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The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment. Show less

Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood. To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D). A long-acting GIPR agonist (LY3537021) was characterized in vitro and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore. In vitro, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. In vivo in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25-64 years]; MAD, n = 38 [aged 25-69 years]; average baseline BMI was 25.9-27.0 kg/m In vivo studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more diverse populations and in cohorts with overweight/obesity to confirm these findings. GOV: NCT04586907. Show less

Our understanding of the intrinsic mechanisms that drive the regeneration of damaged axons after a spinal cord injury is still limited. Microtubules are core components of the eukaryotic cytoskeleton and are essential for axonal growth, in part because their stability is governed by post-translational modifications in mature neurons. Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are expressed in multiple extra-pancreatic tissues, suggesting biological functions beyond classical endocrine signaling; however, their roles in neuronal cytoskeletal regulation are not well defined. Here, we investigated the effects of GIP in cultured cortical neurons. GIP enhanced microtubule stability and increased the number of axons crossing an inhibitory chondroitin sulfate proteoglycan (CSPG) border. Mechanistically, GIP promoted microtubule acetylation via α-tubulin N-acetyltransferase 1 (αTAT1), the major acetyltransferase for α-tubulin, by suppressing αTAT1 ubiquitination and thereby reducing its proteasomal degradation in inhibitory environments. Although the upstream mechanism remains to be determined, this study provides the first evidence that GIP/GIPR signaling modulates microtubule dynamics, highlighting a potential strategy to re-activate neuronal growth machinery after injury. Show less

Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity. Show less

Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5-7.5 mg] or 4 once-weekly doses [5-12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was -4.7% to -8.0% across CT-388 doses vs -0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes. Show less

The incretin hormone glucagon-like peptide-1 (GLP-1) exerts potent effects on glucose metabolism, prompting the development of therapeutic strategies that enhance activity of the GLP-1 receptor (GLP-1R) pathway. Inhibitors of dipeptidyl peptidase 4 (DPP-4) prolong the half-life of endogenous GLP-1 and typically achieve reductions in HbA1c of 0.5%-0.8%. However, large-scale cardiovascular (CV) outcomes trials (CVOTs) with DPP-4 inhibitors demonstrated CV safety but did not show a reduction in CV events. A second incretin-based therapeutic approach was the development of GLP-1R agonists (GLP-1RAs). Various GLP-1RAs, including liraglutide, semaglutide, and dulaglutide, demonstrated a reduction in CV outcomes in large CVOTs. Initially, these medications were only available as injectable agents for subcutaneous administration, but recent technological advancements have enabled the development of orally available GLP-1RAs. A third incretin-based approach is tirzepatide, a dual agonist of GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR), which achieves greater HbA1c reduction and weight loss compared with GLP-1RAs alone. Ongoing large-scale CVOTs will determine its effects on hard cardiovascular endpoints. This Review summarizes the effects of GLP-1 and GLP-1RAs in the CV system as well as clinical data of GLP-1RAs in individuals with CV disease or high CV risk. Show less

Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less

Anti-obesity therapies co-targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor achieve greater weight loss compared with glucagon-like peptide-1 receptor agonists. However, the implications for cardiovascular risk reduction and the mechanisms involved remain unclear. This study aimed to (i) investigate whether genetically proxied body weight reduction via the GIP receptor pathway lowers cardiovascular disease risk and (ii) compare the effect to polygenic weight reduction, excluding GIP-related genes, to assess if the observed benefits are attributable to weight loss per se or involve additional GIP-related effects. Genetic scores were constructed using four variants in GIP-related genes associated with lower body mass index (BMI) and 31 variants linked to lower BMI in general. Observational and one-sample Mendelian randomization (MR) analyses were performed in 408 056 individuals from the UK Biobank and two-sample MR analyses using summary statistics from 419 821 individuals in FinnGen. In one-sample MR analyses, 1 kg/m² lower BMI via the GIP/GIPR score was associated with 29% lower risk of major adverse cardiovascular events (MACE) (P = .0002) and 43% lower risk of heart failure (P = 5 × 10⁻⁵). Corresponding lower risks with the polygenic BMI score were 3% (P = .002) and 13% (P < 1 × 10-300). Two-sample MR analyses showed similar results. Of the reduced risk via the GIP/GIPR score, BMI and glycated haemoglobin (HbA1c) mediated 13% and 22% of the lower risk of MACE and 16% and 17% of the lower risk of heart failure (all P ≤ 7 × 10-5). Genetic proxies for body weight reduction via GIP receptor targeting reduces the risk of MACE and heart failure, mediated partly through lower BMI and partly through lower HbA1c. Show less

