Search Results (269)

Background: Low-glycemic index (GI) carbohydrates like isomaltulose (ISO) are known to enhance incretin release and to improve postprandial glucose control at the following meal (an effect known as second meal effect, or SME), which is particularly beneficial for individuals with metabolic syndrome (MetS). This study aimed to assess the most effective preprandial interval of ISO- or saccharose (SUC) snacks (1 h vs. 3 h preload) to enhance prandial incretin responses to a subsequent meal. Methods: In a randomized crossover design, 15 participants with MetS completed four experimental conditions on four non-consecutive days, combining two preload types (ISO or SUC) and two preload timings (Intervention A: 3 h preload; Intervention B: 1 h preload). Specifically, the four conditions were (1) ISO + Intervention A, (2) SUC + Intervention A, (3) ISO + Intervention B, and (4) SUC + Intervention B. The order of conditions was randomized and separated by a 3–7-day washout period to minimize carryover effects. On each study day, participants consumed two mixed meal tests (MMT-1 and MMT-2) with a standardized preload (50 g ISO or SUC) administered either 3 h or 1 h prior to MMT-2. Blood samples were collected over 9 h at 15 predefined time points for analysis of glucose, insulin, C-peptide, and incretin hormones (GLP-1, GIP, and PYY). Results: The unique digestion profile of ISO resulted in a blunted glucose ascent rate (ΔG/Δt: 0.28 vs. 0.53 mmol/L/min for SUC, p < 0.01), paralleled by synonyms PYY elevation over 540 min monitoring, compared with SUC. ISO also led to higher and more sustained GLP-1 and PYY levels, while SUC induced a stronger GIP response. Notably, the timing of ISO consumption significantly influenced PYY secretion, with the 3 h preload showing enhanced PYY responses and a more favorable SME compared to the 1 h preload. Conclusions: ISO, particularly when consumed 3 h before a meal (vs. 1 h), offers significant advantages over SUC by elevating PYY levels, blunting the glucose ascent rate, and sustaining GLP-1 release. This synergy enhances the second meal effect, suggesting ISO’s potential for managing postprandial glycemic excursions in MetS. Full article

Background and Objectives: The management of type 2 diabetes (T2D) extends beyond glycemic control, requiring a more global strategy that includes optimization of body composition, even more so in the context of sarcopenia and visceral adiposity, as they contribute to poor outcomes. Past reviews have typically been focused on weight reduction or glycemic effectiveness, with limited inclusion of new therapies’ effects on muscle and fat distribution. In addition, the emergence of incretin-based therapies and dual agonists such as tirzepatide requires an updated synthesis of their impacts on body composition. This review attempts to bridge the gap by taking a systematic approach to how current blood-glucose lowering therapies affect lean body mass, fat mass, and the risk of sarcopenia in T2D patients. Materials and Methods: Between January 2015 and March 2025, we conducted a narrative review by searching the PubMed, Scopus, and Web of Science databases for English-language articles. The keywords were combinations of the following: “type 2 diabetes,” “lean body mass,” “fat mass,” “body composition,” “sarcopenia,” “GLP-1 receptor agonists,” “SGLT2 inhibitors,” “tirzepatide,” and “antidiabetic pharmacotherapy.” Reference lists were searched manually as well. The highest precedence was assigned to studies that aimed at adult type 2 diabetic subjects and reported body composition results. Inclusion criteria for studies were: (1) type 2 diabetic mellitus adult patients and (2) reporting measures of body composition (e.g., lean body mass, fat mass, or muscle function). We prioritized randomized controlled trials and large observational studies and excluded mixed diabetic populations, non-pharmacological interventions only, and poor reporting of body composition. Results: Metformin was widely found to be weight-neutral with minimal effects on muscle mass. Insulin therapy, being an anabolic hormone, often leads to fat mass accumulation and increases the risk of sarcopenic obesity. Incretin-based therapies induced substantial weight loss, mostly from fat mass. Notable results were observed in studies with tirzepatide, demonstrating superior reduction not only in fat mass, but also in visceral fat. Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) promote fat loss but are associated with a small yet significant decrease in lean muscle mass. Conclusions: Blood-glucose lowering therapies demonstrated clinically relevant effects on body composition. Treatment should be personalized, balancing glycemic control, cardiovascular, and renal benefits, together with optimal impact on muscle mass along with glycemic, cardiovascular, and renal benefits. Full article

Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5–20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15–25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences. Full article

