OBJECTIVE: Randomized controlled trials with tirzepatide (TZP) displayed unprecedented glucose and body weight lowering efficacy in individuals with type 2 diabetes and/or obesity and a safety profile similar to that of glucagon-like peptide-1 receptor agonists (GLP-1RA), mainly characterized by gastrointestinal (GI) adverse events (AE). Concerns on diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer were also addressed. We aimed to investigate whether the same safety issues emerged from the FDA Adverse Event Reporting System (FAERS) post-marketing surveillance database.
METHODS: OpenVigil 2.1-MedDRA-v24 and AERSMine (data 2004Q1-2023Q3) were used to query the FAERS database. Reports of GI AE, diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer were investigated. The analysis was then filtered for age, gender, and designation as primary suspect. AE occurrence with TZP was compared to insulin, sodium-glucose cotransporter-2 inhibitors, metformin, and GLP-1RA.
RESULTS: Disproportionate reporting of GI [i.e., nausea (ROR 4.01, 95% CI 3.85-4.19)] and pancreato-biliary disorders [i.e., pancreatitis (ROR 3.63, 95% CI 3.15-4.19)], diabetic retinopathy (ROR 4.14, 95% CI 2.34-7.30), and medullary thyroid cancer (ROR 13.67, 95% CI 4.35-42.96) was detected. TZP exhibited a similar risk of GI AE and medullary thyroid cancer and a lower risk of most pancreato-biliary AE and diabetic retinopathy vs. GLP-1RA.
CONCLUSIONS: TZP was associated with an increased risk of specific AE. However, its safety profile was similar to that of GLP-1RA, without increased risk of pancreato-biliary AE, diabetic retinopathy, and medullary thyroid cancer.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain\'s satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

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Antibiotic resistance is increasing among Gram-negative bacteria, prompting the development of new antibiotics as well as alternative treatment approaches. Klebsiella pneumoniae Carbapenemases (KPC) has become a major concern in the treatment of infections, since KPC-producing bacteria are resistant to a number of β -lactam and non β-lactam antibiotics in addition to hydrolyzing carbapenemases. The aim of this study is to examine the synergistic effect of human Glucose-dependent Insulinotropic Polypeptide (GIP) on KPC producer. The K. pneumoniae isolates were identified by using biochemical tests and PCR genotyping. The disc diffusion method was used to assess the antimicrobial susceptibility of each isolate, and the modified Hodge test (MHT) was used to find carbapenemases. Agar well diffusion and minimum inhibitory concentration (MIC) assays were used to validate the synergistic effect of GIP against Klebsiella species. MIC values of chosen antimicrobial compounds demonstrated a considerable synergism impact when combined with human GIP, particularly against KPC strains. The antibacterial activity of the antimicrobial compounds was boosted by 4-16 times due to human GIP, reducing the MIC values. The fractional inhibitory concentration (FIC) ranged from 0.032 to 0.25 for examined antibiotics. Thus, GIP can be considered an antibacterial adjuvant with the potential to supplement the current antibiotic spectrum.

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.