The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates bone remodeling postprandially. Species variations complicate the development of long-acting agonists with similar effects on rodent and human GIP receptors (GIPR). We created a series of long-acting molecules suitable for rat studies based on human GIP, stabilized with Aib insertion in position 2, lipidations in the middle region (compounds 1-4: positions 14/16/17/20) or the C-terminus (compound 5: position 40), and elongation with an exendin-4 tail in the C-terminus (Cex). The compounds were tested in vitro on the human and rat GIPR for cAMP accumulation, beta-arrestin recruitment and internalization. Pharmacokinetic profiling in rats was completed for two compounds, and one was selected for bone remodeling studies in rats (measurements of C-terminal telopeptide (CTX) and procollagen type 1 N-propeptide). All five compounds retained the potency and efficacy of native (human and rat) GIP in cAMP accumulation and arrestin recruitment on human and rat GIPR with no differences in relative activities from native GIP. Only compound 3 induced internalization like species-matched GIP on respective receptors and was chosen for in vivo assessments in rats. Mean T1/2 was 9.1 h, and it decreased plasma levels of CTX compared to vehicle treatment following 1000 µg·kg-1 injections. In conclusion, the long-acting, unbiased compound 3 (hGIP(1-30-Cex)/Aib2/C16-diacid moiety in position 17), with retained activity for the human and rat GIPR, is suitable for bone remodeling studies in rats; hence, a useful tool compound for future research of GIP's therapeutic potential in bone-related diseases.

With recent clinical implementation of tirzepatide, patients with type 2 diabetes mellitus (T2DM) are transitioning from glucagon-like peptide 1 receptor agonists (GLP-1 RA) to a dual gastric inhibitory polypeptide (GIP)/GLP-1 RA-like tirzepatide. Limited literature is available for insulin dose adjustments for patients concurrently using insulin during this transition. In clinical trials, tirzepatide has shown greater glycated hemoglobin (A1c) reduction and glucose-lowering effects compared to GLP-1 RAs, such as semaglutide, suggesting a potential elevated risk of hypoglycemia without proactive insulin adjustments.

The primary objective of this study was to assess the percent change in daily insulin requirements 6 months after transitioning patients from GLP-1 RAs to tirzepatide.

This retrospective cohort study includes patients with T2DM who transitioned from a GLP-1 RA to tirzepatide while concurrently using insulin therapy. Patient-reported doses of insulin and study medications were collected by chart review by investigators, along with baseline demographics and adverse effects as additional endpoints.

Sixty-six patients were included. The median insulin dose reduced from 101 units at baseline to 71 units after 6 months, with a median decrease of 9.5 units (p < 0.001). The median percent change in insulin dose was -9.2%. Patients with a baseline A1c of 8.0% or lower required a larger decrease in insulin compared to patients with a higher baseline A1c (-22.6% vs. 0%, p = 0.018). The intensity of GLP-1 RA and tirzepatide, determined by agent and dose, did not show a difference in insulin requirements (p = 0.279 and p = 0.317, respectively). Hypoglycemia occurred in eight patients (12.1%).

Patients require a reduction in insulin when transitioning from GLP-1 RAs to tirzepatide, especially if baseline A1c is less than or equal to 8.0%. Larger, comparative studies need to be performed to provide specific recommendations for various doses and product types of incretin receptor agonists.

Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretin hormones playing key roles in the control of food intake, nutrient assimilation, insulin secretion and whole-body metabolism. Recent pharmacological advances and clinical trials show that unimolecular co-agonists that target the receptors for the incretins - GIP and glucagon-like peptide 1 (GLP-1) - offer more effective treatment strategies for obesity and type 2 diabetes mellitus (T2D) compared with GLP-1 receptor (GLP1R) agonists alone, suggesting previously underappreciated roles of GIP in regulating food intake and body weight. The mechanisms by which GIP regulates energy balance remain controversial as both agonism and antagonism of the GIP receptor (GIPR) produce weight loss and improve metabolic outcomes in preclinical models. Recent studies have shown that GIPR signalling in the central nervous system (CNS), especially in regions of the brain that regulate energy balance, is essential for its action on appetite regulation. This finding has sparked interest in understanding the mechanisms by which GIP engages brain circuits to reduce food intake and body weight. In this review, we present key knowledge around the actions of GIP on food intake regulation and the potential mechanisms by which GIPR and GIPR/GLP1R agonists may regulate energy balance.

