance satiety and modulate appetite-regulating hormones, including GLP-1, compared with refined-carbohydrate options. These effects are thought to involve appetite-regulating hormones such as GLP-1 and peptide YY (PYY), which play a role in signalling fullness. This hormone is not readily degraded by DPP-4 to GLP-1 in the human body and can act for 12 h or longer.25 Its extensive distribution and involvement in diverse physiological processes emphasize the important role of GLP-1R beyond the regulation of glucose metabolism.38,39,40 The phenotype observed after GLP-1R knockout (KO) includes various physiological and metabolic changes. GLP-1RAs are artificial protein formulations that exhibit partial or complete amino acid sequence similarity to endogenous GLP-1 within the human body. Eli Lilly and Company is currently researching a dual agonist called tirzepatide, which has outperformed semaglutide in phase 3 clinical trials. The journey began in the 1980s with research on Gila monster venom, culminating in the discovery of exendin-4, a stable, effective peptide for treating diabetes, demonstrating the progression from initial discovery to blockbuster diabetes medications. These agonists aim to maximize metabolic benefits and minimize side effects. Recent clinical trials for T2D and obesity have utilized multi-targeting GIP receptor (GIPR), GLP-1R, or GCG receptor (GCGR) agonists. Gastric inhibitory polypeptide (GIP) is produced by intestinal endocrine K cells. A non-inferiority RCT compared 295 T2D patients using 2 mg of EX-LAR weekly with 10 µg of Exenatide twice daily for 30 weeks. In HG medium, human embryonic lung fibroblast (MRC-5) cells were treated with miR-27a, GLP-1, and AMPK inhibitors. GLP-1 increases miR-132 and miR-212 synthesis in pancreatic β-cells via a cAMP and PKA-dependent pathway. Previous research has shown that miR-204 inhibits the production of GLP-1RA in β-cells derived from rats, primary mice, and human islets by directly targeting its 3′ UTR. They confirmed that GLP-1 could control miR-7 and βARR1 transcription, and that miR-7 played a substantial role in β cell cAMP synthesis and GLP-1-induced insulin release. GPCRs with genetic associations to Alzheimer’s disease traits: an underdeveloped target class for disease progression It’s about listening to your body, learning what works, and building the foundation for long-term success. It’s your body’s “meet and greet” with the med. In mice, a GLP-1/dexamethasone conjugate circumvented action in the liver and skeletal system to avoid the deleterious effects on glycemic control and bone turnover, respectively, that is evident with systemic dexamethasone action . Estrogen has pleotropic, beneficial effects on metabolism yet the reproductive endocrine toxicity and tumorigenic potential limits its use in chronic settings other than hormone replacement therapy. In rodents, these effects are restricted to earlier periods in life when β cells have a propensity to proliferate, which they lose in adult animals . Whether or not GLP-1 RA treatment counters this progression (e.g., through β cell-preserving effects ) remains an open question. Another potential reason contributing to withdrawals was a perception of ineffective glycemic and body weight control achieved (including a suspicion to have been randomized to placebo), perhaps as a consequence of the progression of the type 2 diabetes mellitus disease process . A recent real-world retrospective observational study showed that dulaglutide users were less likely to interrupt treatment than semaglutide and exenatide BCise users . Insulin stimulates intestinal Gcg expression while at the same time inhibiting Gcg expression in α-cells 89,137,138. Overexpression of Pdx1 alone is insufficient to block Gcg expression in α-cell cultures (αTC-1 cells), isolated murine islets, or GLUTag enteroendocrine cells . While substantial evidence supports a role of Pdx1 in the negative regulation of Gcg expression, Pdx1 immunoreactivity has also been demonstrated in some Gcg expressing L-cells . In STC-1 cells, disruption of the CRE element in the Gcg enhancer only partially blunts PKA-stimulation of Gcg expression 130,131. In both α-cells and intestinal L-cells, Gcg expression is controlled by certain homeodomain proteins 94,98,100 and by cAMP-activation of protein kinase A (PKA), as demonstrated in primary rat intestinal cultures , isolated pancreatic cell lines 127,128 and enteroendocrine GLUTag and STC-1 cell lines 129,130. Efficacy As a result, activating GLP-1R could be a treatment option for prostate cancer. One of four subjects showed in vivo GLP-1R expression by human metastatic castration-resistant prostate cancer (mCRPC), avid for prostate specific membrane antigen (PSMA) and Ex-4, according to Stein et al. It is important to keep an eye on how GLP-1 mimic medicines fare in the long run and look into GLP-1R as a