Endogenous Incretin Insufficiency in Obesity: Etiological Defect or Metabolic Maladaptation?

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Luís Jesuíno de Oliveira Andrade, Gabriela Correia Matos de Oliveira, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9453154/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Obesity is associated with measurably attenuated postprandial incretin responses, characterized by blunted glucagon-like peptide-1 (GLP-1) secretion and functional resistance to glucose-dependent insulinotropic polypeptide (GIP) signaling. Whether this enteroendocrine dysregulation represents a primary pathophysiological defect anteceding adiposity or a secondary maladaptive consequence of chronic metabolic overload remains unresolved, with substantial implications for the conceptualization and treatment of obesity. Objective: To critically evaluate and synthesize the available evidence regarding endogenous incretin insufficiency in obesity, determining whether this phenomenon constitutes a primary etiological defect or a state-dependent metabolic adaptation. Methods: A structured narrative review was conducted across PubMed/MEDLINE, Embase, Scopus, and Web of Science. Eligible studies encompassed human clinical trials, mechanistic investigations, and translational experimental models addressing endogenous incretin physiology, obesity-associated hormonal dysregulation, and incretin-based pharmacotherapy outcomes. Results: Evidence consistently demonstrates stimulus-dependent impairment of GLP-1 secretion and functional GIP resistance, both partially reversible following weight loss. Pharmacological amplification via GLP-1 receptor agonists, dual incretin agonists, and amylin-based therapies yields robust efficacy, indicating biologically intact but functionally downregulated signaling pathways. A multi-hormonal insufficiency model, rather than isolated incretin deficiency, best accounts for the observed phenotype. Conclusion: Endogenous incretin insufficiency in obesity reflects a state-dependent, adaptive dysregulation of a biologically intact enteroendocrine system, driven by chronic metabolic stress, rather than a primary etiological defect. Therapeutic strategies should prioritize restoration of integrated satiety signaling over isolated hormonal replacement. Endocrinology & Metabolism Enteroendocrine dysfunction GLP-1 secretion Incretin resistance Metabolic maladaptation Figures Figure 1 INTRODUCTION Obesity represents one of the most pressing public health challenges of the twenty-first century, affecting over one billion individuals worldwide and contributing disproportionately to the global burden of type 2 diabetes, cardiovascular disease, and all-cause mortality [ 1 ]. Despite decades of intensive investigation, the precise endocrine mechanisms that predispose certain individuals to pathological adiposity while others maintain metabolic homeostasis under comparable environmental conditions remain incompletely understood. Among the hormonal systems implicated in energy balance regulation, the enteroendocrine axis has attracted growing scientific interest, particularly given its central role in coordinating postprandial satiety signaling, insulin secretion, and gastrointestinal motility [ 2 ]. The gut, far from being a passive digestive organ, functions as the largest endocrine gland in the human body, capable of synthesizing and releasing a diverse repertoire of peptide hormones in response to nutrient stimuli [ 3 ]. Central to this enteroendocrine framework are the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which together account for a substantial proportion of postprandial insulin release, a phenomenon collectively termed the incretin effect [ 4 ]. In lean, metabolically healthy individuals, these hormones are secreted in a tightly regulated, physiologically appropriate manner, orchestrating a coordinated anorexigenic response that limits excessive caloric intake [ 5 , 6 ]. However, accumulating evidence suggests that obese individuals exhibit a measurably blunted incretin response, characterized by reduced postprandial GLP-1 secretion and attenuated GIP signaling, raising a fundamental and still unresolved question: does this hormonal insufficiency represent a primary etiological defect that antecedes and promotes adiposity, or does it emerge secondarily as a maladaptive consequence of the chronic metabolic and inflammatory milieu inherent to established obesity? Resolving this question carries profound therapeutic implications that extend well beyond academic interest. The current pharmacological landscape of obesity management has been substantially shaped by incretin-based therapies, including GLP-1 receptor agonists, which exogenously compensate for diminished endogenous secretion [ 7 ]. While clinically effective, these agents address hormonal insufficiency through exogenous supplementation rather than restoration of intrinsic enteroendocrine function, a distinction that may be critically relevant to long-term metabolic outcomes and treatment sustainability. The underlying question of whether the enteroendocrine system is fundamentally impaired in obesity, and whether such impairment is reversible, has not been systematically addressed in the literature [ 8 ]. The present review aims to critically examine and synthesize the available evidence regarding endogenous incretin insufficiency in obesity, with the specific objective of determining whether this phenomenon constitutes a primary pathophysiological defect or a secondary metabolic adaptation. By interrogating data from mechanistic, epidemiological, and interventional studies, we seek to reframe the conceptual understanding of gut hormone dysregulation in obesity and to identify actionable targets for therapies directed at restoring, rather than merely replacing, physiological enteroendocrine function. METHODS Study Design Given the conceptual and mechanistic complexity of this question, a structured narrative approach was selected to enable integrative interpretation across heterogeneous lines of evidence, including clinical, experimental, and translational studies. Search Strategy A comprehensive literature search was performed using PubMed/MEDLINE, Embase, Scopus, and Web of Science from database inception through the most recent available records. Search terms combined controlled vocabulary and free-text keywords related to obesity and incretin biology, including: “obesity,” “GLP-1,” “glucagon-like peptide-1,” “GIP,” “glucose-dependent insulinotropic polypeptide,” “incretin effect,” “endogenous secretion,” “enteroendocrine function,” “gut hormones,” and “metabolic adaptation.” Boolean operators were applied to optimize sensitivity and specificity. To enhance completeness, reference lists of relevant articles were manually screened to identify additional studies not captured in the primary search. Study Selection Studies were selected based on their relevance to endogenous incretin physiology and its relationship with obesity and metabolic regulation. Eligible studies met the following criteria: investigation of endogenous incretin secretion, signaling, or physiological response; inclusion of populations with obesity or experimental models of obesity; assessment of outcomes related to insulin secretion, appetite regulation, energy balance, or adiposity; publication in peer-reviewed journals in English. Both human and animal studies were included when they provided mechanistic insight. Studies were excluded if they: focused exclusively on pharmacological incretin-based therapies without addressing endogenous physiology; lacked sufficient methodological detail; were non-original reports (e.g., editorials, commentaries, conference abstracts). Study selection was performed through sequential screening of titles/abstracts followed by full-text review. Data Extraction Data were extracted in a structured manner to capture key variables relevant to the study objective, including: study design and population characteristics; measures of adiposity and metabolic status; fasting and postprandial