The global prevalence of obesity is skyrocketing at an alarming rate, with recent data estimating that one-in-eight people are now living with the disease. Obesity is a chronic metabolic disorder that shares underlying pathophysiology with other metabolically-linked diseases such as type 2 diabetes mellitus, cardiovascular disease and diabetic cardiomyopathy. There is a distinct correlation between type 2 diabetes status and the likelihood of heart failure. Of note, there is an apparent sexual dimorphism, with women disproportionately affected with respect to the degree of severity of the cardiac phenotype of diabetic cardiomyopathy that results from diabetes. The current pharmacotherapies available for the attenuation of hyperglycaemia in type 2 diabetes are not always effective, and have varying degrees of efficacy in the setting of heart failure. Insulin can worsen heart failure prognosis whereas metformin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and more recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), have demonstrated cardioprotection with their administration. This review will highlight the advancement of incretin therapies for individuals with diabetes and heart failure and explore newly-reported evidence of the clinical usefulness of GLP-1R agonists in this distinct phenotype of heart failure.

Parkinson's disease (PD) is an age-related progressive disorder that leads to dopaminergic loss and subsequent motor dysfunction. Current therapies mainly deal with symptomatic effects, and hence, therapies targeting progressive neurodegeneration need to developed. In this study, tirzepatide, a coagonist of glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, exhibited a neuroprotective effect in preliminary studies. This study aims to evaluate the effect of tirzepatide, in comparison with exendin-4, in a rat model of PD. The effect of tirzepatide (50 and 100 nmol/kg, s.c.) and exendin-4 (8 μg/kg, s.c.) on behavioral functions, oxidative markers, inflammatory markers, dopamine level, and alpha-synuclein expression were studied against a rotenone (2 mg/kg)-induced toxicity model in rats. Tirzepatide prevented rotenone-induced motor deficits. Additionally, it significantly inhibited the rotenone-induced increase in proinflammatory cytokines TNF-α and IL-6. Furthermore, it upregulated striatal dopamine levels. It alleviated oxidative stress and alpha-synuclein aggregation. Both doses of tirzepatide exert neuroprotective effects in a PD rat model. Furthermore, the effect is dose-dependent, and a 100 nmol/kg dose of tirzepatide was found to be more effective.

Glucagon-like peptide 2 (GLP-2) is a proglucagon-derived peptide released by intestinal endocrine cells. However, its therapeutic potential is limited by rapid inactivation via dipeptidyl peptidase-IV. The elucidation of three-dimensional structures of G-protein-coupled receptors, including GLP-2 receptor, has facilitated the rational design of novel peptide therapeutics. Recent studies have explored various structural modifications based on the structure of GLP-2, such as amino acid substitution, lipidation, and fusion with proteins, to extend the half-life of GLP-2 and enhance its biological activity. One promising avenue involves the development of multifunctional molecules targeting multiple pharmacological systems to boost therapeutic efficacy. This paper reviews the recent advancements in understanding GLP-2, including its physiological roles and structure-activity relationships, and evaluates the development prospects of GLP-2 analogs.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.

In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.

Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

Incretin hormones, primarily composed of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted by enteroendocrine cells (EECs) and play crucial roles in maintaining blood glucose homeostasis. Notably, GIP accounts for two-thirds of the entire incretin effect. However, the secretion and function of GIP are impaired in individuals with type 2 diabetes mellitus (T2DM), and the regulatory mechanisms governing GIP secretion remain unclear.

Our study aims to explore the role of an EEC-enriched protein, Secretagogin (SCGN), in the regulation of GIP secretion.

We collected duodenal tissues from both humans and mice to observe the colocalization of SCGN and GIP in EECs. Additionally, we utilized human cohorts and gene-edited mouse models to investigate the effect of SCGN on GIP secretion. Our study included 128 subjects, comprising 64 individuals diagnosed with newly onset diabetes and 64 age- and sex-matched nondiabetic healthy controls. At the animal level, we employed leptin receptor-deficient (db/db) mice and Scgn knockout mice for our investigations.

Our findings indicate that SCGN is abundantly expressed in GIP-producing K cells within the intestinal epithelium of both humans and mice. We observed a positive correlation between SCGN and GIP levels in postprandial states among patients with T2DM, db/db mice, and their healthy controls. Notably, Scgn knockout mice exhibited decreased GIP and insulin secretion. However, SCGN deficiency did not affect K-cell number, GIP mRNA expression, or intestinal morphology.

Collectively, these findings demonstrate that SCGN is a key regulator of nutrient-induced GIP secretion.

Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes.

To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes.

MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024.

Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity.

The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs.

A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare.

No head-to-head RCTs were available. Heterogeneity prevented meta-analysis.

GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes.

None. (PROSPERO: CRD42024505558).

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become central in managing obesity and type 2 diabetes, primarily through appetite suppression and metabolic regulation. This review explores the mechanisms underlying GLP-1 RA-induced weight loss, focusing on central and peripheral pathways. Centrally, GLP-1 RAs modulate brain regions controlling appetite, influencing neurotransmitter and peptide release to regulate hunger and energy expenditure. Peripherally, GLP-1 RAs improve glycemic control by enhancing insulin secretion, reducing glucagon release, delaying gastric emptying, and regulating gut hormones. They also reduce triglycerides and low-density lipoprotein cholesterol, mitigate adipose tissue inflammation, and minimize ectopic fat deposition, promoting overall metabolic health. Emerging dual and triple co-agonists, targeting GLP-1 alongside glucose-dependent insulinotropic polypeptide, and glucagon pathways, may enhance weight loss and metabolic flexibility. Understanding these mechanisms is crucial as the therapeutic landscape evolves, offering clinicians and researchers insights to optimize the efficacy of current and future obesity treatments.

The present review describes the available literature on the physiologic mechanisms that modulate hunger, appetite, satiation, and satiety with a particular focus on well-established and emerging factors involved in the classic satiety cascade model.

Obesity is a significant risk factor for numerous chronic conditions like cancer, cardiovascular diseases, and diabetes. As excess energy intake is considered by some to be the primary driver of weight gain, tremendous collective effort should be directed toward reducing excessive feeding at the individual and population levels. From this perspective, detailed understanding of physiologic mechanisms that control appetite, and in turn, the design of effective interventions to manage appetite, may represent key strategies in controlling the obesity epidemic. With the obesity's prevalence on the rise worldwide, research on hunger, appetite, satiation and satiety is more relevant than ever. This research aims to provide practical insights for medical practitioners, nutrition professionals, and the broader scientific community in the fight against this global health challenge.

Metabolic peptides can influence metabolic processes and contribute to both inflammatory and/or anti-inflammatory responses. Studies have shown that there are thousands of metabolic peptides, made up of short chains of amino acids, that the human body produces. These peptides are crucial for regulating many different processes like metabolism and cell signaling, as they bind to receptors on various cells. This review will cover the role of three specific metabolic peptides and their roles in hyperinsulinemia, diabetes, inflammation, and neurodegeneration, as well as their roles in type 3 diabetes and dementia. The metabolic peptides glucagon-like peptide 1 (GLP-1), gastric inhibitor polypeptide (GIP), and pancreatic peptide (PP) will be discussed, as dysregulation within their processes can lead to the development of various inflammatory and neurodegenerative diseases. Research has been able to closely investigate the connections between these metabolic peptides and their links to the gut-brain axis, highlighting changes made in the gut that can lead to dysfunction in processes in the brain, as well as changes made in the brain that can lead to dysregulation in the gut. The role of metabolic peptides in the development and potentially reversal of diseases such as obesity, hyperinsulinemia, and type 2 diabetes will also be discussed. Furthermore, we review the potential links between these conditions and neuroinflammation and the development of neurodegenerative diseases like dementia, specifically Parkinson's disease and Alzheimer's disease.

Modulating the endogenous stores of gastrointestinal hormones is considered a promising strategy to mimic gut endocrine function, improving metabolic dysfunction. Here, we exploit mouse and human knock-in and knockout intestinal organoids and show that agents used as commercial lipid excipients can activate nutrient-sensitive receptors on enteroendocrine cells (EECs) and, when formulated as lipid nanocarriers, can bestow biological effects through the release of GLP-1, GIP, and PYY from K and L cells. Studies in wild-type, dysglycemic, and gut Gcg knockout mice demonstrated that the effect exerted by lipid nanocarriers could be modulated by varying the excipients (e.g., nature and quantities), the formulation methodology, and their physiochemical properties (e.g., size and composition). This study demonstrates the therapeutic potential of using nanotechnology to modulate release of multiple endogenous hormones from the enteroendocrine system through a patient-friendly, inexpensive, and noninvasive manner.