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

Disorders in glucose metabolism are well-established features of polycystic ovary syndrome (PCOS) and are linked to its clinical severity and phenotypic variability. This study aimed to assess serum concentrations of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) and to examine their relationships with glucose and insulin levels, selected sex hormone concentrations, body weight, and exposure to tobacco smoke. Women with PCOS exhibited significantly elevated levels of fasting glucose, insulin, GIP, and GLP-1 compared to controls. Tobacco smoke exposure in women with PCOS was associated with reduced DPP-4 levels, which were approximately two-fold lower in smokers than in non-smokers. A significant negative correlation between DPP-4 and cotinine levels further supported this relationship. Comorbidities such as overweight/obesity or insulin resistance (IR) were also linked to elevated incretin hormone levels. However, no significant age-related trends in incretin levels were identified, despite the known association between age and glucose dysregulation. The notable alterations in incretin hormone profiles in PCOS, along with the consistent patterns of GIP or GLP-1 with metabolic and hormonal parameters, suggest that these hormones may play coordinated regulatory roles in the pathophysiology of PCOS. Full article

Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders. Full article

Obesity is a chronic, relapsing disease with multifactorial origins and significant global health implications. Historically, bariatric surgery has been the most effective intervention for achieving sustained weight loss and metabolic improvement, especially in individuals with moderate to severe obesity. However, the therapeutic landscape is rapidly evolving. Recent advances in pharmacotherapy—including GLP-1 receptor agonists, dual and triple incretin agonists, and amylin-based combination therapies—have demonstrated unprecedented efficacy, with some agents inducing 15–25% weight loss, approaching outcomes once exclusive to surgical intervention. These developments challenge the continued applicability of existing bariatric surgery criteria, which were established in an era of limited medical alternatives. In this narrative review, we examine the evolution of surgical eligibility thresholds and critically assess the potential role of novel pharmacotherapies in redefining treatment algorithms. By comparing the efficacy, safety, metabolic benefits, and cost-effectiveness of surgery versus next-generation drugs, we explore whether a more stepwise, pharmacotherapy-first approach may now be justified, particularly in patients with BMI 30–40 kg/m². We also discuss future directions in obesity management, including personalized treatment strategies, perioperative drug use, and the integration of pharmacologic agents into long-term care pathways. As the field advances, a paradigm shift toward individualized, minimally invasive interventions appears inevitable—necessitating a timely re-evaluation of current bariatric surgery guidelines to reflect the expanding potential of medical therapy. Full article

Background: Obesity is a growing global health concern and a modifiable risk factor for multiple pancreatic diseases, including acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC). While these conditions have distinct clinical courses, obesity contributes to their pathogenesis through shared mechanisms, such as visceral adiposity, systemic inflammation, insulin resistance, and ectopic pancreatic fat deposition. Methods: This narrative review synthesizes current evidence from clinical, epidemiological, and mechanistic studies exploring the relationship between obesity and pancreatic diseases. We also critically evaluate the effects of weight loss interventions—including lifestyle modifications, pharmacologic therapies, endoscopic approaches, and bariatric surgery—on the risk and progression of disease. Results: Obesity increases the risk and severity of AP via mechanisms such as gallstone formation, hypertriglyceridemia, and lipotoxicity. In CP, obesity-related intrapancreatic fat and metabolic dysfunction may influence disease progression, although some data suggest a paradoxical protective effect. In PC, obesity accelerates tumorigenesis through chronic inflammation, adipokine imbalance, and activation of oncogenic signaling pathways. Weight loss interventions, particularly bariatric surgery and incretin-based therapies (e.g., GLP-1 receptor agonists and dual agonists such as tirzepatide), show promising effects in reducing disease burden and improving metabolic and inflammatory profiles relevant to pancreatic pathology. Conclusions: Obesity plays a multifaceted role in the pathophysiology of pancreatic diseases. Therapeutic strategies targeting weight loss may alter disease trajectories, improve outcomes, and reduce cancer risk. Further research is needed to define optimal intervention strategies and to identify and validate biomarkers for personalized risk assessment and prevention. Full article

