GLP-1R, GIPR, and GCGR jointly regulate pancreatic hormone secretion, hepatic glucose output, feeding behavior, and energy metabolism. Multi-receptor agonists improve the overall metabolic treatment of obesity and type 2 diabetes by balancing glucose-lowering effects, appetite suppression, and energy expenditure.

Keywords: GLP-1R; GIPR; GCGR; obesity; type 2 diabetes; incretin; glucagon; dual receptor agonist; triple receptor agonist; energy metabolism

1 Molecular Characteristics and Tissue Distribution of GLP-1R, GIPR, and GCGR

1.1 Structural Characteristics of the Three Receptors

GLP-1R, GIPR, and GCGR all belong to the class B1 G protein-coupled receptor family and consist of a relatively large extracellular amino-terminal domain, a seven-transmembrane domain, and an intracellular carboxyl terminus. The carboxyl terminus of a peptide ligand first binds to the extracellular receptor domain, after which the ligand amino terminus enters the transmembrane core and induces receptor activation. All three receptors primarily signal through the Gs protein-adenylyl cyclase-cAMP axis, while β-arrestin recruitment or activation of other signaling branches may occur depending on cell type, ligand structure, and receptor conformation.

1.2 Tissue Distribution of GLP-1R

GLP-1R is mainly expressed in pancreatic β cells, selected neurons in the brainstem and hypothalamus, and vagal nerve-associated pathways. It can also be detected in certain gastrointestinal and cardiovascular tissues. Pancreatic GLP-1R mainly regulates glucose-dependent insulin secretion, whereas GLP-1R in central and neural pathways participates in satiety, food reward, and feeding behavior. Because receptor expression is relatively low in some peripheral tissues, tissue distribution should be evaluated by integrating RNA analysis, specific antibodies, and functional responses.

1.3 Tissue Distribution of GIPR

GIPR is mainly expressed in pancreatic β cells, adipose tissue, bone, and the central nervous system. Pancreatic GIPR enhances glucose-stimulated insulin secretion, adipose-tissue GIPR participates in nutrient uptake, lipid storage, and adipocyte endocrine regulation, and central GIPR contributes to feeding and energy balance. The metabolic effects of GIPR depend on tissue context and nutritional status and cannot be simply classified as promoting or inhibiting fat accumulation.

1.4 Tissue Distribution of GCGR

GCGR is highly expressed in hepatocytes and is the main receptor through which glucagon regulates hepatic glycogenolysis, gluconeogenesis, amino acid catabolism, and the urea cycle. GCGR is also distributed in the kidneys, pancreatic islets, and certain regions of the nervous system, but its systemic metabolic effects are mainly mediated by the liver. Pharmacological GCGR activation can increase hepatic glucose output while also enhancing fatty acid oxidation and energy expenditure. The therapeutic effect therefore depends on the balance between hyperglycemic and fat-reducing actions.

1.5 Receptor Internalization and Signal Duration

All three receptors can undergo phosphorylation, β-arrestin recruitment, and internalization after activation, but different agonists vary in internalization rate, endosomal signaling, and membrane-recycling capacity. Receptor-binding affinity does not fully represent in vivo pharmacological activity. Sustained cAMP signaling, tissue exposure, receptor recycling, and resistance of the ligand to degradation jointly determine glucose-lowering and weight-reducing effects.

Table 1 Major Biological Characteristics of GLP-1R, GIPR, and GCGR

2 Physiological Regulation of Incretin and Glucagon Signaling

2.1 GLP-1 Secretion and Degradation

GLP-1 is mainly secreted by intestinal L cells in response to nutrients including glucose, fatty acids, amino acids, and bile acids. Active GLP-1 includes GLP-1 (7-36) amide and GLP-1 (7-37). After entering the circulation, it is rapidly cleaved by dipeptidyl peptidase-4, resulting in a short circulating half-life for endogenous active GLP-1. The physiological actions of GLP-1 can also be mediated through local intestinal and vagal afferent pathways and do not depend entirely on high peripheral blood concentrations.

2.2 GIP Secretion and Postprandial Responses

GIP is mainly secreted by K cells in the small intestine, and both glucose and fat intake can stimulate its release. GIP is an important regulator of postprandial insulin secretion under healthy conditions, but chronic hyperglycemia can reduce β-cell responsiveness to GIP. Some of the insulinotropic effect of GIP can be restored after glucotoxicity and β-cell status improve.