potential molecular target for advanced PDAC diagnostics and treatment . The study found an elevated incidence of all TC among 2562 case patients with thyroid tumors and 45,184 control subjects . But the real buzz around these drugs grew as it became clear they could also be used as weight loss medications.While PCSK2 is the predominant prohormone convertase in α-cells in non-pathological conditions, α-cell PCSK1 immunoreactivity increases in rodent models of metabolic stress.In healthy and type-2 diabetic humans, it has been consistently demonstrated, that GIP, even in rather high (supraphysiological) doses, does not lead to GLP-1 secretion , , .From week 20 to week 68, participants who discontinued the drug regained an average of 6.9% of their baseline body weight, while those who continued treatment lost an additional 7.9%.6 These findings suggest ongoing treatment with GLP-1 RAs is required to maintain improvements in weight and health, highlighting the chronicity of obesity.Double incretin receptor knock-out (DIRKO) animals revealed that the GLP-1/GLP-1R pathway was important for the integrity of cortical but not trabecular bone .However, this inhibitory effect is significantly weakened in patients with T2DM, indicating that its potential application in diabetes treatment requires further investigation.241 Through this series of complex molecular and cellular mechanisms, GLP-1 plays a vital role in the physiological and pathological processes of metabolic diseases like T2DM.232,233,241,259 (Fig. 2).In the cardiovascular system, GLP-1 can reduce cardiac ischemia-reperfusion injury through the activation of specific signaling pathways, such as the PI3K/Akt pathway.437,438 This involves modulating the cell apoptosis process, for example, by decreasing the Bax/Bcl-2 ratio in cardiomyocytes, reducing cytochrome C release, and caspase activation.438,439 GLP-1 can also enhance endothelial function by promoting the production of NO, possibly through activating eNOS, thereby affecting vasodilation, anti-inflammatory actions, and anti-atherosclerosis.43,192,440,441Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). Daily doses up to 3.0 mg are approved for liraglutide (1.8 mg is the maximum dose for treating type 2 diabetes) , and clinical trials have tested semaglutide at up to 0.4 mg per day (that is, corresponding to 2.8 vs 1.0 mg per week for type 2 diabetes) . (A) Evidence also suggests that GLP-1 receptors in the hepatoportal region (B) and on afferent parasympathetic nerve endings in the intestinal mucosa (C) may generate central nervous system signals influencing insulin secretion and metabolism. The quantitative differences in body weight reduction typically achieved with different GLP-1 RAs critically depend on the respective doses selected in phase 2 studies. Most other glucose-lowering agents, except for sodium/glucose cotransporter-2 (SGLT-2) inhibitors, usually lead to some weight gain (sulfonylureas, insulin, or thiazolidinediones) or are weight neutral (metformin, DPP-4 inhibitors, or α-glucosidase inhibitors) . While such ligand-induced receptor internalization has been demonstrated for many GPCRs (including GLP-1R), its importance for receptor deactivation is controversial and is potentially receptor specific. Desensitization of GPCRs is generally achieved by two families of serine/threonine kinases, the second-messenger-dependent protein kinases and the receptor-specific G protein-coupled receptor kinases (GRKs) 436,437. At some point, the ligand-induced receptor activation has to be terminated, and the sensitivity of the receptor to be activated by its ligand has to be restored. Upon ligand binding, GPCRs located on the cell surface transduce the extracellular signal to the interior of the cell. GLP-1 RAs that are usually injected once daily (liraglutide or lixisenatide) were combined with basal insulin designed for once-daily injection (insulin degludec or insulin glargine), resulting in the fixed-dose combinations iDegLira 28,59 and iGlarLixi 60,61. When a GLP-1 RA is added to (basal) insulin, the combination is as effective as an intensified (basal bolus) insulin regime in terms of HbA1c control, but with a much lower risk of hypoglycemia and weight gain . It should only be used in patients needing a combination of two injectable treatments, especially considering the costs of such a combination. Treatment intensification can mean adding one to three prandial insulin injections per day or adding a GLP-1 RA to ongoing insulin treatment. Therapy with basal insulin may fail because it may be successful in controlling fasting plasma glucose but does not sufficiently limit post-prandial glycemic excursions. In clinical trials, exenatide improved the MDS-UPDRS score (a standardized assessment scale for patients with Parkinson's disease) 230,231. A larger clinical trial is currently ongoing that is investigating