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This review article provides an in-depth examination of various aspects related to tirzepatide, a synthetic peptide given the positive signal by the "United States Food and Drug Administration" for managing type 2 diabetes. Beginning with an overview of diabetes introduction, epidemiology, and issues related to β-cell dysfunction, is explored in the narrative. It further delves into the significance of incretins in the context of diabetes and introduces tirzepatide as a novel "twincretin" owing to its dual agonistic activity on the glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors. The document delves into the chemistry and structure of tirzepatide, providing insights into its unique composition of 39 amino acids derived from native GLP-1, GIP, and semaglutide sequences. Tirzepatide's pharmacology, with a focus on its pharmacokinetic characteristics, and its mechanism of action (MOA) are extensively discussed. Notably, tirzepatide exhibits a preference for GIP receptors, leading to effective reduction of hyperglycemia and positive effects on pancreatic β-cells. Clinical trials examining tirzepatide's impact on glycemic and obesity control are detailed, demonstrating its efficacy in reducing body weight and appetite. Furthermore, the review article explores tirzepatide's effects on cardiovascular and kidney function, highlighting potential renal benefits for diabetic and elevated cardiovascular risk individuals. The narrative also addresses the association between tirzepatide and NAFLD, emphasizing potential benefits in mitigating NAFLD outcomes. Additionally, a comprehensive overview of tirzepatide's side effects, supported by scientific trials, is presented in this article. In conclusion, this review article provides a thorough examination of tirzepatide's multifaceted impact on diabetes management, shedding light on its pharmacological properties, clinical implications, and potential side effects. The information presented contributes to a comprehensive understanding of tirzepatide's role in the evolving landscape of T2D therapeutics. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of dipeptidyl peptidase‐4 inhibitors (DPP4‐Is) and glucagon‐like peptide‐1 receptor agonists (GLP1‐RAs) on diabetic foot ulcer (DFU) and DFU‐related outcomes (lower limb amputation [LLA], DFU‐related hospitalization and mortality). Methods: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4‐Is and sulphonylureas (N = 98 770), and new users of GLP1‐RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. Results: We observed a lower risk of DFU with both DPP4‐I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79‐0.97) and GLP1‐RA use versus insulin use (HR 0.44, 95% CI: 0.32‐0.60) for short‐term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60‐0.92) for long‐term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4‐I use and GLP1‐RA use. The risk of LLA was lower with GLP1‐RA use. The results remained consistent across several sensitivity analyses. Conclusions: Incretin‐based therapy was associated with a lower risk of DFU and DFU‐related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU. [ABSTRACT FROM AUTHOR]

BACKGROUND: The blood pressure (BP) etiologic study is complex due to multifactorial influences, including genetic, environmental, lifestyle, and their intricate interplays. We used a metabolomics approach to capture internal pathways and external exposures and to study BP regulation mechanisms after well-controlled dietary interventions. METHODS: In the ProBP trail (Protein and Blood Pressure), a double-blinded crossover randomized controlled trial, participants underwent dietary interventions of carbohydrate, soy protein, and milk protein, receiving 40 g daily for 8 weeks, with 3-week washout periods. We measured plasma samples collected at baseline and at the end of each dietary intervention. Multivariate linear models were used to evaluate the association between metabolites and systolic/diastolic BP. Nominally significant metabolites were examined for enriching biological pathways. Significant ProBP findings were evaluated for replication among 1311 participants of the BHS (Bogalusa Heart Study), a population-based study conducted in the same area as ProBP. RESULTS: After Bonferroni correction for 77 independent metabolite clusters (α=6.49x10-4), 18 metabolites were significantly associated with BP at baseline or the end of a dietary intervention, of which 11 were replicated in BHS. Seven emerged as novel discoveries, which are as follows: 1-linoleoyl-GPE (18:2), 1-oleoyl-GPE (18:1), 1-stearoyl-2-linoleoyl-GPC (18:0/18:2), 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), maltose, N-stearoyl-sphinganine (d18:0/18:0), and N6-carbamoylthreonyladenosine. Pathway enrichment analyses suggested dietary protein intervention might reduce BP through pathways related to G protein--coupled receptors, incretin function, selenium micronutrient network, and mitochondrial biogenesis. CONCLUSIONS: Seven novel metabolites were identified to be associated with BP at the end of different dietary interventions. The beneficial effects of protein interventions might be mediated through specific metabolic pathways. [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain–gut–microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Introdroduction Methods Results Conclusions Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon‐like peptide‐1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co‐agonists.The objective of this narrative review was to summarize the available data on approved and emerging incretin‐based agents for the treatment of obesity.In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction‐associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation.Many dual and triple co‐agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin‐based therapies; however, data are promising, and further results are eagerly awaited. [ABSTRACT FROM AUTHOR]

