👤 Paolo Fiorina

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone traditionally known for its insulinotropic and adipogenic effects. However, its role in immune modulation and inflammation has recently gained attention, particularly in the context of metabolic diseases. By conducting a comprehensive search into the scientific literature since the discovery of GIP hormone, this review examines the biological evidences linking GIP and inflammation in pre-clinical and clinical studies. Pharmacological approaches targeting the GIP receptor (GIPR) with effects on inflammatory processes are discussed as well, including the latest GIP-based multi-target approaches. The impact of GIP on inflammation appears context-dependent and influenced by tissue-specific receptor expression and metabolic status. While GIP has been shown to exert both pro- and anti-inflammatory effects in experimental models, clinical data are still limited. The success of GIP/glucagon-like peptide-1 (GLP-1) dual agonists in improving glycometabolic and inflammatory outcomes, highlighted the need to disentangle the individual contributions of each pathway. GIPR remains a promising, yet understudied, target in immunometabolism. Future studies are needed to clarify the molecular mechanisms underpinning GIP’s immunomodulatory actions and evaluate the anti-inflammatory potential of GIP-targeting therapies in clinical settings. Show less

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments. Show less

Weight loss in patients with metabolic syndrome has positive effects on cardiovascular and type 2 diabetes risks, but its effects on peripheral cytokines and lipid profiles in patients are still unclear. To determine the effects of diet-induced weight loss on metabolic parameters, lipids and cytokine profiles. Eighteen adult males with metabolic syndrome (defined according to IDF 2009) and Body Mass Index (BMI) between 25 and 35 kg/m After weight loss, a significant improvement in BMI, waist circumference, insulin, fasting blood glucose and HOMA-IR (homeostasis model assessment of insulin resistance) was observed. The analysis of LDL (low-density lipoprotein cholesterol) and HDL (high-density lipoprotein cholesterol) lipoproteins showed a change in their composition with a massive transfer of triacylglycerols from HDL to LDL. This was associated with a significant reduction in peripheral pro-inflammatory cytokines such as IL-6, TNF-α, IL-8 and MIP-1β, leading to an overall decreased inflammatory score. An interesting positive correlation was also observed among peripheral cytokines levels after diet and peripheral levels of CETP (cholesteryl ester transfer protein), an enzyme with a key role in lipid change. Weight loss through caloric restriction is associated with an improvement in peripheral lipid and cytokine profiles that may play a major role in improving cardiovascular risk. Show less