the effects of liraglutide on mild Alzheimer's disease using comprehensive neurological and cognitive assessment . In another trial with non-diabetes subjects at increased risk of Alzheimer's disease, administration of liraglutide for 3 months improved brain region connectivity (assessed by functional MRI), but cognitive functions did not improve . In Alzheimer's disease, the most prevalent form of dementia, animal studies have shown the positive effects of GLP-1 RAs on cognitive impairment 222,223. Parkinson's disease is another neurodegenerative disease for which GLP-1 RAs are being explored as treatment options 221,228. Furthermore, patients not responding to GLP-1 RAs as expected, either when initially exposed to GLP-1 RAs (primary non-responders) or after a satisfactory response period (secondary non-responders), have often been observed in clinical practice. Given the potential of selecting patients with a predicted greater clinical effectiveness , the issue of pharmacogenomics regarding GLP-1 RA still appears to be an under-studied research area. Real-world studies analyzing existing databases documenting medication use and clinical outcomes may help in this respect, but no such analysis seems to be currently available. However, in obese, non-diabetic patients under anti-psychotic drugs, exenatide failed to modify significantly the pattern of bone remodeling .Clinical studies using Exenatide for T2D are more common than those for obesity.It is important to keep an eye on how GLP-1 mimic medicines fare in the long run and look into GLP-1R as a potential molecular target for advanced PDAC diagnostics and treatment .Through a review of phase III clinical trials for exenatide twice daily, lixisenatide, liraglutide, exenatide once weekly, dulaglutide, semaglutide, and oral semaglutide, we identified 14 head-to-head trials that evaluated the safety and efficacy of GLP-1 RA active comparators.13–26 Of the 13 trials, 7 were included in our original publication; 1 trial (HARMONY-7)27 in our original publication that compared albiglutide with liraglutide was removed.4 A summary of the design and baseline characteristics of the head-to-head studies is provided in Table 2.Overexpression of Pdx1 alone is insufficient to block Gcg expression in α-cell cultures (αTC-1 cells), isolated murine islets, or GLUTag enteroendocrine cells .In the isolated perfused porcine ileum, GLP-1 secretion is inhibited by electrical nerve stimulation or by administration of norepinephrine, effects that can be blocked by co-infusion of the nonselective α-adrenergic receptor antagonist phentolamine .It was found that semaglutide, a long-acting GLP-1RA, could improve symptoms caused by sepsis, reduce body temperature, and decrease the bacterial load in multiple organs, along with the levels of inflammatory factors in plasma and lungs.423 These findings further confirmed the central role of the CNS in regulating the anti-inflammatory effects of GLP-1RAs, highlighting the potential application of GLP-1RAs in anti-inflammatory treatment.In contrast to GLP-2 administration, subcutaneous injection of GLP-1 in healthy individuals had no effects on bone formation or resorption markers . Lixisenatide was developed by Sanofi to treat T2DM.64,93 Structurally, lixisenatide is based on the exenatide structure but lacks proline at position 38, and six lysines are linked after serine at position 39.94 The six lysine residues increase the rigidity of the molecule’s structure, thus allowing its drug properties to be improved.78 These changes stabilize its structure, prevent protein degradation of the molecule in the circulation, and increase the circulation time enough to ensure once-daily injection (compared with exenatide, which is injected two or three times daily). The Gila monster, which lives in the deserts of the Americas, can eat up to half its own body weight in one sitting, but its blood sugar remains stable, and its metabolic system runs smoothly despite this large amount of food.52,53 In 1992, Dr. John Enn discovered an exopeptide in the saliva of the Gila monster which he named exendin-4. It predominantly localizes to the cellular membrane of diverse cell types throughout the human body.37 Indeed, GLP-1R is present beyond the confines of the pancreas and extends to a multitude of organs and tissues throughout the body. It is synthesized in L-cells located in the intestinal mucosa, α-cells found in the pancreatic islet, and neurons residing in the nucleus of the solitary tract.29 GLP-1, an endocrine hormone, is secreted by enteroendocrine L-cells located in the distal jejunum, ileum, and colon in response to nutrient ingestion and neuroendocrine stimulation. This graph underscores the expanding research and clinical importance of GLP-1-related therapies in the treatment of diabetes. Lastly, upon streptozotocin-induced destruction of the β-cells, there is