incretin hormone levels; methodologies used to assess incretin response; insulin secretion and glycemic outcomes; appetite- and satiety-related endpoints; mechanistic interpretations regarding causality versus adaptation. Particular emphasis was placed on identifying temporal and mechanistic patterns suggestive of either primary endocrine dysfunction or secondary metabolic adaptation. Analytical Approach An interpretative framework was applied to categorize the evidence into two overarching conceptual models: Etiological Defect Model, in which incretin insufficiency precedes and contributes to the development of obesity; Metabolic Maladaptation Model, in which incretin dysfunction arises as a downstream consequence of obesity-associated metabolic disturbances, including insulin resistance, chronic inflammation, and altered nutrient signaling. Evidence was synthesized qualitatively, with emphasis on biological plausibility, internal consistency across studies, and translational relevance. Converging findings from human and experimental data were integrated to support a coherent pathophysiological interpretation. Assessment of Evidence Quality Although a formal risk-of-bias tool was not applied due to the narrative design, methodological rigor of individual studies was considered during interpretation. Greater weight was assigned to: well-controlled clinical studies; investigations with standardized assessment of incretin responses; studies employing validated hormonal assays; longitudinal or mechanistic designs supporting causal inference. This approach was intended to strengthen the robustness of the conceptual synthesis while preserving the flexibility required for hypothesis-driven analysis. RESULTS Overview of Included Evidence The literature search identified a broad and methodologically heterogeneous body of evidence encompassing human clinical studies, mechanistic investigations, and translational experimental models examining endogenous incretin physiology in obesity. Across studies, considerable variability was observed in the assessment of incretin responses, including differences in nutrient stimuli, timing of hormonal measurements, and analytical methodologies. Despite this heterogeneity, a number of reproducible physiological patterns emerged, allowing for a structured interpretation of the relationship between incretin dynamics and obesity. Altered Endogenous Incretin Secretion in Obesity A consistent finding across multiple studies was the presence of attenuated postprandial GLP-1 responses in individuals with obesity, particularly following mixed-meal or oral glucose challenges. This reduction was not uniformly observed under fasting conditions, suggesting that the impairment is stimulus-dependent rather than constitutive. In contrast, GIP responses appeared relatively preserved or even exaggerated in some cohorts, although evidence indicates a functional resistance at the receptor or post-receptor level, leading to a diminished insulinotropic effect despite preserved secretion. Importantly, studies comparing lean and obese individuals under controlled conditions demonstrated that: the magnitude of the incretin effect is reduced in obesity; this reduction correlates more strongly with insulin resistance and adiposity indices than with absolute hormone concentrations. Taken together, these findings argue against a simple deficiency model and instead suggest a qualitative dysregulation of enteroendocrine signaling. Temporal and Mechanistic Evidence: Cause or Consequence Longitudinal and interventional data provided critical insight into the temporal relationship between incretin dysfunction and obesity. Evidence from: weight loss interventions (dietary or surgical), caloric restriction models, and metabolic normalization studies demonstrated partial restoration of GLP-1 secretion following weight reduction, supporting the notion that incretin impairment is, at least in part, reversible. Similarly, experimental models of diet-induced obesity showed that: chronic nutrient excess, intestinal inflammation, and alterations in gut microbiota are associated with progressive impairment of enteroendocrine cell responsiveness. Altogether, these observations favor a model in which incretin insufficiency emerges as a secondary adaptation, although they do not fully exclude the possibility that subtle pre-existing differences in incretin biology may predispose certain individuals to weight gain. Pharmacological Amplification: Evidence from Incretin-Based Therapies A substantial body of evidence derived from trials using incretin-based pharmacotherapies provides indirect but highly informative insight into endogenous incretin physiology (Table 1 ). Table 1 Summary of Key Pharmacological Evidence Targeting Incretin and Amylin Pathways Class Agent Mechanism Key Effects Pathophysiological Implication GLP-1 RA Semaglutide GLP-1 receptor agonism Significant weight loss, appetite suppression Supports functional insufficiency of endogenous GLP-1 GLP-1 RA Liraglutide GLP-1 receptor agonism Reduced caloric intake, improved glycemia Indicates therapeutic compensation Dual agonist Tirzepatide GLP-1 + GIP receptor agonism Greater weight reduction than GLP-1 alone Suggests preserved but dysregulated GIP axis Amylin analog Pramlintide Amylin receptor agonism Satiety enhancement Highlights non-incretin hormonal deficits Amylin analog Cagrilintide Long-acting amylin analog Sustained weight loss Supports multi-hormonal model Combination Cagrilintide + Semaglutide Amylin + GLP-1 co-agonism Synergistic weight reduction Evidence of integrated neuroendocrine dysfunction GLP-1 Receptor Agonists Agents such as semaglutide, liraglutide, and dulaglutide consistently demonstrate: robust weight loss, reduced energy intake, delayed gastric emptying, and improved glycemic control. The magnitude of these effects, often exceeding what would be expected from physiological GLP-1 levels, suggests that pharmacological activation compensates for an insufficient endogenous anorexigenic signal. However, the supraphysiological nature of receptor stimulation complicates interpretation, as these agents may override, rather than restore, endogenous regulatory pathways. Dual and Triple Agonists More recent agents, particularly tirzepatide, have demonstrated greater weight reduction than GLP-1 monotherapy, despite the paradoxical physiology of GIP in obesity. These findings suggest that: GIP signaling may be context-dependent, and pharmacological co-activation may restore lost synergistic interactions within the enteroinsular axis. This challenges earlier assumptions of GIP as purely obesogenic and supports a more nuanced model of incretin network dysfunction. Amylin and Amylin–Incretin Co-Agonism Therapies targeting amylin pathways, including pramlintide and next-generation agents such as cagrilintide, provide complementary evidence. Amylin analogs: enhance satiety, reduce food intake, and act through distinct but overlapping neuroendocrine circuits. The combination approaches (e.g., cagrilintide plus semaglutide) have demonstrated additive or synergistic effects on weight loss, reinforcing the concept that: obesity is characterized by multi-hormonal insufficiency or resistance, rather than isolated incretin deficiency. Integrated Interpretation of Findings When considered collectively, the available evidence does not support a unidimensional model of primary incretin deficiency. Instead, the data converge toward a multi-layered framework characterized by: stimulus-dependent impairment of GLP-1 secretion; functional resistance to GIP signaling; partial reversibility with weight loss; and robust responsiveness to pharmacological amplification. This pattern is more consistent with a secondary, adaptive dysregulation of the enteroendocrine system, likely driven by chronic metabolic stress. At the same time, the marked efficacy of incretin- and amylin-based therapies underscores that this adaptive state results in a clinically meaningful deficit in physiological satiety signaling, which can be therapeutically exploited (Fig. 1 ). DISCUSSION The present synthesis reframes endogenous incretin dysfunction in obesity not as a primary endocrine deficiency, but as a dynamic and context-dependent maladaptation of the enteroendocrine system, shaped by chronic metabolic stress. This interpretation is strongly supported by converging evidence from physiological studies, interventional trials, and the remarkable efficacy of incretin-based pharmacotherapies. A central finding across the literature is the attenuation of postprandial GLP-1 secretion in individuals with obesity, particularly under nutrient-stimulated conditions. However, this impairment is neither universal nor static. Contemporary mechanistic studies demonstrate that GLP-1 secretion is highly plastic and responsive to metabolic state, with partial restoration observed following weight loss or caloric restriction, suggesting that dysfunction is acquired rather than intrinsic [ 9 , 10 ]. This aligns with evolving models in which enteroendocrine cells adapt to chronic nutrient excess, leading to altered hormone release patterns rather than outright failure. At a systems level, incretin physiology in obesity is better understood as a disruption of signal integration rather than hormone deficiency per se. GLP-1, GIP, and amylin act in concert to regulate satiety, insulin secretion, and gastric motility, forming a coordinated gut–brain–pancreas axis [ 11 ]. Within this network, obesity appears to induce both reduced GLP-1 responsiveness and impaired GIP signaling efficiency, the latter often manifesting as a dissociation between circulating levels and biological activity — consistent with functional GIP resistance [ 12 ]. This distinction between concentration and function is fundamental. It underscores that endocrine dysfunction in obesity cannot be inferred solely from circulating hormone levels, but must incorporate receptor-level signaling competence and neural integration pathways, which remain insufficiently characterized in human studies. The therapeutic landscape provides compelling indirect evidence supporting this interpretation. The advent of highly potent incretin-based therapies, particularly GLP-1 receptor agonists and dual incretin agonists, has fundamentally transformed obesity treatment. Agents such as semaglutide and tirzepatide consistently induce clinically meaningful weight loss in the range of 15–25%, far exceeding traditional pharmacotherapies [ 13 , 14 ]. These effects are mediated primarily through central appetite suppression, delayed gastric emptying, and modulation of reward pathways, rather than simple insulinotropic actions [ 15 ]. It is important to emphasize that the magnitude of these effects challenges the notion of a primary deficiency state. If endogenous incretin systems were fundamentally defective, pharmacological amplification would be expected to yield limited benefit. Instead, the robust response observed across trials suggests that incretin pathways remain biologically intact but are functionally downregulated or insufficiently activated in the obesogenic state [ 16 ]. This concept is further reinforced by the success of dual and multi-agonist strategies. Tirzepatide, a GLP-1/GIP co-agonist, produces greater weight reduction than GLP-1 monotherapy, despite earlier assumptions that GIP signaling contributes to adiposity [ 17 , 18 ]. These findings suggest that GIP is not inherently obesogenic, but rather context-dependent, with its physiological role altered under conditions of metabolic dysregulation. Re-engagement of this pathway through pharmacological co-activation appears to restore lost synergistic signaling within the enteroinsular axis. Parallel advances in amylin-based therapies provide additional support for a multi-hormonal model of obesity. Amylin, co-secreted with insulin, exerts potent anorexigenic effects via central mechanisms distinct from, but complementary to, GLP-1 [ 19 ]. Clinical studies demonstrate that amylin analogs such as pramlintide and next-generation agents like cagrilintide induce significant reductions in energy intake and body weight, particularly when combined with GLP-1 receptor agonists [ 20 , 21 ]. The observed synergy between incretin and amylin pathways is particularly informative. It suggests that obesity is characterized not by isolated dysfunction of a single hormone, but by a broader impairment of integrated satiety signaling, involving multiple overlapping neuroendocrine systems. This aligns with recent translational frameworks describing obesity as a state of multi-hormonal resistance and insufficiency, rather than single-axis failure [ 22 , 23 ]. From a pathophysiological perspective, these findings converge toward a progressive maladaptation model, in which chronic exposure to excess nutrients, low-grade inflammation, and altered gut microbiota lead to: impaired enteroendocrine cell responsiveness, altered hormone secretion dynamics, and reduced central sensitivity to satiety signals. Within this framework, incretin dysfunction emerges as a downstream consequence of metabolic overload, rather than a primary driver of adiposity. This interpretation is further supported by studies demonstrating that weight loss interventions, particularly bariatric surgery, restore GLP-1 secretion and enhance satiety signaling, reinforcing the reversibility of the defect [ 24 ]. However, the degree of reversibility appears heterogeneous. Prolonged exposure to obesity may induce more persistent alterations in gut–brain communication pathways, potentially involving structural and functional changes in enteroendocrine cells and central appetite-regulating circuits [ 25 ]. This raises the possibility that early intervention may be critical to prevent entrenched neuroendocrine dysfunction. GAP STATEMENT Despite substantial advances, several critical gaps remain that limit a definitive understanding of endogenous incretin insufficiency in obesity. The causal directionality remains incompletely resolved. Although longitudinal and interventional studies suggest reversibility of incretin dysfunction, there is a lack of prospective human data demonstrating whether subtle impairments in incretin signaling precede weight gain. Most studies rely on circulating hormone concentrations as surrogate markers, with limited assessment of receptor signaling, intracellular pathways, or neural integration mechanisms. This restricts mechanistic resolution and may obscure key aspects of functional resistance. There is a paucity of data addressing the role of enteroendocrine cell biology in humans, including cell density, differentiation, and responsiveness under obesogenic conditions. Similarly, the contribution of the gut microbiota–enteroendocrine axis remains incompletely characterized. Thus, while pharmacological studies provide strong indirect evidence, they predominantly reflect supraphysiological receptor activation, which may not accurately model endogenous physiology. FUTURE DIRECTIONS Addressing these gaps will require a shift toward integrative, mechanism-focused research strategies. Future studies should prioritize: longitudinal human cohorts to determine whether alterations in incretin dynamics precede or follow weight gain; direct assessment of receptor signaling and downstream pathways, including tissue-specific responsiveness and central nervous system integration; advanced phenotyping of enteroendocrine cells, leveraging single-cell transcriptomics and in vivo imaging approaches; and controlled interventions targeting gut microbiota and intestinal inflammation, to evaluate their impact on incretin secretion and function. In parallel, emerging pharmacological strategies should move beyond receptor agonism toward restoration of endogenous hormone dynamics, including therapies designed to enhance physiological secretion or improve receptor sensitivity. Importantly, the integration of incretin and amylin biology suggests that future treatments may benefit from multi-target approaches that reconstitute coordinated satiety signaling, rather than focusing on individual hormonal pathways. CONCLUSION The available evidence supports a paradigm in which endogenous incretin insufficiency in obesity reflects a state-dependent, adaptive dysregulation of a biologically intact system, rather than a primary etiological defect. Recognizing this distinction reframes both the pathophysiology of obesity and the therapeutic strategies required to treat it, emphasizing the need to move beyond hormonal replacement toward restoration of integrated metabolic homeostasis. Declarations Conflict of Interest: The authors declare no conflicts of interest. 