2.3 Regulation of Glucagon Secretion

Glucagon is mainly secreted by pancreatic α cells. Hypoglycemia, amino acid intake, exercise, and sympathetic activation promote glucagon release, whereas hyperglycemia, insulin, and somatostatin suppress it. After protein intake, increased glucagon promotes amino acid catabolism and prevents hypoglycemia caused by elevated insulin, forming an amino acid-regulatory loop between the liver and pancreatic α cells.

2.4 Glucose-Dependent Insulin Secretion

Activation of GLP-1R and GIPR increases cAMP through Gs proteins and subsequently activates protein kinase A and EPAC2, promoting calcium signaling, mobilization of insulin granules, and exocytosis. This action requires membrane depolarization and increased intracellular calcium caused by glucose metabolism. Therefore, at relatively low glucose concentrations, activation of incretin receptors generally does not independently induce strong insulin secretion.

2.5 Dynamic Balance Between Incretins and Glucagon

After food intake, GLP-1 and GIP enhance insulin secretion and limit the rise in postprandial glucose. During fasting, exercise, and hypoglycemia, glucagon maintains hepatic glucose output through GCGR. The three receptors allow the pancreatic islets, gastrointestinal tract, central nervous system, and liver to dynamically adjust glucose supply, nutrient storage, and energy utilization according to nutritional status.

3 Coordinated Effects of the Three Receptors on Glucose Homeostasis, Appetite, and Energy Metabolism

3.1 Regulation of Glucose Homeostasis by GLP-1R

GLP-1R activation enhances glucose-dependent insulin secretion and indirectly suppresses glucagon release under hyperglycemic conditions, thereby reducing hepatic glucose output. GLP-1R agonism also delays gastric emptying and slows the delivery of nutrients to the small intestine, lowering the postprandial glucose peak.

3.2 Regulation of Pancreatic Islet Function by GIPR

GIPR activation enhances β-cell responsiveness to glucose stimulation and increases early postprandial insulin secretion. When GLP-1R is activated simultaneously, GIPR can further improve glycemic control and may enhance weight loss through central nervous system and adipose-tissue signaling. Its therapeutic effect depends not only on insulin secretion but also on receptor potency, nutritional status, and central exposure.

3.3 Regulation of Hepatic Glucose Output by GCGR

GCGR promotes hepatic glycogenolysis through cAMP-protein kinase A signaling and regulates gluconeogenic enzymes and substrate utilization. This action is necessary for maintaining glucose stability during fasting and hypoglycemia. However, in type 2 diabetes, excessive glucagon secretion or insufficient suppression increases fasting and postprandial hepatic glucose output.

3.4 Central Regulation of Appetite and Food Reward

GLP-1R activation acts on hypothalamic, brainstem, and vagal nerve-associated circuits to enhance satiety and reduce the reward value of high-energy foods. The central effects of GIPR depend on neuronal type and metabolic status and can enhance weight reduction when combined with GLP-1R activation. The effects of GCGR on feeding are mediated more indirectly through hepatic metabolism, circulating signals, and neural afferent pathways.

3.5 Lipid Metabolism and Energy Expenditure

Weight reduction induced by GLP-1R agonism mainly results from decreased energy intake, whereas GCGR activation can promote hepatic fatty acid oxidation, amino acid catabolism, and energy expenditure. GIPR can alter adipose-tissue blood flow, nutrient uptake, and adipocyte function. Multi-receptor agonists combine appetite suppression, insulin secretion, and energy expenditure to produce broader metabolic effects than single-receptor agonism.

3.6 Potency Ratios in Multi-Receptor Agonists

The key to multi-receptor agonism is not maximal activation of every receptor but an appropriate balance of relative potency. Excessive GCGR activity can increase hepatic glucose output and heart rate, excessive GLP-1R activity can worsen nausea and delayed gastric emptying, and insufficient GIPR activity may weaken insulin secretion and synergistic weight reduction.

4 Abnormal GLP-1R, GIPR, and GCGR Signaling in Obesity and Type 2 Diabetes

4.1 Reduced Incretin Effect

The postprandial incretin effect is generally reduced in patients with type 2 diabetes. The insulinotropic action of GLP-1 is relatively preserved, whereas the insulinotropic effect of GIP is more markedly reduced. This is not caused solely by insufficient incretin secretion but by impaired responsiveness resulting from chronic hyperglycemia, β-cell dysfunction, and defects in downstream receptor signaling.