Acromegaly, primarily caused by GH-secreting pituitary neuroendocrine tumors (GH-PitNETs), in about half of cases exhibits resistance to somatostatin receptor ligands (SRLs), making surgery the primary treatment. Recent evidence suggests that glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression in a subset of GH-PitNETs contributes to disease heterogeneity, particularly in tumors showing a paradoxical GH rise after glucose load, which are associated with a less aggressive phenotype and better first-generation SRLs response. This study investigated the functional role of GIPR in somatotroph cells by generating stable human GIPR-expressing GH3 cells (GH3hGIPR) and comparing them with empty vector controls. Functional assays demonstrated that GIPR activation induces cAMP/PKA and MAPK/ERK signaling, enhances GH and prolactin secretion, and increases intracellular calcium oscillations, dependent on extracellular calcium influx. Transcriptomic analysis revealed differential gene expression patterns linked to cell motility, neuronal development, and extracellular matrix remodeling in GH3hGIPR cells, aligning with clinical observations in GIPR+ tumors. However, GIPR overexpression did not alter cell proliferation or viability, suggesting that its role in tumor behavior may depend on additional molecular or epigenetic factors. These findings highlight the importance of GIPR signaling in somatotroph cell function and its potential influence on therapeutic responses, though further studies are needed to clarify its contribution to tumorigenesis and SRL sensitivity. Show less

Aberrant expression of glucose-dependent insulinotropic peptide receptors (GIPR) might regulate increased steroidogenesis in patients with ACTH-independent cortisol hypersecretion. This study investigated the presence of aberrant GIPR expression in patients with ACTH-independent cortisol hypersecretion and bilateral adrenal adenomas.Patients with bilateral adrenal adenomas, ACTH-independent CS and aberrant GIPR screened via mixed meal test were included. Patients' demographic features and laboratory and imaging findings were obtained retrospectively.Twenty-one patients were included. Overt CS findings were present in 14.3% of the patients. One patient (4.7%) had a complete positive response (537% increase) and one patient (4.7%) had a partial response (41% increase) to the mixed meal test. In the remaining 19 patients, a mean change of -10.1% (range: -56.5% to+24.7%) in cortisol levels was observed at 120 min compared to baseline. The patient with a complete positive response was confirmed using 100 µg of IV octreotide. The patient underwent unilateral adrenalectomy after an inadequate long-term response to octreotide LAR therapy. The histopathology revealed bilateral macronodular adrenal cortical disease. We identified a germline heterozygous frameshift variant in the KDM1A gene in the patient's blood sample and a recurrent deletion of the p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample.These results may provide useful insights into the screening of aberrant GIPR expression in patients with ACTH-independent hypercortisolism. It is essential to further investigate which patients require screening. Moreover, a significant cortisol peak observed during the mixed meal test in the presence of these receptors has drawn attention. Show less

Obesity is a chronic, complex condition defined by excessive fat buildup due to an imbalance between caloric consumption and energy expenditure. The significant global rise in prevalence of obesity is associated with numerous comorbidities, such as cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. Conventional management approaches, including diet, exercise, pharmacotherapy, and bariatric surgery, may demonstrate restricted long-term effectiveness owing to inadequate adherence and physiological adjustments. Recent advancements in neuroscience underscore the hypothalamus as a pivotal regulator of energy balance via essential nuclei, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), lateral hypothalamic area (LHA), and ventromedial nucleus (VMN). This review examines the therapeutic potential of a new anti-obesity peptide that targets hypothalamic signalling pathways. Preclinical and clinical evidence endorses the utilization of glucagon-like peptide-1 receptor (GLP-1R) agonists and novel multi-receptor drugs such as AMG 133, which integrate GLP-1R activation with glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism. These therapies exhibit improved weight reduction and metabolic enhancement. Moreover, the integration of hypothalamic peptide therapy with lifestyle modifications or post-bariatric care provides synergistic advantages. Notwithstanding favorable results, peptide therapy encounters obstacles such as administration methods, sustained effectiveness, and expense. Overcoming these obstacles is crucial for the effective implementation of peptide-based treatments in sustained clinical obesity control. Show less