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Int J Obes Suppl 6(Suppl 1):S32–S36 Arellano-García L, Portillo MP, Hadjihambi A, Martínez JA, Milton-Laskibar I (2026) The Gut-Brain Axis in Obesity: Mechanisms, Development, and Therapeutic Perspectives. Curr Nutr Rep 15(1):16 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9453154","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":625227299,"identity":"8f541df6-f53d-4f9b-b18a-929549f2eef9","order_by":0,"name":"Luís Jesuíno de Oliveira Andrade","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPgbGBgYGHiCLGYg/MDAkwGQScOhgYEPWwjiDOC1IgJmHKC0Syc0fGGRs7A2O8x58bNtml8fP3sD44WMOQ555Ay4tiW0SDDxpiRsO8yUb57YlF0v2HGCWnLmNoVjmAG4tQL8cTjA4zGMmndvGnLjhRgIbM+82hsQZOB2WCHQYz397sBbLtnqitDQAHXaAcQNIC2PbYSK08DwE+SU5ceZhHmPDnnPHE2f2HGwG+kWiWAKHFn729McfGHvs7PnOnzF88KOsOrGfvfngh4/bbPJwaQEB5r89UBYjOJpAkcuATwMI/IAx/hBQOApGwSgYBSMSAAAthFHtBhERUQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7714-0330","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":true,"prefix":"","firstName":"Luís","middleName":"Jesuíno de Oliveira","lastName":"Andrade","suffix":""},{"id":625227300,"identity":"8f2b263a-80e5-4eb8-9736-17b2b7b6e12e","order_by":1,"name":"Gabriela Correia Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0002-3447-3143","institution":"UNAERP - Electro Bonini Hospital and Cidinha Bonini Maternity Hospital - Ribeirão Preto, São Paulo, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"Correia Matos","lastName":"de Oliveira","suffix":""},{"id":625227301,"identity":"4c9cc379-3d8f-477d-bc24-6d6cf9ee25bf","order_by":2,"name":"Alcina Maria Vinhaes Bittencourt","email":"","orcid":"https://orcid.org/0000-0003-0506-9210","institution":"School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Alcina","middleName":"Maria Vinhaes","lastName":"Bittencourt","suffix":""},{"id":625227302,"identity":"edc6d78e-97ff-4ade-a9b2-be1baf3378bd","order_by":3,"name":"Osmário Jorge de Mattos Salles","email":"","orcid":"https://orcid.org/0009-0002-1859-0478","institution":"Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Osmário","middleName":"Jorge de Mattos","lastName":"Salles","suffix":""},{"id":625227303,"identity":"613c1c9a-691e-467d-8db0-17c2d1cef616","order_by":4,"name":"Luís Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0003-4854-6910","institution":"Department of Health, Santa Cruz State University, Ilhéus, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Luís","middleName":"Matos","lastName":"de Oliveira","suffix":""}],"badges":[],"createdAt":"2026-04-17 23:55:51","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9453154/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9453154/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107382667,"identity":"6cbdc16b-afd0-450e-aa22-2f62489c4778","added_by":"auto","created_at":"2026-04-21 03:07:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":297882,"visible":true,"origin":"","legend":"\u003cp\u003eConceptual model of enteroendocrine dysfunction in obesity\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9453154/v1/d8f9e33ab571c653d2cdd08d.png"},{"id":107705599,"identity":"b83af5aa-75e2-4d9d-ad35-8884d2391be8","added_by":"auto","created_at":"2026-04-24 09:13:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":465232,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9453154/v1/f3004b54-4d6c-4cd9-b654-f2c41383511d.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEndogenous Incretin Insufficiency in Obesity: Etiological Defect or Metabolic Maladaptation?\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eObesity represents one of the most pressing public health challenges of the twenty-first century, affecting over one billion individuals worldwide and contributing disproportionately to the global burden of type 2 diabetes, cardiovascular disease, and all-cause mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite decades of intensive investigation, the precise endocrine mechanisms that predispose certain individuals to pathological adiposity while others maintain metabolic homeostasis under comparable environmental conditions remain incompletely understood. Among the hormonal systems implicated in energy balance regulation, the enteroendocrine axis has attracted growing scientific interest, particularly given its central role in coordinating postprandial satiety signaling, insulin secretion, and gastrointestinal motility [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The gut, far from being a passive digestive organ, functions as the largest endocrine gland in the human body, capable of synthesizing and releasing a diverse repertoire of peptide hormones in response to nutrient stimuli [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCentral to this enteroendocrine framework are the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which together account for a substantial proportion of postprandial insulin release, a phenomenon collectively termed the incretin effect [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In lean, metabolically healthy individuals, these hormones are secreted in a tightly regulated, physiologically appropriate manner, orchestrating a coordinated anorexigenic response that limits excessive caloric intake [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, accumulating evidence suggests that obese individuals exhibit a measurably blunted incretin response, characterized by reduced postprandial GLP-1 secretion and attenuated GIP signaling, raising a fundamental and still unresolved question: does this hormonal insufficiency represent a primary etiological defect that antecedes and promotes adiposity, or does it emerge secondarily as a maladaptive consequence of the chronic metabolic and inflammatory milieu inherent to established obesity?\u003c/p\u003e \u003cp\u003eResolving this question carries profound therapeutic implications that extend well beyond academic interest. The current pharmacological landscape of obesity management has been substantially shaped by incretin-based therapies, including GLP-1 receptor agonists, which exogenously compensate for diminished endogenous secretion [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While clinically effective, these agents address hormonal insufficiency through exogenous supplementation rather than restoration of intrinsic enteroendocrine function, a distinction that may be critically relevant to long-term metabolic outcomes and treatment sustainability. The underlying question of whether the enteroendocrine system is fundamentally impaired in obesity, and whether such impairment is reversible, has not been systematically addressed in the literature [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present review aims to critically examine and synthesize the available evidence regarding endogenous incretin insufficiency in obesity, with the specific objective of determining whether this phenomenon constitutes a primary pathophysiological defect or a secondary metabolic adaptation. By interrogating data from mechanistic, epidemiological, and interventional studies, we seek to reframe the conceptual understanding of gut hormone dysregulation in obesity and to identify actionable targets for therapies directed at restoring, rather than merely replacing, physiological enteroendocrine function.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eGiven the conceptual and mechanistic complexity of this question, a structured narrative approach was selected to enable integrative interpretation across heterogeneous lines of evidence, including clinical, experimental, and translational studies.