4.2 Decline in Pancreatic β-Cell Function

Chronic hyperglycemia, elevated free fatty acids, oxidative stress, and endoplasmic reticulum stress can reduce β-cell responsiveness to GLP-1 and GIP and impair glucose-stimulated insulin secretion. As β-cell reserve progressively declines, the glucose-lowering capacity remains limited even when receptor agonist intensity is increased.

4.3 Abnormal Glucagon Secretion

Type 2 diabetes is commonly associated with elevated fasting glucagon or insufficient postprandial glucagon suppression, causing hepatic glucose output to remain active when it is not required. Abnormal α-cell glucose sensing, reduced intra-islet insulin and somatostatin signaling, and altered hepatic glucagon sensitivity can all contribute to this process.

4.4 Impaired Central Satiety Signaling

In obesity, hypothalamic inflammation, leptin resistance, and abnormal reward circuitry can reduce the effectiveness of physiological satiety signals. Long-acting GLP-1R and multi-receptor agonists provide stronger and more sustained receptor stimulation and can partially overcome the short duration of endogenous peptide signaling and insufficient central responsiveness.

4.5 Metabolic Abnormalities in Adipose Tissue and the Liver

Adipocyte hypertrophy, hypoxia, and inflammation reduce the storage capacity of adipose tissue, increase fatty acid spillover into the liver and skeletal muscle, and aggravate insulin resistance. Hepatic insulin resistance and relative glucagon excess jointly promote hepatic glucose output and lipid accumulation, forming a metabolic cycle in which hyperglycemia, fatty liver, and hyperinsulinemia reinforce one another.

5 Glucose-Lowering and Weight-Reducing Mechanisms of GLP-1R Single-Receptor Agonists

5.1 Enhancement of Insulin Secretion

GLP-1R agonists increase cAMP levels in β cells and enhance insulin granule release after glucose stimulation. Because this action is glucose-dependent, the risk of severe hypoglycemia is relatively low when these agents are used alone. However, hypoglycemia remains a concern when they are combined with exogenous insulin or sulfonylureas.

5.2 Suppression of Abnormal Glucagon Signaling

GLP-1R agonists reduce glucagon secretion under hyperglycemic conditions, thereby decreasing hepatic glycogenolysis and gluconeogenesis. This effect is primarily mediated indirectly through intra-islet insulin, somatostatin, and neural regulation, and does not require all α cells to directly express high levels of GLP-1R.

5.3 Delayed Gastric Emptying

GLP-1R agonists slow the movement of gastric contents into the small intestine, reducing postprandial glucose absorption and glucose peaks. The gastric-emptying effect of short-acting agonists is generally more pronounced. Some tachyphylaxis can occur during sustained use of long-acting agonists, so long-term glucose-lowering and weight-reducing effects depend more strongly on pancreatic islet and central mechanisms.

5.4 Suppression of Appetite and Energy Intake

GLP-1R agonists enhance satiety through central nervous system and vagal nerve-associated pathways, reduce meal size, and decrease preference for high-energy foods. Their weight-reducing effect mainly results from sustained reductions in energy intake rather than a marked increase in basal energy expenditure.

5.5 Improvement of Insulin Resistance and Hepatic Steatosis

As body weight and visceral fat decrease, insulin sensitivity in the liver and skeletal muscle improves, and free fatty acid flux and hepatic lipid accumulation decline. Improvements in blood glucose, lipids, and inflammatory status further reduce β-cell burden. However, the relative contributions of weight-dependent and weight-independent mechanisms differ among metabolic outcomes.

5.6 Limitations of Single-Receptor Agonism

The maximum dose of GLP-1R agonists is often limited by nausea, vomiting, diarrhea, constipation, and delayed gastric emptying. Individual sensitivity to appetite suppression and gastrointestinal reactions varies substantially. Increased food intake and weight regain after treatment discontinuation also indicate that obesity generally requires sustained therapy and lifestyle management.

6 Synergistic Therapeutic Mechanisms of Dual and Triple Receptor Agonists

6.1 Dual GLP-1R/GIPR Agonism

Dual GLP-1R/GIPR agonists simultaneously enhance glucose-dependent insulin secretion, central satiety signaling, and regulation of adipose-tissue metabolism. Tirzepatide is a representative dual GLP-1R/GIPR agonist. Its effects are not simply the sum of two single-receptor agonists but depend jointly on relative receptor potency, tissue exposure, pharmacokinetics, and internalization characteristics.