Fructose ingestion increases circulating glucagon-like peptide-1 (GLP-1) and insulin, yet the specific contributions of these hormonal responses to glycaemic control remain incompletely defined. We hypothesised that fructose metabolism in intestinal L-cells triggers GLP-1 secretion, which then potentiates insulin secretion and counteracts fructose-induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24 h ad libitum fructose ingestion. In both lean (NSY.B6-a/a) and obese diabetic (NSY.B6-A Show less

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology. Show less

Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios. Show less

Cardiometabolic diseases (CVDs) are the leading cause of premature mortality and disability worldwide, arising from of cardiovascular and metabolic dysregulation. This review focuses on six critical therapeutic targets established in cardiometabolic regulation: GLP-1R, GIPR, FGFR1/β-Klotho, PCSK9, NF-κB, and the NLRP3 inflammasome. Drawing on curated structural datasets, we analyze the mechanisms of action and map key binding domain features that govern ligand efficacy and specificity. Dual GLP-1R/GIPR agonists, such as tirzepatide, demonstrate superior outcomes in glycemic control and weight reduction. Concurrently, inhibiting PCSK9, NF-κB, and NLRP3 helps to lower cholesterol and reduce harmful inflammation, offering cardioprotection. Structural analysis across these targets reveals complementary motifs (aromatic, hydrophobic, and polar residues). These insights guide the rational design of next-generation multi-target ligands (molecules capable of modulating two or more biological targets involved in related disease pathways, producing integrated therapeutic effects). Such integrated agents are promising for providing combined cardiovascular and metabolic benefits, thus reducing the risks associated with complex therapeutic drug combinations. Show less

Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the synergistic effects of tirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a potential way for better maintenance of metabolic homeostasis in obesity management. Show less

Intestinal dysmotility in type 2 diabetes mellitus (T2DM) may involve impaired cholinergic and incretin-mediated regulation. This study compared cholinergic-induced jejunal contractility and evaluated the effects of Glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP) in relation to the expression of these peptides, their receptors, and Dipeptidyl peptidase 4 (DPP-4) in jejunal muscle of obese patients with and without T2DM. Jejunal samples were collected from 32 obese patients undergoing bariatric surgery (14 with and 18 without T2DM). Jejunal muscular tissue was examined for expression of GLP-1, GIP, and for expression and localization of DPP-4 and incretin receptors (GLP-1R and GIPR). In addition, DPP-4 enzymatic activity was quantitatively assessed. Contractility of circular and longitudinal muscle strips was assessed GLP-1 receptors were detected in smooth muscle nuclei and enteric ganglia, while GIP receptors localized to both muscle layers. DPP-4 was present in neural and muscular compartments. In T2DM, GIPR and DPP-4 expression and activity were increased, while GIP protein was reduced. GLP-1 protein levels tended to be higher. Longitudinal muscle contractility independent of neural input was reduced in T2DM. GLP-1 selectively inhibited circular muscle contractions in both groups, whereas GIP had no effect. This study demonstrates that reduced cholinergic activity in longitudinal muscle, lower GIP, and increased GLP-1 in T2DM indicate a shifted local incretin environment that may collectively suppress jejunal contractility. Show less