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eA comprehensive literature search was performed using PubMed/MEDLINE, Embase, Scopus, and Web of Science from database inception through the most recent available records.\u003c/p\u003e \u003cp\u003eSearch terms combined controlled vocabulary and free-text keywords related to obesity and incretin biology, including: \u0026ldquo;obesity,\u0026rdquo; \u0026ldquo;GLP-1,\u0026rdquo; \u0026ldquo;glucagon-like peptide-1,\u0026rdquo; \u0026ldquo;GIP,\u0026rdquo; \u0026ldquo;glucose-dependent insulinotropic polypeptide,\u0026rdquo; \u0026ldquo;incretin effect,\u0026rdquo; \u0026ldquo;endogenous secretion,\u0026rdquo; \u0026ldquo;enteroendocrine function,\u0026rdquo; \u0026ldquo;gut hormones,\u0026rdquo; and \u0026ldquo;metabolic adaptation.\u0026rdquo; Boolean operators were applied to optimize sensitivity and specificity.\u003c/p\u003e \u003cp\u003eTo enhance completeness, reference lists of relevant articles were manually screened to identify additional studies not captured in the primary search.\u003c/p\u003e\n\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003eStudies were selected based on their relevance to endogenous incretin physiology and its relationship with obesity and metabolic regulation.\u003c/p\u003e \u003cp\u003eEligible studies met the following criteria: investigation of endogenous incretin secretion, signaling, or physiological response; inclusion of populations with obesity or experimental models of obesity; assessment of outcomes related to insulin secretion, appetite regulation, energy balance, or adiposity; publication in peer-reviewed journals in English.\u003c/p\u003e \u003cp\u003eBoth human and animal studies were included when they provided mechanistic insight.\u003c/p\u003e \u003cp\u003eStudies were excluded if they: focused exclusively on pharmacological incretin-based therapies without addressing endogenous physiology; lacked sufficient methodological detail; were non-original reports (e.g., editorials, commentaries, conference abstracts).\u003c/p\u003e \u003cp\u003eStudy selection was performed through sequential screening of titles/abstracts followed by full-text review.\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eData were extracted in a structured manner to capture key variables relevant to the study objective, including: study design and population characteristics; measures of adiposity and metabolic status; fasting and postprandial incretin hormone levels; methodologies used to assess incretin response; insulin secretion and glycemic outcomes;\u003c/p\u003e \u003cp\u003eappetite- and satiety-related endpoints; mechanistic interpretations regarding causality versus adaptation.\u003c/p\u003e \u003cp\u003eParticular emphasis was placed on identifying temporal and mechanistic patterns suggestive of either primary endocrine dysfunction or secondary metabolic adaptation.\u003c/p\u003e\n\u003ch3\u003eAnalytical Approach\u003c/h3\u003e\n\u003cp\u003eAn interpretative framework was applied to categorize the evidence into two overarching conceptual models:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eEtiological Defect Model, in which incretin insufficiency precedes and contributes to the development of obesity;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMetabolic Maladaptation Model, in which incretin dysfunction arises as a downstream consequence of obesity-associated metabolic disturbances, including insulin resistance, chronic inflammation, and altered nutrient signaling.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eEvidence was synthesized qualitatively, with emphasis on biological plausibility, internal consistency across studies, and translational relevance. Converging findings from human and experimental data were integrated to support a coherent pathophysiological interpretation.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of Evidence Quality\u003c/h2\u003e \u003cp\u003eAlthough a formal risk-of-bias tool was not applied due to the narrative design, methodological rigor of individual studies was considered during interpretation. Greater weight was assigned to: well-controlled clinical studies; investigations with standardized assessment of incretin responses; studies employing validated hormonal assays; longitudinal or mechanistic designs supporting causal inference.\u003c/p\u003e \u003cp\u003eThis approach was intended to strengthen the robustness of the conceptual synthesis while preserving the flexibility required for hypothesis-driven analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOverview of Included Evidence\u003c/h2\u003e \u003cp\u003eThe literature search identified a broad and methodologically heterogeneous body of evidence encompassing human clinical studies, mechanistic investigations, and translational experimental models examining endogenous incretin physiology in obesity. Across studies, considerable variability was observed in the assessment of incretin responses, including differences in nutrient stimuli, timing of hormonal measurements, and analytical methodologies.\u003c/p\u003e \u003cp\u003eDespite this heterogeneity, a number of reproducible physiological patterns emerged, allowing for a structured interpretation of the relationship between incretin dynamics and obesity.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAltered Endogenous Incretin Secretion in Obesity\u003c/h2\u003e \u003cp\u003eA consistent finding across multiple studies was the presence of attenuated postprandial GLP-1 responses in individuals with obesity, particularly following mixed-meal or oral glucose challenges. This reduction was not uniformly observed under fasting conditions, suggesting that the impairment is stimulus-dependent rather than constitutive.\u003c/p\u003e \u003cp\u003eIn contrast, GIP responses appeared relatively preserved or even exaggerated in some cohorts, although evidence indicates a functional resistance at the receptor or post-receptor level, leading to a diminished insulinotropic effect despite preserved secretion.\u003c/p\u003e \u003cp\u003eImportantly, studies comparing lean and obese individuals under controlled conditions demonstrated that: the magnitude of the incretin effect is reduced in obesity; this reduction correlates more strongly with insulin resistance and adiposity indices than with absolute hormone concentrations.\u003c/p\u003e \u003cp\u003eTaken together, these findings argue against a simple deficiency model and instead suggest a qualitative dysregulation of enteroendocrine signaling.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTemporal and Mechanistic Evidence: Cause or Consequence\u003c/h2\u003e \u003cp\u003eLongitudinal and interventional data provided critical insight into the temporal relationship between incretin dysfunction and obesity.\u003c/p\u003e \u003cp\u003eEvidence from: weight loss interventions (dietary or surgical), caloric restriction models, and metabolic normalization studies demonstrated partial restoration of GLP-1 secretion following weight reduction, supporting the notion that incretin impairment is, at least in part, reversible.\u003c/p\u003e \u003cp\u003eSimilarly, experimental models of diet-induced obesity showed that: chronic nutrient excess, intestinal inflammation, and alterations in gut microbiota are associated with progressive impairment of enteroendocrine cell responsiveness.\u003c/p\u003e \u003cp\u003eAltogether, these observations favor a model in which incretin insufficiency emerges as a secondary adaptation, although they do not fully exclude the possibility that subtle pre-existing differences in incretin biology may predispose certain individuals to weight gain.