an acute increase in islet PCSK1 and Gcg expression and increased processing of proglucagon to GLP-1 . In contrast, PC2 (a.k.a. PCSK2) is highly expressed in the pancreas , and its expression in α-cells results in cleavage of Gcg into “pancreatic type” glucagon, GRPP, MPGF, and a small intervening peptide (IP1). While the mechanism underlying insulin inhibition of pancreatic glucagon production warrants further clarification, it is thought to be achieved by through transcriptional mechanisms via an insulin-responsive element (IRE) in the Gcg promoter of the α-cells . Interestingly, β-cell specific deletion of Foxa2 also results in postnatal death due to severe hypoglycemia, but the low glucose level in Foxa2-negative mice seems to be caused by hyperinsulinemia rather than by changes in Gcg expression . Pax6 can also bind to the G3 element , and it plays a key role in regulating Gcg expression and α-cell development, because mice lacking Pax6 fail to produce glucagon-producing α-cells . In addition to establishing efficacy, ensuring that access is safe, equitable and appropriately regulated is essential for lining up the series of GLP-1RA-based mental health treatments yet to come. The findings demonstrate that the administration of escalating doses of semaglutide led to reduced self-administration of alcohol, lower alcohol cravings and a reduced number of cigarettes per day among smokers. By using a hybrid of outpatient treatment and controlled lab testing, researchers were able to assess measures of alcohol consumption and cravings in both settings. The authors, however, recommend that careful safety and adverse event reporting and continued regulatory agency oversight are crucial, in line with increasing GLP-1RA prescriptions and clinical studies. The authors carefully describe the key insights of individual studies, in addition to including meta-analyses in which randomized controlled trials for specific GLP-1RA interventions have been performed, providing a useful reference work for readers. GLP-1 medicines for weight loss and diabetes: what you need to know Table 3 summarizes recent insights gained from comprehensive studies characterizing semaglutide's (and liraglutide) effects on diet-induced obesity in rodents 72,73. Semaglutide, the GLP-1 RA with the highest efficacy regarding weight loss in clinical trials of type 2 diabetes patients (Figure 4), is also undergoing evaluation as a weight-loss agent in obese subjects without diabetes mellitus , , . As depicted in Figure 5, not only HbA1c was lowered significantly more and HbA1c targets were achieved in a higher proportion of patients, but also fasting plasma glucose concentrations and body weight were controlled better with long-acting GLP-1 RAs . The fact that a combination of a GLP-1 RA with basal insulin is a highly efficacious glucose-lowering treatment regime for advanced stages of type 2 diabetes has led to the development of fixed-dose combinations. In studies comparing basal insulin and GLP-1 RAs alone and in combination with each other, the combination achieved the lowest HbA1c or highest HbA1c reduction and a body weight transformation in between GLP-1 RA alone (lowest) and insulin alone (highest) . These factors can impact not only the rate but also the extent of weight loss achieved through GLP-1 agonist therapy. Research suggests that consistent engagement with healthcare professionals for support can further enhance adherence rates and overall success in maintaining weight loss. Maintaining a balanced diet, engaging in regular physical activity, and monitoring caloric intake are essential components for sustaining weight loss achieved through GLP-1 agonist therapy. Many people embarking on a weight management GLP-1 (Glucagon-like peptide-1) agonists often experience a mix of anticipation and frustration. "I like to think about weight loss kind of like the stock market where you're looking at the overall trend," Dr. Meghan explains. The GIP component is hypothesized to provide an additional mechanism to buffer against the hyperglycemic effects of glucagon , thus permitting triple agonists of higher potency at the glucagon receptor that in theory could drive more body weight loss. Chronic co-administration of selective mono-agonists to obese non-human primates resulted in significantly more body weight loss when compared to the individual treatments, thus demonstrating the translation of these acute effects observed in humans and the chronic effects observed in primates . Most studies report the absence , , or very restricted expression of the GLP-1 receptor in a small subset (10%) of α-cells , and treatment of isolated rat α-cells with GLP-1 enhances rather than inhibits the release of glucagon , , . In α-cells, insulin further enhances translocation of GABA-A receptors , and GABA released from β-cells enhances glucose inhibition of glucagon secretion .