Diabetes mellitus (DM) has a millennia-long history, with early references dating back to ancient Egypt and India. However, it was not until the 20th century that the connection between diabetes and insulin was fully understood. The sequencing of insulin in the 1950s initiated the convergence of biotechnology and diabetes management, leading to the development of recombinant human insulin in 1982. This marked the start of peptide-based therapies in DM. Recombinant peptides for DM treatment: Numerous recombinant peptides have been developed since, starting with modified insulin molecules, with the aim of bettering DM management through fine-tuning the glycemic response to insulin. Peptide-based therapies in DM have expanded substantially beyond insulin to include agonists of Glucagon-like peptide-1 receptor and Glucose-dependent insulinotropic polypeptide receptor, glucagon receptor antagonists, and even peptides exerting multiple receptor agonist effects, for better metabolic control. Insulin pumps, continuous glucose monitoring, and automated insulin delivery systems: The development of modern delivery systems combined with real-time glucose monitoring has significantly advanced diabetes care. Insulin pumps evolved from early large devices to modern sensor-augmented pumps with automated shutoff features and hybrid closed-loop systems, requiring minimal user input. The second-generation systems have demonstrated superior outcomes, proving highly effective in diabetes management. Islet cell transplantation, organoids, and biological pancreas augmentation represent innovative approaches to diabetes management. Islet cell transplantation aims to restore insulin production by transplanting donor beta cells, though challenges persist regarding graft survival and the need for immunosuppression. Organoids are a promising platform for generating insulin-producing cells, although far from clinical use. Biological pancreas augmentation relies on therapies that promote beta-cell (re)generation, reduce stress, and induce immune tolerance. Further biotechnology-driven perspectives in DM will include metabolic control via biotechnology-enabled tools such as custom-designed insulin hybrid molecules, machine-learning algorithms to control peptide release, and engineering cells for optimal peptide production and secretion.

Endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate islet cell function. GLP-1 receptor agonists (GLP-1RAs) have been associated with an elevated risk of acute pancreatitis. Data on the pancreatic safety of tirzepatide (a dual GLP-1 and GIP agonist) and its effects on islet cell function in randomized controlled trials (RCTs) are scarce. Moreover, no meta-analysis has comprehensively examined such effects of tirzepatide.

Electronic databases were searched for RCTs with tirzepatide as the intervention and a placebo or active comparator as the control. The primary outcome was adjudication-confirmed pancreatitis; secondary outcomes were the percent changes from baseline in serum pancreatic amylase, lipase, insulin, C-peptide, glucagon, and homeostasis model assessment of insulin resistance (HOMA2-IR).

Seventeen RCTs with 18 published reports involving 14,645 subjects were analyzed. Over a follow-up duration of 12-72 weeks, tirzepatide had identical risks of pancreatitis to placebo (tirzepatide 5 mg: RR 2.04, 95% CI [0.27-15.69], p = 0.49; 10 mg: RR 0.63, 95% CI [0.08-5.12], p = 0.67; and 15 mg: RR 1.26, 95% CI [0.36-4.98], p = 0.72). Tirzepatide was also associated with comparable risks of pancreatitis to insulin and GLP-1RAs. However, tirzepatide (at all doses) caused greater increases in pancreatic amylase and lipase than placebo and insulin. Individuals on tirzepatide 15 mg and GLP-1RAs had similar risks of having increased lipase levels. The percent reductions in fasting insulin were greater with tirzepatide 10 and 15 mg than with placebo. All doses of tirzepatide caused greater percent reductions in fasting insulin, C-peptide, and glucagon than GLP-1RAs. Compared to placebo and GLP-1RAs, the percent reductions in HOMA2-IR were greater with all doses of tirzepatide.

The meta-analysis provides evidence of the safety of tirzepatide regarding pancreatitis and establishes its positive effect on islet cell functions and insulin resistance.

Alpha cells in the pancreas, traditionally known for their role in secreting glucagon to regulate blood glucose levels, are gaining recognition for their involvement in the pathophysiology of type 1 diabetes (T1D). In T1D, autoimmune destruction of beta cells results in insulin deficiency, which in turn may dysregulate alpha cell function, leading to elevated glucagon levels and impaired glucose homeostasis. This dysfunction is characterized by inappropriate glucagon secretion, augmenting the risk of life-threatening hypoglycemia. Moreover, insulin deficiency and autoimmunity alter alpha cell physiological responses, further exacerbating T1D pathophysiology. Recent studies suggest that alpha cells undergo transdifferentiation and interact with beta cells through mechanisms involving gamma-aminobutyric acid (GABA) signaling. Despite these advances, the exact pathways and interactions remain poorly understood and are often debated. Understanding the precise role of alpha cells in T1D is crucial, as it opens up avenues for developing new therapeutic strategies for T1D. Potential strategies include targeting alpha cells to normalize glucagon secretion, utilizing glucagon receptor antagonists, enhancing GABA signaling, and employing glucagon-like peptide-1 (GLP-1) receptor agonists. These approaches aim to improve glycemic control and reduce the risk of hypoglycemic events in individuals with T1D. This review provides an overview of alpha cell function in T1D, highlighting the emerging focus on alpha cell dysfunction in the context of historically well-developed beta cell research.

