# The Multifaceted Nature of GLP-1: Molecular Mechanisms and Signaling Pathways in Metabolic and Neurodegenerative Diseases **Authors:** Małgorzata Katarzyna Kowalska, Ahmed El-Mallul, Weronika Hudecka, Joanna Elżbieta Lubojańska, Piotr Jan Lubojański, Sara Małgorzata Orłowska, Łukasz Bednarczyk PMC · DOI: 10.3390/ijms27041886 · International Journal of Molecular Sciences · 2026-02-15 ## TL;DR This paper reviews how GLP-1 agonists help treat diabetes, obesity, and possibly neurodegenerative diseases by affecting metabolic and molecular pathways. ## Contribution The paper synthesizes evidence on GLP-1 agonists' mechanisms and effectiveness across multiple diseases, highlighting their potential beyond metabolic disorders. ## Key findings - GLP-1 agonists improve glycemic control, weight loss, and metabolic parameters in clinical trials. - They show neuroprotective effects and positive cardiovascular impacts. - Further research is needed to explore new clinical applications of GLP-1 agonists. ## Abstract The aim of this article is to present the current state of knowledge regarding the use of GLP-1 agonists in the treatment of type 2 diabetes, obesity, and other potential clinical indications, including neurodegenerative conditions. The article describes the characteristics of the diseases discussed, with particular emphasis on the pathophysiological mechanisms and the impact of metabolic disorders on the course of the diseases. In addition, the specific role of GLP-1 receptor agonists and their mechanisms of action leading to improved clinical outcomes were discussed, including their impact on molecular pathways involved in glucose metabolism regulation, inflammatory processes, carcinogenesis, and neuroprotection. Based on meta-analyses of available clinical trials, the evidence supporting the effectiveness of GLP-1 agonist therapy in glycemic control, weight loss, and improvement of metabolic parameters was synthesized. Additionally, potential benefits beyond the metabolic system are discussed, including neuroprotective effects and impact on patients’ cardiovascular profiles, as well as risks and adverse effects associated with the use of GLP-1 agonists. The collected data indicate the growing role of GLP-1 agonists as an innovative and effective therapeutic strategy, while emphasizing the need for further research in the context of new clinical indications. ## Linked entities - **Proteins:** GCG (glucagon) - **Diseases:** type 2 diabetes (MONDO:0005148), obesity (MONDO:0011122) ## Full-text entities - **Genes:** RAPGEF4 (Rap guanine nucleotide exchange factor 4) [NCBI Gene 11069] {aka CAMP-GEFII, CGEF2, EPAC, EPAC 2, EPAC2, Nbla00496}, SCT (secretin) [NCBI Gene 6343], GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, MMP13 (matrix metallopeptidase 13) [NCBI Gene 4322] {aka CLG3, MANDP1, MDST, MMP-13}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, Gcg (glucagon) [NCBI Gene 24952] {aka GLP-1, Glp1, Glp2}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, SNAR-E (small NF90 (ILF3) associated RNA E) [NCBI Gene 100170220], PYCARD (PYD and CARD domain containing) [NCBI Gene 29108] {aka ASC, CARD5, TMS, TMS-1, TMS1}, CREB1 (cAMP responsive element binding protein 1) [NCBI Gene 1385] {aka CREB, CREB-1}, PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, ALB (albumin) [NCBI Gene 213] {aka FDAHT, HSA, PRO0883, PRO0903, PRO1341}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, ABCC8 (ATP binding