UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity.

Metabolic surgery is an effective treatment option for type 2 diabetes. However, the therapeutic scope has been limited by unexpected inconsistent outcomes. This study aims to overcome these obstacles by determining fundamental mechanisms from a novel perspective by analyzing and comparing the surgical anatomy, clinical characteristics, and outcomes of metabolic surgery, including duodenal-jejunal bypass, Roux-en-Y gastric bypass, biliopancreatic diversion, one anastomosis gastric bypass, and their modified procedures, predominantly focusing on nonobese patients to mitigate confounding effects from overweighted type 2 diabetes. Regional epithelial cell growth and unique villus formation along the anterior-posterior axis of the small intestine depend on crosstalk between the epithelium and the underlying mesenchyme. Due to altered crosstalk between the epithelium and the opposite mesenchyme at the anastomotic site, the enteroendocrine lineage of the distal intestine is replaced by the proximal epithelium after the bypass procedure. Subsequent intestinal compensatory proliferation accelerates the expansion of the replaced epithelium, including enteroendocrine cells. The primary reasons for unsatisfactory results are incomplete duodenal exclusion and insufficient biliopancreatic limb length. We anticipate that this novel mechanism will have a significant impact on metabolic surgery outcomes and provide valuable insight into optimizing its effectiveness in type 2 diabetes.

OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is a ligand of glucose-dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone-like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism.
METHODS: Cell counting Kit-8 (CCK-8) was used to measure cell survival. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2\', 7\'-Dichloro dihydrofluorescein diacetate (DCFH-DA), and glucose intake was detected with 2-NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin-eosin (HE) staining, immunofluorescence staining and tract-tracing were used to observe the morphology of the injured spinal cord. Basso-Beattie-Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury.
RESULTS: GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up-regulating the level of hypoxia-inducible factor 1α (HIF-1α) in an Akt-dependent manner.
CONCLUSIONS: GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo.

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

Background: Tirzepatide-a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist-is used to treat type 2 diabetes. However, the efficacy and safety of tirzepatide in patients undergoing hemodialysis remain unclear. Methods: We conducted a single-center retrospective study of patients with type 2 diabetes undergoing hemodialysis who were transitioned from dulaglutide to tirzepatide. We continuously monitored glucose levels in patients undergoing hemodialysis before and after switching from dulaglutide to tirzepatide. Results: Fourteen patients (mean age: 61.9 ± 9.9 years, male: female = 11:3) were included in this study. After switching to tirzepatide, time in range increased to 50.8% from 42.7% (p = 0.02), time above range decreased to 37.8% from 48.4% (p = 0.02), and mean glucose levels decreased to 137.4 mg/dL from 156.6 mg/dL (p = 0.006). In contrast, there was no significant difference in time below range before and after tirzepatide administration (11.3% and 8.9%) (p = 0.75). Three patients experienced dyspepsia (21.4%), and one patient experienced nausea (7.1%); however, no critical adverse events were reported. Conclusion: Transitioning from dulaglutide to tirzepatide improved glycemic control without increasing hypoglycemia in patients undergoing hemodialysis for type 2 diabetes.

Incretin hormones potentiate the glucose-induced insulin secretion following enteral nutrient intake. The best characterised incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which are produced in and secreted from the gut in response to nutrient ingestion. The property of incretins to enhance endogenous insulin secretion only at elevated blood glucose levels makes them interesting therapeutics for type 2 diabetes mellitus with a better safety profile than exogenous insulin. While incretin therapeutics (especially GLP-1 agonists, and more recently also GLP-1 / GIP dual agonists and other drugs that influence the incretin metabolism (e.g., dipeptidyl peptidase-4 (DPP-4) inhibitors)) are already widely used treatment options for human type 2 diabetes, these drugs are not yet approved for the therapy of feline diabetes mellitus. This review provides an introduction to incretins and feline diabetes mellitus in general and summarises the current study situation on incretins as therapeutics for feline diabetes mellitus to assess their possible future potential in feline medicine. Studies to date on the use of GLP-1 receptor agonists (GLP-1RA) in healthy cats largely confirm their insulinotropic effect known from other species. In diabetic cats, GLP-1RAs appear to significantly reduce glycaemic variability (GV, an indicator for the quality of glycaemic control), which is important for the management of the disease and prevention of long-term complications. However, for widespread use in feline diabetes mellitus, further studies are required that include larger numbers of diabetic cats, and that consider and test a possible need for dose adjustments to overweight and diabetic cats. Also evaluation of the outcome of GLP-1RA monotherapy will be neceessary.

Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials.

Forty percent of Americans are obese and 20% are overweight. Until recently, notwithstanding great efforts to combat this chronic, worsening epidemic, the only therapy that \"worked\" was surgery. However, recently, a new class of safe drugs (incretins) have been developed that cause obese patients to lose ∼20 to 25% of their body weight. Herein we recount this revolution and its implications.