Background: Dipeptidyl peptidase 4 (DPP-4) plays a crucial role in breaking down various substrates. It also has effects on the insulin signaling pathway, contributing to insulin resistance, and involvement in inflammatory processes like obesity and type 2 diabetes mellitus. Emerging effects of DPP-4 on bone metabolism include an inverse relationship between DPP-4 activity levels and bone mineral density, along with an increased risk of fractures. Main body: The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y—both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals. Conclusion: The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body's mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4's effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals. [ABSTRACT FROM AUTHOR]

Introduction: Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic β-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects. Methods: A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations. Results and discussion: The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic β-cell function and the integrated capacity to handle glucose. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is associated with an increased risk of fractures due to deterioration of bone quality, which can be referred to as "diabetic osteodystrophy." Furthermore, the risk of fracture is increased in DM, even if bone mineral density is normal or high and is associated with increased morbidity if a fracture develops. In addition to the pathophysiological mechanisms of DM, diabetesrelated complications and drugs used in the treatment of DM may also affect bone health. Moreover, the increased risk of falling due to microvascular complications, hypoglycemia, and postural hypotension also contributes to the development of fractures. Individuals with DM should be screened for osteoporosis with recommendations similar to those of the general population. When diagnosing osteoporosis and deciding on treatment, it should be kept in mind that DM may be an important risk factor, and lower threshold values of the T score should be used. [ABSTRACT FROM AUTHOR]

Health research, including drug safety research, is communicated, in part, by being cited; understanding these citations can help determine its reach and impact. We analyzed the uptake of a Canadian Network for Observational Drug Effect Studies study of the heart failure risk of incretin-based drugs using quantitative and qualitative bibliometric approaches. A Scopus® search (2016–2020) returned 127 citing articles, mostly single studies and review articles. Many were also high impact journals, with intended audiences of other researchers, policy makers, and practitioners. Using the Becker Model, 93% contributed to "advancing knowledge." Research impact can be difficult to establish. We have demonstrated one comprehensive approach that can be further adapted and automated; researchers and funders need to determine the best indicators, tools, and frameworks to use that are feasible and context relevant. [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