Obesity is considered a global pandemic. In Mexico, 7/10 adults, 4/10 adolescents, and 1/3 children are overweight or obese, and it is estimated that 90% of cases of type 2 diabetes (T2D) are attributable to these pathologies. Visceral adipose tissue (VAT) presents increased lipolysis, lower insulin sensitivity, and greater metabolic alterations. Glucagon-like peptide-1 (GLP-1) is a polypeptide incretin hormone that stimulates insulin secretion dependent on the amount of oral glucose consumed, reduces plasma glucagon concentrations, slows gastric emptying, suppresses appetite, improves insulin synthesis and secretion, and increases the sensitivity of β cells to glucose. Liraglutide is a synthetic GLP-1 analog that reduces VAT and improves the expression of Glucose transporter receptor type 4 (GLUT 4R), Mitogen-activated protein (MAP kinases), decreases Fibroblast growth factor type β (TGF-β), reactivates the peroxisome proliferator-activated receptor type ɣ (PPAR-ɣ) pathway, and decreases chronic inflammation. Currently, there are many studies that explain the decrease in VAT with these medications, but there are no studies that compare the decrease in patients with obesity and prediabetes vs. obesity and type 2 diabetes to know which population obtains a greater benefit from treatment with this pharmacological group; this is the reason for this study. The primary objective was to compare the difference in the determination of visceral adipose tissue in people with obesity and type 2 diabetes vs. obesity and prediabetes treated with liraglutide. Methods: A quasi-experimental, analytical, prolective, non-randomized, non-blinded study was conducted over a period of 6 months in a tertiary care center. A total of 36 participants were divided into two arms; group 1 (G1: Obesity and prediabetes) and group 2 (G2: Obesity and type 2 diabetes) for 6 months. Inclusion criteria: men and women ≥18 years with type 2 diabetes, prediabetes, and obesity. Exclusion criteria: Glomerular filtration rate (GFR) < 60 mL/min/1.73 m² elevated transaminases (>5 times the upper limit of normal), and use of non-weight-modifying antidiabetic agents. Conclusions: No statistically significant difference was found in the decrease in visceral adipose tissue when comparing G1 (OB and PD) with G2 (OB and T2D). When comparing intragroup in G2 (OB and T2D), greater weight loss was found [(−3.78 kg; p = 0.012) vs. (−3.78 kg; p = 0.012)], as well differences in waist circumference [(−3.9 cm; p = 0.049) vs. (−3.09 cm; p = 0.017)], and glucose levels [(−1.75 mmol/L; p = 0.002) vs. (−0.56 mmol/L; p = 0.002)], A1c% [(−1.15%; p = 0.001) vs. (−0.5%; p = 0.000)]. Full article

Obesity, hypertension, and chronic kidney disease (CKD) constitute the deadly trinity of modern threats for populations of both developed and developing countries. These diseases (together with type 2 diabetes) are closely linked in their pathophysiology and result in increasing cardiovascular (CV) morbidity and premature death from CV causes. In this review, we focused on the kidney as the target of obesity-related disorders. Obesity-related glomerulosclerosis (ORG) represents a pattern of renal injury caused solely or predominantly by obesity; usually, it is superimposed on chronic kidney disease (CKD) from other causes, such as diabetic kidney disease, hypertensive kidney disease, type 2 cardiorenal syndrome, primary or secondary glomerulopathies, and others. Adipose tissue contributes to kidney injury in several ways: it releases proinflammatory cytokines and growth factors, leading to podocyte and mesangial cell injury and glomerulosclerosis. In particular, perirenal adipose tissue (PRAT), besides exerting paracrine and endocrine effects on the kidney, modifies its function via compression on renal parenchyma and vessels. The intrinsic ability of the kidneys in obesity to increase the reabsorption of sodium warrants intraglomerular hypertension and hyperfiltration, followed by progressive renal injury. Lifestyle interventions and pharmacological agents, as well as metabolic (bariatric) surgery resulting in weight reduction, may also be beneficial for the kidneys. Using GLP1 receptor agonists (with a special focus on subcutaneous semaglutide and tirzepatide) seems to be the most promising treatment strategy for preventing kidney injury in obese individuals. Full article

A growing global trend of adult obesity and the increasing prevalence of overweight/obesity in children indicate a higher risk in the future of adult diseases related to obesity. Current anti-obesity medications regulate appetite and metabolism by acting either in peripheral tissues or in the central nervous system. On the other hand, subsequent weight regain is a typical response to weight loss methods, and there is little evidence that current anti-obesity medications can help maintain long-term weight loss without causing a range of undesirable side effects. The combination of anti-obesity drugs targets multiple molecular pathways and structures in the central nervous system that are involved in weight regulation. This systematic review involves trials performed in pediatric populations, published up to 2025 and systematically searched on the ClinicalTrials.gov database, using “Glucagon like peptide-1 analog, Glucagon like peptide-1 receptor agonists” as the criterion for the “Intervention/treatment” category. We evaluated the entero-insular axis in pediatric patients with obesity, along with the mechanisms of action and therapeutic potential of the Glucagon like peptide-1receptor agonists. We analyzed incretin hormones and summarized the drugs approved by the Food and Drug Administration. Our objective is to identify new treatment strategies as we improve our understanding of the pathophysiology of obesity and the incretin axis. Full article