6.2 Dual GLP-1R/GCGR Agonism

Dual GLP-1R/GCGR agonists use GLP-1R to reduce appetite, promote insulin secretion, and limit hyperglycemia, while using GCGR to enhance fatty acid oxidation and energy expenditure. GLP-1R activity must sufficiently offset GCGR-mediated increases in hepatic glucose output, making the potency ratio between the two receptors critical for efficacy and safety.

6.3 Dual GIPR/GCGR Agonism

GIPR activation enhances glucose-dependent insulin secretion and can partially buffer the increase in blood glucose caused by GCGR activation. This combination acts simultaneously on the pancreatic islets, adipose tissue, and liver, but its ability to suppress appetite and produce sustained weight loss depends on central exposure and the signaling characteristics of GIPR.

6.4 Triple GLP-1R/GIPR/GCGR Agonism

Triple agonists integrate GLP-1R-mediated suppression of food intake, GIPR-mediated enhancement of pancreatic islet function, and GCGR-mediated increases in energy expenditure into a single molecule. Retatrutide is a representative molecule in this class and is designed to further improve body weight and hepatic fat while maintaining glycemic control.SAR441255 is also a single-molecule triagonist that activates GLP-1R, GIPR, and GCGR with relatively balanced potency and can be used to investigate how these three receptors coordinately regulate body weight and glycemic control.

Figure 1. Mechanism by which the SAR441255 triagonist promotes weight loss and improves glycemic control through coordinated activation of GLP-1R, GIPR, and GCGR

6.5 Signaling Bias and Receptor Internalization

Multi-receptor agonists may show different biases in cAMP production, β-arrestin recruitment, receptor internalization, and endosomal signaling. Reducing rapid internalization or prolonging cell-surface signaling may improve sustained pharmacological activity but can also alter receptor desensitization, tissue selectivity, and adverse effects. Candidate molecules therefore cannot be evaluated using cAMP potency alone.

Multi-receptor synergy should involve mechanistically complementary effects. For example, GLP-1R and GIPR enhance insulin secretion and limit the hyperglycemic effect of GCGR, while GCGR adds an energy-expenditure mechanism to the appetite-dependent weight-reducing effect of GLP-1R. An imbalanced receptor profile may convert an additional target into a source of adverse effects rather than improved efficacy.

Table 2 Differences Between Single-Receptor and Multi-Receptor Agonist Strategies

7 Clinical Applications of Multi-Receptor-Targeted Drugs in Obesity and Type 2 Diabetes

7.1 Glycemic Control in Type 2 Diabetes

GLP-1R single-receptor agonists and GLP-1R/GIPR dual agonists lower fasting and postprandial glucose and improve glycated hemoglobin. Actual efficacy is influenced by baseline glucose, disease duration, β-cell reserve, renal function, and concomitant medications and cannot be predicted solely from receptor agonist potency.

7.2 Weight Management in Obesity

Multi-receptor agonists promote weight loss through sustained appetite suppression, reduced food intake, improved adipose-tissue function, and increased energy expenditure. Treatment evaluation should include waist circumference, visceral fat, blood pressure, triglycerides, and insulin resistance rather than relying only on total body weight.

7.3 Obesity With Type 2 Diabetes

Patients with both obesity and type 2 diabetes exhibit hyperglycemia, insulin resistance, abnormal fat distribution, and cardiovascular risk factors. Multi-receptor agonists act simultaneously on the pancreatic islets, central nervous system, liver, and adipose tissue and are suitable for metabolic phenotypes requiring both glycemic and weight control.

7.4 Metabolic Dysfunction-Associated Steatotic Liver Disease

GLP-1R agonism reduces hepatic fat through weight loss and improved insulin resistance. Dual or triple agonists with GCGR activity may additionally enhance hepatic fatty acid oxidation and lipid mobilization. A reduction in hepatic fat does not necessarily indicate simultaneous reversal of hepatic inflammation and fibrosis, so imaging, liver enzymes, and histological indicators should be evaluated separately.

7.5 Cardiovascular and Renal Metabolic Risk

Improvements in body weight, glucose, blood pressure, inflammation, and blood lipids can jointly reduce cardiorenal metabolic risk. However, the long-term cardiovascular and renal effects of different molecules cannot be inferred solely from receptor composition. Drugs with GCGR activity also require monitoring of heart rate, blood pressure, and hepatic metabolic changes.