BACKGROUND: Obesity is a pathology that highly contributes to the development of type 2 diabetes mellitus and cardiovascular diseases. Meanwhile, different obesity phenotypes have varying levels of risk, and the indication of early predictors that can help determine the likelihood of developing cardiometabolic disorders is an important task. Since obesity is characterized by excessive energy intake, hormones involved in energy homeostasis (leptin and other adipokines, ghrelin, incretins) can be considered as serious candidates for the role of such predictors. The profile of changes in their level in the post-­nutrition status testifies in favor of the development of resistance not only to insulin, but also to leptin, and to ghrelin, and, possibly, to incretins.AIM: This study aims to investigate the relationship between the dynamics of the level of hormones involved in energy homeostasis in a sample with a standard carbohydrate breakfast and metabolic health.MATERIALS AND METHODS: Metabolic parameters (including НОМА-IR and НОМА-B, lipid profile, glucose level, blood pressure) were assessed in 90 obese patients (BMI 37.31±4.83 kg/m2). Additionally, biomarkers such as adiponectin, CRP were measured. Levels of leptin, ghrelin, GLP1 and GIP were assessed before and 60 minutes after a standard carbohydrate breakfast. These hormone levels were classified depending on the nature of the changes, considering the physiological dynamics described in the literature in healthy people or not. Patients were divided into groups of metabolically healthy and ­metabolically unhealthy obesity, first using the most commonly known criteria (Meigs et al.), then based on the criteria discussed in the literature for perfectly healthy obesity, in which there are no metabolic disorders.RESULTS: The analysis revealed that patients without metabolic disorders had a ghrelin level profile similar to that in healthy people without obesity, while patients with at least one of the manifestations of the metabolic syndrome showed evidence of ghrelin resistance (the level of ghrelin on an empty stomach was reduced, and after food it was not adequately reduced). Adiponectin levels were normal in metabolically healthy patients. Incretin levels showed unidirectional changes in obesity, regardless of metabolic status. The level of CRP did not differ between the groups. The glycemic level was significantly lower in metabolically healthy patients (the group was characterized by normal insulin levels and had a lower degree of insulin resistance).CONCLUSION: The data obtained allow us to consider ghrelin resistance as an early and rather sensitive indicator of the development of metabolic disorders in obesity.

Abstract Background Dipeptidyl peptidase 4 (DPP-4) plays a crucial role in breaking down various substrates. It also has effects on the insulin signaling pathway, contributing to insulin resistance, and involvement in inflammatory processes like obesity and type 2 diabetes mellitus. Emerging effects of DPP-4 on bone metabolism include an inverse relationship between DPP-4 activity levels and bone mineral density, along with an increased risk of fractures. Main body The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y—both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals. Conclusion The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body's mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4's effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals.

Abstract Background The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. Results We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. Conclusions Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

The prevalence of obesity and type 2 diabetes continues to grow, which determines the need to develop new methods of prevention in order to reduce the population risks of developing these diseases. The current direction is to limit the consumption of easily digestible carbohydrates and use low-calorie or non-calorie sweeteners instead. Currently, there is an increase in the use of non-calorie sweeteners in the manufacture of food. In this regard, the study of their possible effects on metabolic processes is of great importance.This review presents studies that have shown different effects of non-calorie sweeteners on carbohydrate and fat metabolism, body weight, the composition of intestinal microbiota, as well as the regulation of eating behavior. Some studies show that low-calorie sugar substitutes can be used in obese people as part of a comprehensive weight loss program, as well as in patients with type 2 diabetes mellitus with the aim of reducing postprandial hyperglycemia. Other studies demonstrate the negative effect of a number of low-calorie sweeteners on carbohydrate metabolism.The main search for materials was carried out in Pubmed databases, eLIBRARY.ru, Google Scholar. Temporary search criteria 2012–2023 The relevant additional literature was included after a manual search in the literature lists of the included articles.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis and cardiometabolic risk factors like obesity, type 2 diabetes, and dyslipidemia. Persistent metabolic injury may promote inflammatory processes resulting in metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Mechanistic insights helped to identify potential drug targets, thereby supporting the development of novel compounds modulating disease drivers. The U.S. Food and Drug Administration has recently approved the thyroid hormone receptor β-selective thyromimetic resmetirom as the first compound to treat MASH and liver fibrosis. This review provides a comprehensive overview of current and potential future pharmacotherapeutic options and their modes of action. Lessons learned from terminated clinical trials are discussed together with the first results of trials investigating novel combinational therapeutic approaches. Approval of resmetirom as the first anti-MASH agent may revolutionize the therapeutic landscape. However, long-term efficacy and safety data for resmetirom are currently lacking. In addition, heterogeneity of MASLD reflects a major challenge to define effective agents. Several lead compounds demonstrated efficacy in reducing obesity and hepatic steatosis, while anti-inflammatory and antifibrotic effects of monotherapy appear less robust. Better mechanistic understanding, exploration of combination therapies, and patient stratification hold great promise for MASLD therapy. [ABSTRACT FROM AUTHOR]

Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has demonstrated remarkable effectiveness in lowering glucose levels and reducing weight in the SURPASS and SURMOUNT trials. However, its mechanism of action in vivo remains incompletely understood. Although pancreatic beta cell express both GLP-1 and GIP receptors, the insulinotropic effect of GIP is attenuated under hyperglycemic conditions. Tirzepatide may enhance the role of GLP-1 and potentially restore the insulinotropic effect of GIP. Furthermore, the expression of GIP receptors in adipose tissue suggests that tirzepatide may directly impact adipose tissue function, contributing to its ability to regulate hyperglycemia and obesity. Despite these insights, the precise mechanism of action of tirzepatide remains unknown, as its unprecedented effects cannot be solely attributed to reduced food intake. Further research is warranted to fully comprehend the therapeutic potential of this agent. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is a debilitating condition associated with significant morbidity and mortality. In recent years, the kidney effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in the management of type 2 diabetes and obesity. This review delves into the intricate interactions between the kidney, GLP-1RAs, and glucagon, shedding light on their mechanisms of action and potential kidney benefits. Both GLP-1 and glucagon, known for their opposing roles in regulating glucose homeostasis, improve systemic risk factors affecting the kidney, including adiposity, inflammation, oxidative stress, and endothelial function. Additionally, these hormones and their pharmaceutical mimetics may have a direct impact on the kidney. Clinical studies have provided evidence that incretins, including those incorporating glucagon receptor agonism, are likely to exhibit improved kidney outcomes. Although further research is necessary, receptor polypharmacology holds promise for preserving kidney function through eliciting vasodilatory effects, influencing volume and electrolyte handling, and improving systemic risk factors. [ABSTRACT FROM AUTHOR]

Agonists targeting the receptors of incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute apotential barrier to their use, particularly at higher doses. Multiple studies reviewed inthis article document thediverse effects of these drugs onthe glucagon-likepeptide-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery. [ABSTRACT FROM AUTHOR]

Testosterone, an anabolic hormone, can prevent or revert type 2 diabetes in men at high risk. Incretinbased weight-loss therapy is effective in both men and women, but reduces lean mass, as well as fat mass. Exercise may be the vital ingredient for preserving muscle and improving cardiometabolic health. [ABSTRACT FROM AUTHOR]

Objective of this review is to summarise the systemic actions of the incretins and the metabolic hormones produced by the pancreatic islets and their interactions with their respective receptors. [ABSTRACT FROM AUTHOR]

According to cohort studies, cereal fiber, and whole-grain products might decrease risk for type 2 diabetes (T2DM), inflammatory processes, cancer, and cardiovascular diseases. These associations, mainly affect insoluble, but not soluble cereal fiber. In intervention studies, soluble fiber elicit anti-hyperglycemic and anti-inflammatory short-term effects, partially explained by fermentation to short-chain fatty acids, which acutely counteract insulin resistance and inflammation. ß-glucans lower cholesterol levels and possibly reduce liver fat. Long-term benefits are not yet shown, maybe caused by T2DM heterogeneity, as insulin resistance and fatty liver disease – the glycometabolic points of action of soluble cereal fiber – are not present in every patient. Thus, only some patients might be susceptive to fiber. Also, incretin action in response to fiber could be a relevant factor for variable effects. Thus, this review aims to summarize the current knowledge from human studies on the impact of soluble cereal fiber on glycometabolic gastrointestinal hormones. Effects on GLP-1 appear to be highly contradictory, while these fibers might lower GIP and ghrelin, and increase PYY and CCK. Even though previous results of specific trials support a glycometabolic benefit of soluble fiber, larger acute, and long-term mechanistic studies are needed in order to corroborate the results. [ABSTRACT FROM AUTHOR]

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP‐1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co‐morbidities. [ABSTRACT FROM AUTHOR]