The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly being supplemented by biological and biosimilar agents. This trend is particularly evident in the development and advancement of anti-diabetic and hypolipemic therapies. This review explores advances in the treatment of hypercholesterolemia and hypertriglyceridemia, elevated lipoprotein(a) [Lp(a)], diabetes, and obesity associated with metabolic syndrome. It focuses mainly on biopharmaceuticals such as proteins and nucleotide-based drugs (antisense oligonucleotides, small interfering RNA), but also on dipeptidyl peptidase-4 (DPP-4) inhibitors classified as incretin drugs along with glucagon-like peptide-1 (GLP-1) analogues. Due to the substantial role of SGLT-2 (sodium/glucose cotransporter 2) inhibitors in novel diabetes therapies, especially for managing cardiovascular risk, this group of compounds was also included in this review. Many clinical data in the field of effectiveness of biopharmaceuticals in metabolic disorders are provided. Therefore, in this review, we mainly include a brief history of drug development and approval, first synthesis and structure modifications, which relevantly influence pharmacokinetics, and safety. We provide only brief comparison of biological drugs with metformin and sulphonylureas derivatives. Databases such as PubMed, Scopus, and Google Scholar are searched for the period between 2000 and 2024. Full article

Small-molecule glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent an innovative advancement in oral therapeutics, addressing key limitations associated with injectable peptide-based incretin therapies. These nonpeptidic agents exert their actions primarily through non-canonical binding orthosteric sites within the GLP-1 receptor transmembrane domain, enabling selective G protein (Gs)-biased signaling with reduced β-arrestin-mediated adverse effects. Orforglipron has notably advanced through Phase 3 clinical development, demonstrating significant reductions in hemoglobin A1c and body weight (up to 7.9%) with favorable tolerability. Conversely, promising candidates such as danuglipron and lotiglipron were discontinued due to hepatotoxicity, underscoring critical safety concerns intrinsic to small-molecule GLP-1RA development. Current clinical candidates, including GSBR-1290, CT-996, and ECC5004, continue to offer substantial potential due to their oral bioavailability, simplified dosing regimens, and favorable gastrointestinal tolerability. Nevertheless, challenges persist regarding hepatic safety, pharmacodynamic variability, and limited long-term outcome data. This review integrates current structural, pharmacological, and clinical evidence, highlights key mechanistic innovations—including biased agonism, covalent binding strategies, and allosteric modulation—and discusses future directions for this rapidly evolving therapeutic class in metabolic disease management. Full article

Obesity and type 2 diabetes mellitus (T2DM) are global health crises with significant morbidity and mortality. Retatrutide, a novel triple receptor agonist targeting glucagon-like peptide-1 (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and glucagon receptors, represents a groundbreaking advancement in obesity and T2DM pharmacotherapy. This review synthesizes findings from preclinical and clinical studies, highlighting retatrutide’s mechanisms, efficacy, and safety profile. Retatrutide’s unique molecular structure enables potent activation of GLP-1, GIP, and glucagon receptors, leading to significant weight reduction, improved glycemic control, and favorable metabolic outcomes. Animal studies demonstrate retatrutide’s ability to delay gastric emptying, reduce food intake, and promote weight loss, with superior efficacy compared to other incretin-based therapies. Phase I and II clinical trials corroborate these findings, showing dose-dependent weight loss, reductions in Glycated Hemoglobin (HbA1c) levels, and improvements in liver steatosis and diabetic kidney disease. Common adverse effects are primarily gastrointestinal and dose-related. Ongoing Phase III trials, such as the TRIUMPH studies, aim to further evaluate retatrutide’s long-term safety and efficacy in diverse patient populations. While retatrutide shows immense promise, considerations regarding cost and the quality of weight loss beyond BMI reduction warrant further investigation. Retatrutide heralds a new era in obesity and T2DM treatment, offering hope for improved patient outcomes. Full article

Emerging clinical data support the paradoxical notion that glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism and antagonism can provide additive weight loss when combined with a glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonist. In this review, we examine data that motivated the initiation of these seemingly contradictory drug discovery programs. We focus on the physiologic role of GIP in humans, human genetics evidence, rodent genetic models, and preclinical rodent and non-human primate pharmacology studies. Furthermore, we highlight where early preclinical findings translated into relevant clinical efficacy in the development of tirzepatide and maridebart cafraglutide (MariTide). Full article