The case reports a woman in her 70s, with type 2 diabetes and chronic kidney disease in G4 stage. The patient had elevated HbA1c, and she was switched from linagliptin, a dipeptidyl peptidase 4 inhibitor, to dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). Thereafter, the HbA1c level decreased; however, since the dulaglutide supply became a problem, the patient was switched to tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA. To date, no clinical studies have evaluated the efficacy and safety of switching from GLP-1RA to GIP/GLP-1RA, but we report this case because efficacy was observed in this patient. The therapeutic effects after switching to tirzepatide included decrease in HbA1c, increase in eGFR, and decrease in BUN, when compared to when dulaglutide was used. A change from dulaglutide to tirzepatide, could inhibit renal impairment progression and improve renal function.

Black chokeberry (Aronia melanocarpa (Michx.) Elliott) is recognized for its potential health benefits, largely attributed to its high phenolic content. However, many phenolic compounds possess a low bioavailability, potentially limiting their beneficial effects. Fermentation of chokeberry has been proposed as a method to improve bioavailability, bioactive composition, sensory qualities, and nutritional value. This systematic review provides an overview of fermented chokeberry products, including compound composition, sensory attributes, and health benefits observed in in vivo and in vitro studies. While sensory evaluations highlighted diverse flavour profiles and acceptability, human intervention studies suggested potential benefits for glucose-dependent insulinotropic peptide increase. Animal models indicated anti-obesity and immunomodulatory properties, while in vitro studies demonstrate antioxidant, anti-melanogenesis, and anti-diabetic effects. Despite some promising findings in human and animal trials, challenges such as participant adherence and dosing inconsistencies force further protocol improvements. Through continuous scientific research, fermented chokeberry products may emerge as functional foods contributing to human health.

Incretin-based therapies have emerged as effective treatments for type 2 diabetes (T2D) and obesity. However, not all patients achieve optimal outcomes with existing treatments, highlighting the need for more effective solutions.

We present a comprehensive evaluation of Tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, for managing obesity and T2D. We conducted a systematic search of Cochrane, PubMed, Scopus, and Web of Science databases from inception to April 2024. The focus of the review is on the development and therapeutic potential of TZP, with detailed exploration on pharmacodynamics, pharmacokinetics, clinical efficacy, and safety. Furthermore, it reviews TZP's impacts on glycemic control, weight management, and its potential cardiovascular (CV) benefits.

TZP represents a significant advancement in the dual-targeted approach to treating T2D and obesity. Its unique mechanism of action offers superior efficacy in reducing glycemic levels and body weight compared to existing therapies. New data suggesting improvements in CV outcomes indicate that TZP could set a new standard in the treatment paradigm. While long-term data on efficacy and safety are still forthcoming, current evidence positions TZP as a promising option for patients who have not reached their therapeutic goals with existing treatments.

Diabetes is a global disease that can lead to a range of complications. Currently, the treatment of type 2 diabetes focuses on oral hypoglycemic drugs and insulin analogues. Studies have shown that drugs such as oral metformin are useful in the treatment of diabetes but can limit the liver's ability to release sugar. The development of glucose-lowering peptides has provided new options for the treatment of type 2 diabetes. Peptide drugs have low oral utilization due to their easy degradation, short half-life, and difficulty passing through the intestinal mucosa. Therefore, improving the oral utilization of peptide drugs remains an urgent problem. This paper reviews the research progress of peptide drugs in the treatment of diabetes mellitus and proposes that different types of nano-formulation carriers, such as liposomes, self-emulsifying drug delivery systems, and polymer particles, should be combined with peptide drugs for oral administration to improve their absorption in the gastrointestinal tract.

This study aimed to evaluate the role of serum Glucagon-Like Peptide-1 (GLP-1), Glucagon-Like Peptide-2 (GLP-2), and Glucose-Dependent Insulinotropic Polypeptide (GIP) levels in relation to obesity and gestational diabetes mellitus (GDM) in pregnancy.

A case-control study was conducted, including 96 pregnant women with singleton pregnancies who underwent the Oral Glucose Tolerance Test (OGTT) for GDM diagnosis during the 24th-28th weeks of gestation. Blood samples were collected for measuring GLP-1, GLP-2, GIP, and fasting glucose. Statistical analyses included receiver operating characteristic (ROC) curves and correlation analysis.