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePharmacological Amplification: Evidence from Incretin-Based Therapies\u003c/h2\u003e \u003cp\u003eA substantial body of evidence derived from trials using incretin-based pharmacotherapies provides indirect but highly informative insight into endogenous incretin physiology (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Key Pharmacological Evidence Targeting Incretin and Amylin Pathways\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClass\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMechanism\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKey Effects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePathophysiological Implication\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLP-1 RA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSemaglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGLP-1 receptor agonism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSignificant weight loss, appetite suppression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSupports functional insufficiency of endogenous GLP-1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLP-1 RA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiraglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGLP-1 receptor agonism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReduced caloric intake, improved glycemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIndicates therapeutic compensation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDual agonist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTirzepatide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGLP-1\u0026thinsp;+\u0026thinsp;GIP receptor agonism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGreater weight reduction than GLP-1 alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSuggests preserved but dysregulated GIP axis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmylin analog\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePramlintide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmylin receptor agonism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSatiety enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHighlights non-incretin hormonal deficits\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmylin analog\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCagrilintide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLong-acting amylin analog\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSustained weight loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSupports multi-hormonal model\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCagrilintide\u0026thinsp;+\u0026thinsp;Semaglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmylin\u0026thinsp;+\u0026thinsp;GLP-1 co-agonism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSynergistic weight reduction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEvidence of integrated neuroendocrine dysfunction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eGLP-1 Receptor Agonists\u003c/h2\u003e \u003cp\u003eAgents such as semaglutide, liraglutide, and dulaglutide consistently demonstrate: robust weight loss, reduced energy intake, delayed gastric emptying, and improved glycemic control.\u003c/p\u003e \u003cp\u003eThe magnitude of these effects, often exceeding what would be expected from physiological GLP-1 levels, suggests that pharmacological activation compensates for an insufficient endogenous anorexigenic signal.\u003c/p\u003e \u003cp\u003eHowever, the supraphysiological nature of receptor stimulation complicates interpretation, as these agents may override, rather than restore, endogenous regulatory pathways.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eDual and Triple Agonists\u003c/h2\u003e \u003cp\u003eMore recent agents, particularly tirzepatide, have demonstrated greater weight reduction than GLP-1 monotherapy, despite the paradoxical physiology of GIP in obesity.\u003c/p\u003e \u003cp\u003eThese findings suggest that: GIP signaling may be context-dependent, and pharmacological co-activation may restore lost synergistic interactions within the enteroinsular axis.\u003c/p\u003e \u003cp\u003eThis challenges earlier assumptions of GIP as purely obesogenic and supports a more nuanced model of incretin network dysfunction.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAmylin and Amylin\u0026ndash;Incretin Co-Agonism\u003c/h2\u003e \u003cp\u003eTherapies targeting amylin pathways, including pramlintide and next-generation agents such as cagrilintide, provide complementary evidence.\u003c/p\u003e \u003cp\u003eAmylin analogs: enhance satiety, reduce food intake, and act through distinct but overlapping neuroendocrine circuits.\u003c/p\u003e \u003cp\u003eThe combination approaches (e.g., cagrilintide plus semaglutide) have demonstrated additive or synergistic effects on weight loss, reinforcing the concept that: obesity is characterized by multi-hormonal insufficiency or resistance, rather than isolated incretin deficiency.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eIntegrated Interpretation of Findings\u003c/h2\u003e \u003cp\u003eWhen considered collectively, the available evidence does not support a unidimensional model of primary incretin deficiency. Instead, the data converge toward a multi-layered framework characterized by: stimulus-dependent impairment of GLP-1 secretion; functional resistance to GIP signaling; partial reversibility with weight loss; and robust responsiveness to pharmacological amplification.\u003c/p\u003e \u003cp\u003eThis pattern is more consistent with a secondary, adaptive dysregulation of the enteroendocrine system, likely driven by chronic metabolic stress.\u003c/p\u003e \u003cp\u003eAt the same time, the marked efficacy of incretin- and amylin-based therapies underscores that this adaptive state results in a clinically meaningful deficit in physiological satiety signaling, which can be therapeutically exploited (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present synthesis reframes endogenous incretin dysfunction in obesity not as a primary endocrine deficiency, but as a dynamic and context-dependent maladaptation of the enteroendocrine system, shaped by chronic metabolic stress. This interpretation is strongly supported by converging evidence from physiological studies, interventional trials, and the remarkable efficacy of incretin-based pharmacotherapies.\u003c/p\u003e \u003cp\u003eA central finding across the literature is the attenuation of postprandial GLP-1 secretion in individuals with obesity, particularly under nutrient-stimulated conditions. However, this impairment is neither universal nor static. Contemporary mechanistic studies demonstrate that GLP-1 secretion is highly plastic and responsive to metabolic state, with partial restoration observed following weight loss or caloric restriction, suggesting that dysfunction is acquired rather than intrinsic [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This aligns with evolving models in which enteroendocrine cells adapt to chronic nutrient excess, leading to altered hormone release patterns rather than outright failure.\u003c/p\u003e \u003cp\u003eAt a systems level, incretin physiology in obesity is better understood as a disruption of signal integration rather than hormone deficiency per se. GLP-1, GIP, and amylin act in concert to regulate satiety, insulin secretion, and gastric motility, forming a coordinated gut\u0026ndash;brain\u0026ndash;pancreas axis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Within this network, obesity appears to induce both reduced GLP-1 responsiveness and impaired GIP signaling efficiency, the latter often manifesting as a dissociation between circulating levels and biological activity \u0026mdash; consistent with functional GIP resistance [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis distinction between concentration and function is fundamental. It underscores that endocrine dysfunction in obesity cannot be inferred solely from circulating hormone levels, but must incorporate receptor-level signaling competence and neural integration pathways, which remain insufficiently characterized in human studies.