7.6 Adverse Reactions and Dose Escalation

Common adverse reactions include nausea, vomiting, diarrhea, constipation, abdominal discomfort, and excessive appetite suppression. Gradual dose escalation can reduce initial gastrointestinal reactions. Drugs with GCGR activity additionally require monitoring of blood glucose, heart rate, liver enzymes, and amino acid metabolism.

7.7 Body Composition and Nutritional Management

Rapid weight loss generally reduces both fat mass and lean mass. Dual-energy X-ray absorptiometry or other body-composition methods should therefore be used to evaluate changes in adipose and muscle tissues. Adequate protein intake, resistance exercise, and an appropriate rate of weight loss help reduce excessive loss of lean body mass.

8 Evaluation of Receptor Binding, Signaling Activity, and Metabolic Effects

8.1 Receptor-Binding Evaluation

Recombinant receptor proteins, receptor-expressing cells, or cell-membrane preparations can be used for ligand-binding and competitive-binding assays. Major parameters include equilibrium dissociation constants, half-maximal inhibitory concentrations, association rates, and dissociation rates. Multi-receptor agonists should be tested separately against all three receptors using the same assay platform and comparable receptor-expression conditions to obtain comparable relative affinities.

8.2 cAMP Signaling Activity

cAMP is the most direct functional readout of GLP-1R, GIPR, and GCGR activation. Evaluation should compare half-maximal effective concentration, maximum response, and signal duration and should use endogenous ligands such as GLP-1, GIP, and glucagon as references. A single EC50 value is insufficient to determine the potency balance of a multi-receptor agonist.

8.3 β-Arrestin Recruitment and Receptor Internalization

β-Arrestin recruitment reflects receptor phosphorylation and desensitization tendencies, whereas receptor-internalization assays evaluate loss of cell-surface receptors and intracellular trafficking. Integrated analysis of cAMP, β-arrestin, and internalization results can determine whether a candidate agonist displays signaling bias and whether bias differs among receptors.

8.4 Evaluation of Pancreatic Hormone Secretion

GLP-1R and GIPR activity can be assessed using glucose-stimulated insulin secretion assays, with low, medium, and high glucose conditions included to confirm glucose dependence. GCGR-related studies can measure hepatocyte cAMP, glycogenolysis, and glucose output while simultaneously measuring insulin, C-peptide, and glucagon.

8.5 Evaluation of Food Intake and Gastric Emptying

Feeding studies should separately record first-meal intake, cumulative food intake, food preference, and meal frequency. Conditioned taste-aversion experiments or related assessments should be used to exclude reductions in food intake caused by nausea or discomfort. Gastric emptying should be evaluated independently and should not be directly interpreted as a central satiety effect.

8.6 Energy Expenditure and Substrate Utilization

Indirect calorimetry measures oxygen consumption, carbon dioxide production, respiratory exchange ratio, and activity levels and is used to analyze total energy expenditure and utilization of lipid and carbohydrate substrates. Energy-expenditure results should be interpreted together with body weight, lean mass, food intake, and ambient temperature to avoid misclassifying body-size differences as drug effects.

8.7 Evaluation of Blood Glucose, Body Weight, and Hepatic Metabolism

Comprehensive metabolic evaluation includes fasting glucose, oral glucose tolerance, glycated hemoglobin, insulin, C-peptide, glucagon, body weight, waist circumference, and body composition. Candidate drugs with GCGR activity should additionally be evaluated for hepatic glucose output, hepatic fat, plasma amino acids, urea-cycle indicators, and fatty acid oxidation.

Table 3 Major Evaluation Indicators in GLP-1R, GIPR, and GCGR Research

9 Products

9.1 Receptors, Ligands, and Functional Intervention Products

9.2 Receptor Agonists and Signal-Regulating Compounds

GLP-1R, GIPR, and GCGR regulate insulin secretion, feeding behavior, nutrient handling, and hepatic energy metabolism, respectively. The therapeutic advantages of multi-receptor agonists arise from the complementarity of these mechanisms, but glucose-lowering efficacy, weight reduction, and safety depend on receptor potency ratios, signaling bias, tissue exposure, and dose-escalation strategy.

For more related articles, please see below:

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[2] A Detailed Guide to the Construction of Animal Models for Metabolic Diseases