Among the 96 women, no significant difference in age was observed between the groups, but Body Mass Index (BMI) was significantly higher in GDM-O (Gestational Diabetes Mellitus-Obese) and non-GDM-O groups (p < 0.001). GLP-1 had an area under the curve (AUC) of 0.666 (95% CI: 0.553-0.778, p = 0.005) for diagnosing GDM. The optimal GLP-1 cutoff was 815.86 ng/mL, with 65% sensitivity and 77% specificity. A significant correlation was found between GLP-2 and GIP (r = 0.289, p = 0.004), but no significant correlations were observed between GLP-1 and other peptides or gestational age (p > 0.05).

Impaired secretion of GLP-1, GLP-2, and GIP likely contributes to the pathogenesis of GDM. GLP-1 may serve as a potential biomarker for diagnosing GDM.

Type 2 diabetes (T2D) and obesity are prevalent metabolic disorders affecting millions of individuals worldwide. A new effective therapeutic drug called tirzepatide for the treatment of obesity and T2D is a dual agonist of the GIP receptor and GLP-1 receptor. Tirzepatide is clinically more effective than GLP-1 receptor agonists but the reasons why are not well understood. Tirzepatide reportedly stimulates the GIP receptor more potently than the GLP-1 receptor. However, tirzepatide signaling has not been thoroughly investigated at the E354 (wildtype) or Q354 (E354Q) GIP receptor variants. The E354Q variant is associated increased risk of T2D and lower body mass index. To better understand GIP receptor signaling we characterized the activity of endogenous agonists and tirzepatide at both GIP receptor variants. Using Cos7 cells we examined wildtype and E354Q GIP receptor signaling, analyzing cAMP and IP1 accumulation as well as AKT, ERK1/2 and CREB phosphorylation. GIP(1-42) and GIP(1-30)NH2 displayed equipotent effects on these pathways excluding CREB phosphorylation where GIP(1-30)NH2 was more potent than GIP(1-42) at the E354Q GIP receptor. Tirzepatide favored cAMP signaling at both variants. These findings indicate that tirzepatide is a biased agonist towards Gαs signaling and suggests it equally activates the wildtype and E354Q GIP receptor variants. We also observed differences between the pharmacology of the GIP receptor variants with endogenous peptides, which may help to explain differences in phenotype. These findings contribute to a comprehensive understanding of GIP receptor signaling, and will aid development of therapies combating T2D and obesity.

Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.

We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.

AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.

This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis.

Obesity is a heterogeneous, complex, and chronic disease that has a detrimental impact on disability-adjusted life years across the globe. Recent advancements in our understanding of gut-brain communication at the molecular level have driven the development of next-generation anti-obesity medications (AOMs). Glucagon-like peptide-1 receptor agonists (GLP1RAs) remain the front-runners in this rapidly evolving landscape of hormone-based AOMs. Two GLP1RAs, namely Liraglutide and Semaglutide, have been approved by the Food and Drug Administration (FDA) and European Medicine Agency (EMA) for use in clinical practice for weight loss. Three oral GLP1RAs, namely Semaglutide, Danuglipron, and Orforglipron, are undergoing advanced clinical trials in individuals with obesity. Amylin receptor agonist (AMYRA) Cagrilintide, when used alone or in combination with Semaglutide, has demonstrated substantial weight reduction in clinical trials. Tirzepatide, a dual agonist for the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, has been observed to be associated with a significant placebo-subtracted weight reduction of 17.8% in a 72-week randomized controlled trial. Novel approaches targeting glucagon signalling have also yielded promising preliminary results. Three long-acting GLP1R/glucagon receptor (GCGR) dual agonists, namely Survodutide, Mazdutide, and Pemvidutide, exhibited significant weight loss in clinical trials. Retatrutide, a GLP1R/GCGR/GIPR tri-agonist, has been associated with a placebo-subtracted weight reduction of -22.1% in a 48-week phase-II trial. As a note of caution, long-term data on such medications' safety and cardiovascular benefits is yet to be ascertained. Our review provides a comprehensive overview of the approved and emerging hormone-based AOMs, highlighting the diversity of options that might become available in the near future.

Tirzepatide, a novel dual agonist of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), has demonstrated greater magnitude of weight loss compared to semaglutide in a phase 3 clinical trial. However, the effect of tirzepatide on incidence of type 2 diabetes (T2D) in individuals with overweight and obesity, and the effect on major adverse cardiovascular outcomes in individuals with pre-existing T2D, remains unknown.

