Adipose tissue (AT) represents a plastic organ that can undergo significant remodeling in response to metabolic demands. With its numerous checkpoints, the incretin system seems to play a significant role in controlling glucose homeostasis and energy balance. The importance of the incretin hormones, namely the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic peptide (GIP), in controlling the function of adipose cells has been brought to light by recent studies. Notably, a “paradigm shift” in reevaluating the role of the incretin system in AT as a potential target to treat obesity-linked metabolic disorders resulted from the demonstration that a disruption of the GIP and GLP-1 signaling axis in fat is associated with adiposity-induced insulin-resistance (IR) and/or type 2 diabetes mellitus (T2D). We will briefly discuss the (patho)physiological functions of GLP-1 and GIP signaling in AT in this review, emphasizing their potential impacts on lipid storage, adipogenesis, glucose metabolism and inflammation. We will also address the conundrum with the perturbation of the incretin axis in white or brown fat tissue and the emergence of metabolic disorders. In order to reduce or avoid adiposity-related metabolic complications, we will finally go over a potential scientific rationale for suggesting AT as a novel target for GLP-1 and GIP receptor agonists and co-agonists.

Patients suffering from acromegaly and Cushing’s Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts’ consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.

Background/Objectives: Incretin-based medications have transformed obesity management by enabling substantial body weight reduction. However, the rapid and pronounced loss of body mass necessitates a comprehensive, multidisciplinary approach incorporating nutritional and physical activity strategies to preserve lean mass, optimize functional outcomes, and prevent long-term complications. This narrative review provides a critical overview of this emerging clinical concern, which is expected to gain increasing relevance in the coming years. Methods: A literature review was conducted up to 31 October 2025, focusing on studies addressing nutritional, physical activity, and adjunctive interventions in adults with obesity treated with incretin-based medications. Results: Incretin-based agents induce significant weight loss, comparable to bariatric surgery, predominantly targeting adipose tissue. Nevertheless, these medications also cause rapid reductions in muscle and bone mass, often accompanied by nutrient deficiencies, which may compromise metabolic health and physical function. Tailored nutritional strategies—including hypocaloric diets enriched in protein and fiber, as well as amino acid, vitamin, and mineral supplementation—are critical to preserve lean mass and support sustained weight maintenance. Concurrently, structured, supervised physical activity, encompassing aerobics, resistance, and strength training, mitigates muscle loss and enhances functional capacity. Emerging pharmacological agents designed to promote adipose tissue reduction while preserving lean mass, as well as interventions targeting gut microbiota modulation, may represent promising adjunctive strategies to optimize long-term outcomes further. Conclusions: While incretin-based medications produce substantial weight loss, their impact on lean mass underscores the necessity of integrating personalized nutrition, supplementation, and structured exercise to preserve muscle, prevent malnutrition, and optimize long-term health and obesity outcomes.

In the years immediately after its discovery, glucagon was considered only as an "antidote" for the treatment of insulin-induced hypoglycemia. The advent of specific radioimmunoassay (RIA) techniques has enabled a better understanding of glucagon's role, revealing its close connection with the pathogenesis of diabetes mellitus. This review briefly summarizes the studies regarding the pathophysiology of glucagon and its different therapeutic implications in metabolic disorders. A comprehensive literature search was conducted utilizing PubMed and Scopus, employing the keywords "glucagon", "insulin", "glucose counterregulation", and "diabetes mellitus". This search was restricted to studies published within the past fifteen years, without imposing limitations on study types. However, we mention certain historical aspects of the discovery of glucagon. In type 1 diabetes mellitus, research has concentrated on glucagon's role as a direct counterregulatory hormone to insulin, and on delineating the condition of "glucagon excess" in absolute insulin deficiency, considered a critical factor in the onset of diabetic ketoacidosis (DKA). Conversely, in type 2 diabetes mellitus, research has transitioned from glucagon antagonism to the "paradoxical" activity of glucagon agonism, given its potential positive effects on energy consumption. This has facilitated the development of incretin-based molecules with multi-receptor action, demonstrating significant clinical efficacy in glycemic control, weight loss, and hepatic fat diminution. This review highlights the fundamental role of glucagon in the pathogenesis of diabetes mellitus and its significant therapeutic implications, based on recent research findings.

Aims: To provide a comprehensive overview of the cardiovascular and renal effects of glucose‐dependent insulinotropic polypeptide (GIP) by integrating its physiological role with recent human trial data on tirzepatide, the first dual GIP and glucagon‐like peptide‐1 (GLP‐1) receptor agonist. Materials and Methods: This narrative review synthesizes key physiological data of native GIP across tissues—especially the heart, vessels, kidney, and adipose tissue—and summarizes clinical evidence from the SUMMIT and the SURPASS programmes. Central to this review is the analysis of the SURPASS‐CVOT trial, which compared the cardiovascular protective effects of tirzepatide versus dulaglutide in individuals with type 2 diabetes and established atherosclerotic CV disease. Results: Preclinical data regarding GIP receptor modulation in the cardiorenal district remains controversial, a contention partially reflected in recent clinical evidence. Within the innovative framework of SURPASS‐CVOT, tirzepatide established non‐inferiority to dulaglutide for 3‐point MACE while slowing eGFR decline in participants with high‐risk chronic kidney disease. Furthermore, the SUMMIT trial demonstrated that in individuals with obesity and heart failure (HF) with preserved ejection fraction, tirzepatide reduced the composite endpoint of CV death or worsening HF events, regardless of baseline kidney function. Despite these advancements, knowledge gaps persist regarding the potential synergistic cardiorenal benefits of combining dual incretin agonism with sodium‐glucose cotransporter‐2 inhibitors. Conclusion: While adding GIP receptor agonism to GLP‐1 receptor agonism clearly improves cardiometabolic risk factors, its precise and independent contribution to long‐term CV and renal protection remains to be fully elucidated. Ongoing outcome trials, such as SURMOUNT‐MMO and TREASURE‐CKD, will provide additional insights into these effects. Furthermore, emerging strategies—including combining GIP receptor antagonism with GLP‐1 receptor agonism or moving toward triple agonism—represent promising alternatives to favorably modify the multiple determinants of cardiometabolic risk.

Type 1 diabetes mellitus (T1DM) represents a complex clinical challenge for health systems. The autoimmune destruction of pancreatic beta cells leads to a complete lack of insulin production, exposing people to a lifelong risk of acute (DKA, coma) and chronic complications (macro and microvascular). Physical activity (PA) has widely demonstrated its efficacy in helping diabetes treatment. Nutritional management of people living with T1DM is particularly difficult. Balancing macronutrients, their effects on glycemic control, and insulin treatment represents a complex clinical challenge for the diabetologist. The effects of PA on glycemic control are largely unpredictable depending on many individual factors, such as intensity, nutrient co-ingestion, and many others. Due to this clinical complexity, we have reviewed the actual scientific literature in depth to help diabetologists, sport medicine doctors, nutritionists, and all the health figures involved in diabetes care to ameliorate both glycemic control and the nutritional status of T1DM people engaging in PA. Two electronic databases (PubMed and Scopus) were searched from their inception to January 2024. The main recommendations for carbohydrate and protein ingestion before, during, and immediately after PA are explained. Glycemic management during such activity is widely reviewed. Micronutrient needs and nutritional supplement effects are also highlighted in this paper.