Osteoarthritis (OA) is a progressive joint disease with no disease-modifying therapies. Incretin-related signaling pathways, including GLP1R, GIPR, ADCY3, and CREB1, may influence cartilage homeostasis and inflammation, but their transcriptional profiles across cohorts remain unclear. To evaluate the expression, diagnostic potential, and functional context of GLP1R, GIPR, ADCY3, and CREB1 in OA cartilage through an integrative meta-analysis of public transcriptomic datasets. We systematically searched the GEO database, identifying 147 records. After screening and applying inclusion criteria, four datasets were included (GSE114007, GSE117999, GSE169077, GSE220243; total N = 83). Expression data were normalized within each dataset, converted to per-gene z-scores, and analyzed using random-effects meta-analysis. Machine learning classifiers (logistic regression, random forest, XGBoost) were trained with leave-one-dataset-out validation. Functional enrichment was performed using g:Profiler. Protocol registration: PROSPERO CRD420251177348. CREB1 (pooled mean difference +0.459, p = 0.036) and GLP1R (+0.518, p = 0.016) were significantly upregulated in OA cartilage, ADCY3 was downregulated (-0.552, p = 0.010), while GIPR showed no significant change. Heterogeneity was low (I A multi-cohort transcriptomic analysis suggests the involvement of a GLP1R-ADCY3-cAMP-CREB1 axis in OA cartilage, with reproducible upregulation of CREB1 and GLP1R. Although sample-level classification was modest, pathway-level signals and experimental evidence support CREB1 as a biomarker candidate and therapeutic target. These findings provide a rationale for prospective validation studies and translational exploration of incretin-pathway modulation in OA. Show less

To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism. Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA) were established to evaluate the impact of GIP on androgen synthesis Administration of GIP significantly reduced testosterone secretion in a DHEA-induced PCOS mouse model. Consistent with these findings, GIP treatment decreased testosterone release and downregulated the expression of GIP receptor (GIPR), steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1) in NCI-H295R cells. Notably, RNA-seq revealed that Our study demonstrated that the administration of GIP reduces androgen synthesis in PCOS mouse models and at the cellular level, suggesting its potential as a novel therapeutic target for managing PCOS. Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that affects the human blood glucose levels. Previous studies have confirmed the role of the gastric inhibitory polypeptide receptor (GIPR) gene in T2DM, obesity, and other human diseases. This study aimed to identify the molecular role of 5 SNPs (rs1800436, rs1800437, rs2302382, rs10423928, and rs34125392) in the GIPR gene in patients with T2DM in the Saudi population. This prospective case-control study enrolled 118 T2DM cases and 118 control participants based on the inclusion and exclusion criteria. Serum was collected from peripheral blood for biochemical tests, while EDTA blood was used for HbA1c and molecular analysis. In this study, T2DM cases were compared with control population to study the baseline characteristics along with molecular data. Genotyping and allelic association analysis showed that rs2302382, (OR-2.757 and OR-2.303) and rs10423928 (OR-3.859 and 2.206) are associated, while genotyping analysis alone showed rs34125392 (OR-1.776) is associated. The co-dominant model (OR-2.226) was associated with obese vs. non-obese participants among T2DM cases (p = 0.039). Females showed a positive association with rs2302382 (OR-3.701; p = 0.003) and rs10423928 (OR-2.343; p = 0.033) SNPs, while males showed a positive association with rs1800437 (OR-1.849; p = 0.040) rs2302382 (OR-2.418; p = 0.016), and rs10423928 (OR-3.641; p = 0.019) SNPs. ANOVA analysis and linkage disequilibrium exhibited a positive association along with gene-gene interaction in GMDR analysis. Linear regression, haplotype analysis and Frutcherman-Reingold, circle, and Kamada-Kawali models showed negative association. Our findings confirm a strong and significant association between rs2302382, rs10423928 and rs34125392 SNPs in T2DM. Additional analyses, such as ANOVA, haplotype analysis, gene-gene interaction, and graphical depiction models revealed genetic interactions among the studied SNPs. Show less

Incretin mimetics, especially dual/triple agonists, are effective for type 2 diabetes and obesity, though mechanisms remain unclear. This study applied PET using [ In vitro binding assays on frozen HEK293 cell sections overexpressing human GLP-1R, GIPR, or GCGR assessed [ [ PET imaging in pigs demonstrated in vivo GLP-1R engagement by SAR441255 and tirzepatide, and GIPR engagement by SAR441255 in the pancreas. SAR441255 exhibited dose-dependent GLP-1R occupancy in the pancreas and brain regions linked to appetite regulation. The study was funded by Uppsala Diabetes Center, Diabetesfonden, ExoDiab, Diabetes Wellness Sweden, Barndiabetesfonden, Science for Life Laboratory, and the Swedish Research Council. Show less