We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (TriNetX LLC, Cambridge, MA, USA) a global federated database. The data used in this study was collected on 5th June 2024. Two cohorts of individuals were generated: 1) without pre-existing T2D and, 2) with T2D. We adopted an active comparator new user design on new initiations of either tirzepatide or semaglutide therapy. Analysis began from the index event which was defined as individuals on respective therapy for 6 months only. Analysis of outcomes was conducted off-drug, in individuals without a pre-existing history of the disease of interest. Individuals were followed up for 12 months post the index event. Primary outcome for cohort 1 was incidence of T2D, and for cohort 2 was composite: all-cause mortality, cerebral infarction, acute coronary syndrome, and heart failure. Secondary outcomes for cohort 1 were change in HbA1c and body weight and for cohort 2: incidence of micro- and macrovascular complications, suicidal ideation and/or attempt, and all-cause mortality. We propensity score matched (1:1) for potential confounders: baseline demographics, socioeconomic circumstances, HbA1c, weight, relevant co-morbidities, and anti-obesity, hypoglycaemic and cardioprotective agents.

The study population without T2D consisted of 13,846 individuals, equally split between tirzepatide and semaglutide users. Tirzepatide was associated with both lower risk for incident T2D (HR 0.73, 95% CI 0.58-0.92, p < 0.001) and greater weight loss (-7.7 kg, [95% CI -6.8, -8.5 kg], p < 0.001), compared to semaglutide (-4.8 kg, [95% CI -3.9, -5.6 kg], p < 0.001). In individuals with pre-existing T2D (n = 8446), tirzepatide was associated with lower risk of the composite outcome (HR 0.54, 95% CI 0.38-0.76, p < 0.001), cerebral infarction (HR 0.45, 95% CI 0.24-0.84, p = 0.010) and all-cause mortality (HR 0.33, 95% CI 0.15-0.73, p = 0.004) compared to semaglutide.

Tirzepatide is associated with significantly reduced risk of developing T2D and major adverse cardiovascular events in individuals living with obesity and T2D respectively. Randomised controlled trials investigating the utility of dual incretin agonists in the primary prevention of T2D and cardiovascular disease in higher risk populations are now required.

Nil.

Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.

The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.

Obesity and type 2 diabetes mellitus (T2DM) are widespread, non-communicable diseases that are responsible for considerable levels of morbidity and mortality globally, primarily in the form of cardiovascular disease (CVD). Changes to lifestyle and behaviour have insufficient long-term efficacy in most patients with these diseases; metabolic surgery, although effective, is not practically deliverable on the scale that is required. Over the past two decades, therapies based on incretin hormones, spearheaded by glucagon-like peptide 1 (GLP1) receptor agonists (GLP1RAs), have become the treatment of choice for obesity and T2DM, and clinical evidence now suggests that these agents have benefits for CVD. We review the latest advances in incretin-based pharmacotherapy. These include 'GLP1 plus' agents, which combine the known advantages of GLP1RAs with the activity of additional hormones, such as glucose-dependent insulinotropic peptide, glucagon and amylin, to achieve desired therapeutic goals. Second-generation non-peptidic oral GLP1RAs promise to extend the benefits of GLP1 therapy to those who do not want, or cannot have, subcutaneous injection therapy. We conclude with a discussion of the knowledge gaps that must be addressed before incretin-based therapies can be properly deployed for maximum benefit in the treatment of obesity and T2DM.

One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The mechanisms by which GLP-1 receptor agonism cause weight reduction are becoming increasingly understood. However, the mechanisms by which GIP receptor-modulating medications cause weight loss remain to be clarified.

This review describes GLP-1 and GIP physiology and explores the conflicting data regarding GIP and weight management. It details examples of how to reconcile the contradictory findings that both GIP receptor agonism and antagonism cause weight reduction. Specifically, it discusses the concept of 'biased agonism' wherein exogenous peptides cause different post-receptor signaling patterns than native ligands. It discusses how GIP effects in adipose tissue and the central nervous system may cause weight reduction. It describes GIP receptor-modulating compounds and their most current trials regarding weight reduction.

Effects of GIP receptor-modulating compounds on different tissues have implications for both weight reduction and other cardiometabolic diseases. Further study is needed to understand the implications of GIP agonism on not just weight reduction, but also cardiovascular disease, liver disease, bone health and fat storage.

For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to ∼20%-30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.

Bariatric surgery is a well-established treatment for obesity and type 2 diabetes. Tirzepatide, a dual GIP/GLP-1 receptor agonist, has emerged as a promising therapy for type 2 diabetes. This study aimed to compare the effects of bariatric surgery, semaglutide (a GLP-1 receptor agonist), and tirzepatide in Sprague-Dawley rats fed a high-fat diet.