\u003c/p\u003e \u003cp\u003eThe therapeutic landscape provides compelling indirect evidence supporting this interpretation. The advent of highly potent incretin-based therapies, particularly GLP-1 receptor agonists and dual incretin agonists, has fundamentally transformed obesity treatment. Agents such as semaglutide and tirzepatide consistently induce clinically meaningful weight loss in the range of 15\u0026ndash;25%, far exceeding traditional pharmacotherapies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These effects are mediated primarily through central appetite suppression, delayed gastric emptying, and modulation of reward pathways, rather than simple insulinotropic actions [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is important to emphasize that the magnitude of these effects challenges the notion of a primary deficiency state. If endogenous incretin systems were fundamentally defective, pharmacological amplification would be expected to yield limited benefit. Instead, the robust response observed across trials suggests that incretin pathways remain biologically intact but are functionally downregulated or insufficiently activated in the obesogenic state [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis concept is further reinforced by the success of dual and multi-agonist strategies. Tirzepatide, a GLP-1/GIP co-agonist, produces greater weight reduction than GLP-1 monotherapy, despite earlier assumptions that GIP signaling contributes to adiposity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These findings suggest that GIP is not inherently obesogenic, but rather context-dependent, with its physiological role altered under conditions of metabolic dysregulation. Re-engagement of this pathway through pharmacological co-activation appears to restore lost synergistic signaling within the enteroinsular axis.\u003c/p\u003e \u003cp\u003eParallel advances in amylin-based therapies provide additional support for a multi-hormonal model of obesity. Amylin, co-secreted with insulin, exerts potent anorexigenic effects via central mechanisms distinct from, but complementary to, GLP-1 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Clinical studies demonstrate that amylin analogs such as pramlintide and next-generation agents like cagrilintide induce significant reductions in energy intake and body weight, particularly when combined with GLP-1 receptor agonists [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe observed synergy between incretin and amylin pathways is particularly informative. It suggests that obesity is characterized not by isolated dysfunction of a single hormone, but by a broader impairment of integrated satiety signaling, involving multiple overlapping neuroendocrine systems. This aligns with recent translational frameworks describing obesity as a state of multi-hormonal resistance and insufficiency, rather than single-axis failure [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, these findings converge toward a progressive maladaptation model, in which chronic exposure to excess nutrients, low-grade inflammation, and altered gut microbiota lead to: impaired enteroendocrine cell responsiveness, altered hormone secretion dynamics, and reduced central sensitivity to satiety signals.\u003c/p\u003e \u003cp\u003eWithin this framework, incretin dysfunction emerges as a downstream consequence of metabolic overload, rather than a primary driver of adiposity. This interpretation is further supported by studies demonstrating that weight loss interventions, particularly bariatric surgery, restore GLP-1 secretion and enhance satiety signaling, reinforcing the reversibility of the defect [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the degree of reversibility appears heterogeneous. Prolonged exposure to obesity may induce more persistent alterations in gut\u0026ndash;brain communication pathways, potentially involving structural and functional changes in enteroendocrine cells and central appetite-regulating circuits [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This raises the possibility that early intervention may be critical to prevent entrenched neuroendocrine dysfunction.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eGAP STATEMENT\u003c/h2\u003e \u003cp\u003eDespite substantial advances, several critical gaps remain that limit a definitive understanding of endogenous incretin insufficiency in obesity.\u003c/p\u003e \u003cp\u003eThe causal directionality remains incompletely resolved. Although longitudinal and interventional studies suggest reversibility of incretin dysfunction, there is a lack of prospective human data demonstrating whether subtle impairments in incretin signaling precede weight gain.\u003c/p\u003e \u003cp\u003eMost studies rely on circulating hormone concentrations as surrogate markers, with limited assessment of receptor signaling, intracellular pathways, or neural integration mechanisms. This restricts mechanistic resolution and may obscure key aspects of functional resistance.\u003c/p\u003e \u003cp\u003eThere is a paucity of data addressing the role of enteroendocrine cell biology in humans, including cell density, differentiation, and responsiveness under obesogenic conditions. Similarly, the contribution of the gut microbiota\u0026ndash;enteroendocrine axis remains incompletely characterized.\u003c/p\u003e \u003cp\u003eThus, while pharmacological studies provide strong indirect evidence, they predominantly reflect supraphysiological receptor activation, which may not accurately model endogenous physiology.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eFUTURE DIRECTIONS\u003c/h2\u003e \u003cp\u003eAddressing these gaps will require a shift toward integrative, mechanism-focused research strategies.\u003c/p\u003e \u003cp\u003eFuture studies should prioritize: longitudinal human cohorts to determine whether alterations in incretin dynamics precede or follow weight gain; direct assessment of receptor signaling and downstream pathways, including tissue-specific responsiveness and central nervous system integration; advanced phenotyping of enteroendocrine cells, leveraging single-cell transcriptomics and in vivo imaging approaches; and controlled interventions targeting gut microbiota and intestinal inflammation, to evaluate their impact on incretin secretion and function.\u003c/p\u003e \u003cp\u003eIn parallel, emerging pharmacological strategies should move beyond receptor agonism toward restoration of endogenous hormone dynamics, including therapies designed to enhance physiological secretion or improve receptor sensitivity.\u003c/p\u003e \u003cp\u003eImportantly, the integration of incretin and amylin biology suggests that future treatments may benefit from multi-target approaches that reconstitute coordinated satiety signaling, rather than focusing on individual hormonal pathways.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe available evidence supports a paradigm in which endogenous incretin insufficiency in obesity reflects a state-dependent, adaptive dysregulation of a biologically intact system, rather than a primary etiological defect. Recognizing this distinction reframes both the pathophysiology of obesity and the therapeutic strategies required to treat it, emphasizing the need to move beyond hormonal replacement toward restoration of integrated metabolic homeostasis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest:\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNCD Risk Factor Collaboration (NCD-RisC) (2024) Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet 403(10431):1027\u0026ndash;1050\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrucker DJ, Holst JJ (2023) The expanding incretin universe: from basic biology to clinical translation. Diabetologia 66(10):1765\u0026ndash;1779\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGribble FM, Reimann F (2019) Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol 15(4):226\u0026ndash;237\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNauck MA, Meier JJ (2016) The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol 4(6):525\u0026ndash;536\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRanganath LR, Beety JM, Morgan LM, Wright JW, Howland R, Marks V (1996) Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 38(6):916\u0026ndash;919\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarr RD, Larsen MO, Winzell MS, Jelic K, Lindgren O, Deacon CF et al (2008) Incretin and islet hormonal responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab 295(4):E779\u0026ndash;E784\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLau J, Bloch P, Sch\u0026auml;ffer L, Pettersson I, Spetzler J, Kofoed J et al (2015) Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem 58(18):7370\u0026ndash;7380\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWachsmuth HR, Weninger SN, Duca FA (2022) Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med 54(4):377\u0026ndash;392\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolst JJ (2024) GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 6(10):1866\u0026ndash;1885\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlcaino C, Reimann F, Gribble FM (2025) Incretin hormones and obesity. J Physiol 603(24):7645\u0026ndash;7659\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenkilde MM (2024) Advances in incretin-based therapeutics for obesity. Nat Rev Endocrinol 20(2):67\u0026ndash;68\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasuda Y, Ohbayashi K, Iwasaki Y (2025) Comparing the anorexigenic effects and mechanisms of gut-derived GLP-1 and its receptor agonists: insights into incretin-based therapies for obesity. Diabetol Int 16(3):448\u0026ndash;456\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang JY, Kang JW, Wu CY, Peng TR, Liao LM, Lee MC et al (2024) The effects of incretin-based therapies on weight reduction and metabolic parameters in children with obesity: A systematic review and meta-analysis. Obes Rev 25(4):e13686\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZufry H, Hariyanto TI (2026) Head-to-head comparison of tirzepatide and semaglutide for weight loss: A systematic review and meta-analysis. Obes Res Clin Pract. :S1871\u0026ndash;403X(26)00019\u0026thinsp;\u0026ndash;\u0026thinsp;0.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM\u0026uuml;llertz ALO, Sandsdal RM, Jensen SBK, Torekov SS (2024) Potent incretin-based therapy for obesity: A systematic review and meta-analysis of the efficacy of semaglutide and tirzepatide on body weight and waist circumference, and safety. Obes Rev 25(5):e13717\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZufry H, Hariyanto TI (2026) Head-to-head comparison of tirzepatide and semaglutide for weight loss: A systematic review and meta-analysis. Obes Res Clin Pract. :S1871\u0026ndash;403X(26)00019\u0026thinsp;\u0026ndash;\u0026thinsp;0.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWong HJ, Sim B, Teo YH, Teo YN, Chan MY, Yeo LLL et al (2025) Efficacy of GLP-1 Receptor Agonists on Weight Loss, BMI, and Waist Circumference for Patients With Obesity or Overweight: A Systematic Review, Meta-analysis, and Meta-regression of 47 Randomized Controlled Trials. Diabetes Care 48(2):292\u0026ndash;300\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhawaji A, A Jaly A A, Bakri H, Ravi R, Hattan A, Khawaji A et al (2025) Weight Loss Efficacy of Tirzepatide Compared to Placebo or GLP-1 Receptor Agonists in Adults With Obesity or Overweight: A Meta-Analysis of Randomized Controlled Trials With \u0026ge;\u0026thinsp;20 Weeks Treatment Duration. J Obes 2025:3442754\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLutz TA (2016) Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure. Int J Obes Suppl 6(Suppl 1):S15\u0026ndash;S21\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarvey WT, Bl\u0026uuml;her M, Osorto Contreras CK, Davies MJ, Winning Lehmann E, Pietil\u0026auml;inen KH et al (2025) Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med 393(7):635\u0026ndash;647\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePanou T, Gouveri E, Popovic DS, Papanas N (2024) Amylin analogs for the treatment of obesity without diabetes: present and future. Expert Rev Clin Pharmacol. :1\u0026ndash;9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCapone F, Nambiar N, Schiattarella GG (2024) Beyond Weight Loss: the Emerging Role of Incretin-Based Treatments in Cardiometabolic HFpEF. Curr Opin Cardiol 39(3):148\u0026ndash;153\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePsaltis JP, Marathe JA, Nguyen MT, Le R, Bursill CA, Marathe CS, Nelson AJ et al (2025) Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future. Med Res Rev 45(1):29\u0026ndash;65\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaferr\u0026egrave;re B (2016) Bariatric surgery and obesity: influence on the incretins. Int J Obes Suppl 6(Suppl 1):S32\u0026ndash;S36\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArellano-Garc\u0026iacute;a L, Portillo MP, Hadjihambi A, Mart\u0026iacute;nez JA, Milton-Laskibar I (2026) The Gut-Brain Axis in Obesity: Mechanisms, Development, and Therapeutic Perspectives. Curr Nutr Rep 15(1):16\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Enteroendocrine dysfunction, GLP-1 secretion, Incretin resistance, Metabolic maladaptation","lastPublishedDoi":"10.21203/rs.3.rs-9453154/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9453154/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003eObesity is associated with measurably attenuated postprandial incretin responses, characterized by blunted glucagon-like peptide-1 (GLP-1) secretion and functional resistance to glucose-dependent insulinotropic polypeptide (GIP) signaling. Whether this enteroendocrine dysregulation represents a primary pathophysiological defect anteceding adiposity or a secondary maladaptive consequence of chronic metabolic overload remains unresolved, with substantial implications for the conceptualization and treatment of obesity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo critically evaluate and synthesize the available evidence regarding endogenous incretin insufficiency in obesity, determining whether this phenomenon constitutes a primary etiological defect or a state-dependent metabolic adaptation. \u003cstrong\u003eMethods:\u003c/strong\u003e A structured narrative review was conducted across PubMed/MEDLINE, Embase, Scopus, and Web of Science. Eligible studies encompassed human clinical trials, mechanistic investigations, and translational experimental models addressing endogenous incretin physiology, obesity-associated hormonal dysregulation, and incretin-based pharmacotherapy outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Evidence consistently demonstrates stimulus-dependent impairment of GLP-1 secretion and functional GIP resistance, both partially reversible following weight loss. Pharmacological amplification via GLP-1 receptor agonists, dual incretin agonists, and amylin-based therapies yields robust efficacy, indicating biologically intact but functionally downregulated signaling pathways. A multi-hormonal insufficiency model, rather than isolated incretin deficiency, best accounts for the observed phenotype.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eEndogenous incretin insufficiency in obesity reflects a state-dependent, adaptive dysregulation of a biologically intact enteroendocrine system, driven by chronic metabolic stress, rather than a primary etiological defect. Therapeutic strategies should prioritize restoration of integrated satiety signaling over isolated hormonal replacement.\u003c/p\u003e","manuscriptTitle":"Endogenous Incretin Insufficiency in Obesity: Etiological Defect or Metabolic Maladaptation?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 03:07:56","doi":"10.21203/rs.3.rs-9453154/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab6e42e9-7d0a-4b1a-b6b5-00f76d505028","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66550619,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2026-04-21T03:07:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 03:07:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9453154","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9453154","identity":"rs-9453154","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}