BackgroundCurrent therapeutic strategies for Alzheimer's disease (AD) demonstrate limited efficacy in decelerating disease progression, underscoring an exigent need for the development of more potent disease-modifying therapeutics.ObjectiveThe primary aim of this research was to identify novel therapeutic targets to improve AD prognosis.MethodsFirst, we conducted a meta-analysis of brain tissue transcriptome datasets from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) associated with AD. Next, Mendelian randomization (MR) and summary-based MR (SMR) analyses were utilized to screen for potential AD drug targets. Colocalization analyses were employed to examine whether DNA methylation, gene expression, and AD risk are driven by shared single nucleotide polymorphisms (SNPs). Finally, single-gene gene set enrichment analysis (GSEA), protein-protein interaction (PPI) networks, drug prediction, and molecular docking were employed to infer potential biological mechanisms.ResultsA meta-analysis of twelve brain tissue datasets revealed 262 druggable AD-related DEGs. According to MR analysis, Show less

Glucagon-like peptide-1 (GLP-1) is a hormone known for its critical functions in managing blood sugar and offering cardiovascular benefits. Our study focuses on Glucagon Like Peptide 1 Receptor (GLP1R) agonists that act beyond glycemic control in cardiovascular and metabolic health. A comprehensive bioinformatic analysis was conducted, incorporating GLP1R, Gastric Inhibitory Polypeptide Receptor (GIPR), Gastric Inhibitory Polypeptide (GIP) and glucagon receptor (GCGR) to assess the effects of GLP1R agonists on gene and metabolite interactions. Interaction network analysis revealed 130 common genes among GLP1R, GLP1R/GIPR, GLP1R/GIP, and GLP1R/GIPR/GCGR associated with diabetes-related processes, including obesity and hyperglycemia. Enriched terms related to cardiovascular diseases, such as hypertension, calcium regulation in cardiac cells, and amino acid accumulation-induced mTOR activation. We also observed enrichment in gene sets linked to longevity and less recognized terms like fatty liver disease. In GLP1R/GIP, behavior-related terms and gastric acid secretion were identified; GLP1R/GIPR/GCGR linked to fibrosarcoma, thought/speech disturbances, and adipogenesis. The metabolite-gene layer revealed enrichment in galactose metabolism, platelet homeostasis, and nitric-oxide pathways. We found that GLP1R agonists network-level associations are stronger with heart diseases than sodium-glucose co-transporter 2 inhibitors, suggesting greater therapeutic benefits. Integrating networks with metabolites highlighted key interactors and clarified GLP1R agonists' mechanisms and therapeutic potential. Show less

Epicardial adipose tissue (EAT) is a visceral fat depot surrounding the myocardium. It contributes to coronary artery disease (CAD) through local inflammation, while its metabolic activity, including the expression of uncoupling protein-1 (UCP-1) and incretin receptors (GLP-1R, GIPR), may exert protective effects. The relationship between EAT immunohistochemical features and imaging-derived volume remains unclear. We prospectively studied 50 patients undergoing cardiac surgery: 25 with CAD undergoing coronary artery bypass grafting and 25 without CAD undergoing valve replacement. EAT samples were immunohistochemically stained for CD3, CD68, MPO, UCP-1, GLP-1R, and GIPR. Preoperative CT was used to quantify EAT volume. Patients with CAD more frequently had higher CD3 immunopositivity compared to the control group (84.0 vs. 58.3%, EAT in CAD exhibits increased T-cell infiltration and elevated UCP-1 expression, indicating an inflammatory yet metabolically active profile. Larger EAT volume was associated with UCP-1 and GLP-1R expression, underscoring the immunometabolic role of EAT in CAD. Show less