Rats were divided into surgery, semaglutide, and tirzepatide treatment groups, along with a control group (sham). Weight, oral glucose tolerance, and levels of metabolic markers were assessed, along with adipose and liver tissue analysis.

Surgery led to a 15.5% weight reduction, while rats treated with semaglutide exhibited a 10.7% reduction. Tirzepatide treatment at various concentrations (10, 50, and 100 nmol/kg) resulted in weight reductions of 5.0%, 14.9%, and 17.7%, respectively, compared to the sham group. Metabolic analyte levels decreased in intervention groups compared to the sham group, indicating improved metabolic health and glucose tolerance. Adipose tissue weight and hepatic liver fat droplets decreased in the intervention groups.

Bariatric surgery and tirzepatide treatment significantly improved metabolic parameters in obese rats. Tirzepatide, particularly at higher concentrations, showed pronounced improvements compared to surgery and semaglutide. These findings suggest that high doses of tirzepatide could be explored as an alternative to bariatric surgery for the treatment of obesity.

Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure.

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus.

The GIPR from humans, mice, rats, pigs, dogs and cats was studied in vitro for cognate ligand affinity, G protein activation (cAMP accumulation), recruitment of beta-arrestin and internalization. Variants of the mouse, rat and human GIPRs with swapped C-terminal tails were studied in parallel.

The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for Gαs activation, especially, the mouse GIPR shows reduced receptor desensitization, internalization and beta-arrestin recruitment. Using an enzyme-stabilized, long-acting GIP analogue, the species differences were even more pronounced. 'Tail-swapped' human, rat and mouse GIPRs were all fully functional in their Gαs coupling, and the mouse GIPR regained internalization and beta-arrestin 2 recruitment properties with the human tail. The human GIPR lost the ability to recruit beta-arrestin 2 when its own C-terminus was replaced by the rat or mouse tail.

Desensitization of the human GIPR is dependent on the C-terminal tail. The species-dependent functionality of the C-terminal tail and the different species-dependent internalization patterns, especially between human and mouse GIPRs, are important factors influencing the preclinical evaluation of GIPR-targeting therapeutic compounds.

In healthy humans, the complex biochemical interplay between organs maintains metabolic homeostasis and pathological alterations in this process result in impaired metabolic homeostasis, causing metabolic diseases such as diabetes and obesity, which are major global healthcare burdens. The great advancements made during the last century in understanding both metabolic disease phenotypes and the regulation of metabolic homeostasis in healthy individuals have yielded new therapeutic options for diseases like type 2 diabetes (T2D). However, it is unlikely that highly desirable more efficacious treatments will be developed for metabolic disorders until the complex systemic regulation of metabolic homeostasis becomes more intricately understood. Hormones produced by pancreatic islet beta-cells (insulin) and alpha-cells (glucagon) are pivotal for maintaining metabolic homeostasis; the activity of insulin and glucagon are reciprocally correlated to achieve strict control of glucose levels (normoglycaemia). Metabolic hormones produced by other pancreatic islet cells and incretins produced by the gut are also crucial for maintaining metabolic homeostasis. Recent studies highlighted the incomplete understanding of metabolic hormonal synergism and, therefore, further elucidation of this will likely lead to more efficacious treatments for diseases such as T2D. The objective of this review is to summarise the systemic actions of the incretins and the metabolic hormones produced by the pancreatic islets and their interactions with their respective receptors.

In recent years, significant progress has been made to pharmacologically combat the obesity pandemic, particularly with regard to biochemically tailored drugs that simultaneously target the receptors for glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP). But while the pharmacological benefits of GLP-1 receptor (GLP-1R) agonism are widely acknowledged, the role of the GIP system in regulating systems metabolism remains controversial. When given in adjunct to GLP-1R agonism, both agonism and antagonism of the GIP receptor (GIPR) improves metabolic outcome in preclinical and clinical studies, and despite persistent concerns about its potential obesogenic nature, there is accumulating evidence indicating that GIP has beneficial metabolic effects via central GIPR agonism. Nonetheless, despite growing recognition of the GIP system as a valuable pharmacological target, there remains great uncertainty as to where and how GIP acts in the brain to regulate metabolism, and how GIPR agonism may differ from GIPR antagonism in control of energy metabolism. In this review we highlight current knowledge on the central action of GIP, and discuss open questions related to its multifaceted biology in the brain and the periphery.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD.

Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed.

In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders.

Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.