cassette subfamily C member 8) [NCBI Gene 6833] {aka ABC36, HHF1, HI, HRINS, MODY12, MRP8}, Sst (somatostatin) [NCBI Gene 20604] {aka SOM, SRIF, SS, Smst}, KCNJ11 (potassium inwardly rectifying channel subfamily J member 11) [NCBI Gene 3767] {aka BIR, HHF2, IKATP, KIR6.2, MODY13, PHHI}, SNAP25 (synaptosome associated protein 25) [NCBI Gene 6616] {aka CMS18, DEE117, RIC-4, RIC4, SEC9, SNAP}, NPY (neuropeptide Y) [NCBI Gene 4852] {aka PYY4}, CASP1 (caspase 1) [NCBI Gene 834] {aka ICE, IL1BC, P45}, GCGR (glucagon receptor) [NCBI Gene 2642] {aka GGR, GL-R, MVAH}, CITED2 (Cbp/p300 interacting transactivator with ED-rich tail 2) [NCBI Gene 10370] {aka ASD8, MRG-1, MRG1, P35SRJ, VSD2}, DPP4 (dipeptidyl peptidase 4) [NCBI Gene 1803] {aka ADABP, ADCP2, CD26, DPPIV, TP103}, MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314] {aka CHDS6, MMP-3, SL-1, STMY, STMY1, STR1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, RYR2 (ryanodine receptor 2) [NCBI Gene 6262] {aka ARVC2, ARVD2, RYR-2, RyR, VACRDS, VTSIP}, Ucp1 (uncoupling protein 1) [NCBI Gene 24860] {aka Ucp, Ucpa, Uncp}, CACNA1C (calcium voltage-gated channel subunit alpha1 C) [NCBI Gene 775] {aka CACH2, CACN2, CACNA1C-IT2, CACNL1A1, CCHL1A1, CaV1.2}, Il1b (interleukin 1 beta) [NCBI Gene 24494] {aka IL-1F2}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, OCLN (occludin) [NCBI Gene 100506658] {aka BLCPMG, PPP1R115, PTORCH1}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, AGRP (agouti related neuropeptide) [NCBI Gene 181] {aka AGRT, ART, ASIP2}, HNF1A (HNF1 homeobox A) [NCBI Gene 6927] {aka HNF-1-alpha, HNF-1A, HNF1, HNF1alpha, IDDM20, LFB1}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, SNAPIN (SNAP associated protein) [NCBI Gene 23557] {aka BLOC1S7, BLOS7, BORCS3, NEDBAC, SNAPAP}, IL23A (interleukin 23 subunit alpha) [NCBI Gene 51561] {aka IL-23, IL-23A, IL23P19, P19, SGRF}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, CARTPT (CART prepropeptide) [NCBI Gene 9607] {aka CART}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, CRP (C-reactive protein) [NCBI Gene 1401] {aka PTX1}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, GIP (gastric inhibitory polypeptide) [NCBI Gene 2695], LEP (leptin) [NCBI Gene 3952] {aka LEPD, OB, OBS}, RIMS2 (regulating synaptic membrane exocytosis 2) [NCBI Gene 9699] {aka CRSDS, OBOE, RAB3IP3, RIM2}, ADIPOQ (adiponectin, C1Q and collagen domain containing) [NCBI Gene 9370] {aka ACDC, ACRP30, ADIPQTL1, ADPN, APM-1, APM1}, TJP1 (tight junction protein 1) [NCBI Gene 7082] {aka ZO-1}, RAP1A (RAP1A, member of RAS oncogene family) [NCBI Gene 5906] {aka C21KG, G-22K, KREV-1, KREV1, RAP1, SMGP21}, Cck (cholecystokinin) [NCBI Gene 12424], LEPR (leptin receptor) [NCBI Gene 3953] {aka CD295, LEP-R, LEPRD, OB-R, OBR, huB219}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, CDKN1A (cyclin dependent kinase inhibitor 1A) [NCBI Gene 1026] {aka CAP20, CDKN1, CIP1, MDA-6, P21, SDI1}, CACNA1D (calcium voltage-gated channel subunit alpha1 D) [NCBI Gene 776] {aka CACH3, CACN4, CACNL1A2, CCHL1A2, Cav1.3, PASNA}, Ghrl (ghrelin) [NCBI Gene 58991] {aka 2210006E23Rik, Ghr, MTLRP, MTLRPAP, m46} - **Diseases:** vascular damage (MESH:D057772), gastrointestinal side effects (MESH:D064420), Binge Eating (MESH:D002032), inflammatory joint diseases (MESH:D007592), Prediabetes (MESH:D011236), abdominal pain (MESH:D015746), weight loss (MESH:D015431), chronic kidney disease (MESH:D051436), swelling (MESH:D004487), pancreatitis (MESH:D010195), neuroinflammation (MESH:D000090862), glucose metabolism disorders (MESH:D044882), insulin deficiency (MESH:D007333), cocaine addiction (MESH:D019970), AD (MESH:D000544), impaired (MESH:D060825), heart attack (MESH:D009203), agitation (MESH:D011595), renal failure (MESH:D051437), Crohn's disease (MESH:D003424), mental disorders (MESH:D001523), EAE (MESH:D004679), addiction (MESH:D019966), hypoglycemia (MESH:D007003), Gastrointestinal adverse events (MESH:D002318), neurotoxic (MESH:D020258), CKD (MESH:D012080), NASH (MESH:D065626), gastrointestinal (MESH:D005767), Diabetes (MESH:D003920), ischemic (MESH:D002545), Huntington's disease (MESH:D006816), end-stage renal failure (MESH:D007676), gallstones (MESH:D042882), colitis (MESH:D003092), OAC (MESH:D009369), hypertension (MESH:D006973), endometrial, ovarian, and meningioma cancers (MESH:D008579), thyroid cell hyperplasia (MESH:D013968), pain (MESH:D010146), Thyroid cancer (MESH:D013964), demyelination (MESH:D003711), endometrial cancer (MESH:D016889), death (MESH:D003643), dyslipidemia (MESH:D050171), carcinogenic (MESH:D011230), PD (MESH:D010300), AUD (MESH:D000437), CRC (MESH:D015179), mitochondrial dysfunction (MESH:D028361), growth retardation (MESH:D006130), skin lesions (MESH:D012871), atherosclerosis (MESH:D050197), injury to (MESH:D014947), neoplastic disease (MESH:D004194), Neurodegenerative Diseases (MESH:D019636), Nerve cell dysfunction (MESH:D005155), headaches (MESH:D006261), inflammation (MESH:D007249), gastrointestinal symptoms (MESH:D012817) - **Chemicals:** triglyceride (MESH:D014280), bupropion (MESH:D016642), corticosterone (MESH:D003345), naltrexone (MESH:D009271), Efpeglenatide (MESH:C000709212), nicotine (MESH:D009538), carbohydrate (MESH:D002241), beinaglutide (MESH:C061970), amino acid (MESH:D000596), degludec (MESH:C571886), sodium (MESH:D012964), orlistat (MESH:D000077403), Lixisenatide (MESH:C479460), CA-exendin-4 (-), fat (MESH:D005223), disulfiram (MESH:D004221), glycolic acid (MESH:C031149), glucose (MESH:D005947), serotonin (MESH:D012701), cholesterol (MESH:D002784), glycine (MESH:D005998), blood glucose (MESH:D001786), lisdexamfetamine (MESH:D000069478), cAMP (MESH:D000242), calcium (MESH:D002118), ROS (MESH:D017382), GABA (MESH:D005680), acamprosate (MESH:D000077443), Dopamine (MESH:D004298), alcohol (MESH:D000438), topiramate (MESH:D000077236), mazdutide (MESH:C000719829), palmitic acid (MESH:D019308), Exenatide (MESH:D000077270), lipid (MESH:D008055), glycogen (MESH:D006003), beta-carotene (MESH:D019207), acetylcholine (MESH:D000109), pioglitazone (MESH:D000077205), Cotadutide (MESH:C000624433), taspoglutide (MESH:C541736), ATP (MESH:D000255), phentermine (MESH:D010645), sodium dextran sulfate (MESH:D016264), metformin (MESH:D008687) - **Species:** Canis lupus familiaris (dog, subspecies) [taxon 9615], Homo sapiens (human, species) [taxon 9606], Alistipes (genus) [taxon 239759], Rattus norvegicus (brown rat, species) [taxon 10116], Bacteroides (genus) [taxon 816], Mus musculus (house mouse, species) [taxon 10090], Akkermansia muciniphila (species) [taxon 239935] - **Mutations:** alanine residue in position 2, lysine at position 26 ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12941302/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12941302/full.md ## References 144 references — full list in the complete paper: https://tomesphere.com/paper/PMC12941302/full.md --- Source: https://tomesphere.com/paper/PMC12941302