Obesity is a complex, multifactorial disease wherein the excessive accumulation of adipose tissue leads to adverse health outcomes, such as diabetes, cardiovascular disease and musculoskeletal disorders. Obesity also impacts both the risk and the clinical prognosis of heart failure (HF). The accumulation of adipose tissue results in metabolic dysregulation, including increased levels of pro-inflammatory cytokines and adipokines. These alterations are strongly associated with the development and progression of HF. Another significant comorbidity in patients with HF is sarcopenia, characterized by progressive loss of muscle mass and strength, affecting the quality of life. The study aims to critically synthesize the mechanisms by which modern pharmacological treatments-sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dual GIPR/GLP-1R agonists-modulate body mass composition, and to analyze the specific implications of these changes (e.g., visceral fat reduction versus lean mass loss) for heart failure (HF) prognosis and management. Show less

Epicardial adipose tissue (EAT), the visceral fat of the heart, is highly inflammatory fat depot with pro-inflammatory transcriptome and proteosome. EAT contributes to the development and progression of coronary artery disease (CAD) and atrial fibrillation (AF) through multifactorial inflammatory pathways. However, the paradigm linking EAT inflammation and cardiovascular risk was recently reevaluated. EAT inflammation may be also necessary process for adipose tissue remodeling and expansion to accommodate excess lipids. EAT inflammation may be also considered an adaptive response of adipose tissue to the effects of glucagon-like peptide-1 receptor (GLP-1Rs) and glucose-dependent insulinotropic polypeptide (GIP) analogs. The presence of GLP-1 (GLP-1R) and GIP receptors (GIP-R) suggest direct interaction of these agents with EAT. EAT GLP-1R and GIP-R activation can induce a beneficial balance between increased adipogenesis and reduced ectopic fat accumulation. Cardiovascular effects of liraglutide, semaglutide and tirzepatide can be mediated by EAT inflammation. Show less

Multi-target peptide therapeutics targeting glucagon receptor (GCGR), glucagon-like peptide-1 receptor (GLP1R), and glucose-dependent insulinotropic polypeptide receptor (GIPR) represent a promising approach for treating diabetes and obesity. Triple agonist peptides demonstrate promising therapeutic potential compared to single-target approaches, yet rational design remains computationally challenging due to complex sequence-structure activity relationships. Existing methods, primarily based on convolutional neural networks, impose limitations including fixed sequence lengths and inadequate representation of molecular topology. Graph Attention Networks (GAT) offer advantages in capturing molecular structures and variable-length peptide sequences while providing interpretable insights into receptor-specific binding determinants. A dataset of 234 peptide sequences with experimentally determined binding affinities was compiled from multiple sources. Peptides were represented as molecular graphs with seven-dimensional node features encoding physicochemical properties and positional information. The GAT architecture employed a shared encoder with task-specific prediction heads, implementing transfer learning to address limited GIPR training data. Performance was evaluated using 5-fold cross-validation and independent validation on 24 literature-derived sequences. A genetic algorithm framework was developed for peptide sequence optimization, incorporating multi objective fitness evaluation based on predicted binding affinity, biological plausibility, and sequence novelty. Cross-validation demonstrated robust GAT performance across all receptors, with GCGR achieving high accuracy (AUC ROC: 0.915 ± 0.050), followed by GLP1R (AUC-ROC: 0.853 ± 0.059), and GIPR showing acceptable performance despite limited data (AUC-ROC: 0.907 ± 0.083). Comparative analysis revealed receptor-specific advantages: GAT significantly outperformed CNN for GCGR prediction (RMSE: 0.942 vs. 1.209, p = 0.0013), while CNN maintained superior GLP1R performance (RMSE: 0.552 vs. 0.723). Genetic algorithm optimization measurable improvement over baseline, with 4.0% fitness Enhancement and generation of 20 candidates exhibiting mean binding probabilities exceeding 0.5 across all targets. The GAT-based framework provides a computational approach in computational peptide design, demonstrating receptor-specific advantages and robust optimization capabilities. Genetic algorithm optimization enables systematic exploration of sequence space within existing agonist scaffolds while maintaining biological constraints. This approach provides a rational framework for prioritizing experimental validation efforts in triple agonist development. Show less