Background: Incretins, i.e., glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) promote insulin secretion to reduce postprandial blood sugar. Previous studies found incretins in the salivary glands. However, the role of GLP-1 and GIP in the submandibular gland (SMG) is unclear. This study investigates the effects of a high-fat diet (HFD) on the expression of GLP-1 and GIP throughout the development of rat SMG. Methods: Pregnant 11-week-old Wistar rats were divided into two groups: those fed on a standard diet (n = 5) and those fed on a HFD (n = 5). From day 7 of pregnancy and throughout the lactation period, all the rats were fed on either a chow diet or HFD. The newborns were divided into four subgroups (n = 6): standard diet males (SM), HFD males (HM), standard diet females (SF), and HFD females (HF). The SMGs of 3- and 10-week-old rats from each subgroup were collected under general anesthesia. Moreover, body weight, food intake, and fasting blood sugar were measured. The mRNA expression of GLP-1 and GIP was quantified, and the localization was observed using immunohistochemistry (p < 0.05). Results: GLP-1 mRNA expression was statistically significantly more upregulated in HM than in HF at 3 weeks. Moreover, GLP-1 mRNA expression was significantly higher in HM than in both SM and HF at 10 weeks. Although a decreasing trend was observed in GIP mRNA expression in both 3- and 10-week-old rats fed on a HFD, a significant difference between HM and SM only occurred at 3 weeks. Furthermore, the GIP mRNA expression of HM was lower than that of HF at 10 weeks. Immunohistochemical staining revealed GLP-1 and GIP expression mainly in the SMG duct system. Moreover, vacuolated cytoplasm in the duct was observed in rats fed on a HFD. Conclusion: Exposure to HFD during pre- and post-natal periods increased GLP-1 mRNA expression in the SMGs of male rats. However, GIP expression decreased following the HFD in male newborns. Furthermore, a decreasing trend of GIP mRNA expression was observed in male newborns after HFD feeding. Sex influenced incretin hormones secretion and obesity-related conditions. HFD during pre- and post-natal periods reprograms the epigenome, contributing to subsequent disease development. [ABSTRACT FROM AUTHOR]

New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioral mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood-brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood-brain barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies. [ABSTRACT FROM AUTHOR]

We are entering a new era in the management of adiposity-based chronic disease (ABCD) with type 2 diabetes (T2D) and related chronic kidney disease (CKD). ABCD, T2D and CKD can affect almost every major organ system and have a particularly strong impact on the incidence of cardiovascular disease (CVD) and heart failure. ABCD and the associated insulin resistance are at the root of many cardiovascular, renal and metabolic (CKM) disorders, thus an integrated therapeutic framework using weight loss (WL) as a disease-modifying intervention could simplify the therapeutic approach at different stages across the lifespan. The breakthrough of highly effective WL drugs makes achieving a WL of >10% possible, which is required for a potential T2D disease remission as well as for prevention of microvascular disease, CKD, CVD events and overall mortality. The aim of this review is to discuss the link between adiposity and CKM conditions as well as placing weight management at the centre of the holistic CKM syndrome approach with a focus on CKD. We propose the clinical translation of the available evidence into a transformative Dysfunctional Adipose Tissue Approach (DATA) for people living with ABCD, T2D and CKD. This model is based on the interplay of four essential elements (i.e. adipocentric approach and target organ protection, dysfunctional adiposity, glucose homeostasis, and lifestyle intervention and de-prescription) together with a multidisciplinary person-centred care. DATA could facilitate decision-making for all clinicians involved in the management of these individuals, and if we do this in a multidisciplinary way, we are prepared to meet the adipocentric challenge. [ABSTRACT FROM AUTHOR]

Background: Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity, resulting in long-term weight loss and rapid remission of type 2 diabetes mellitus. Improved glucagon-like peptide 1 (GLP-1) levels is one factor that contributes to the positive effects. Prior to RYGB, GLP-1 response is blunted which can be attributed to intestinal ketogenesis. Intestinal produced ketone bodies inhibit GLP-1 secretion in enteroendocrine cells via an unidentified G-protein coupled receptors (GPCRs). A possible class of GPCRs through which ketone bodies may reach are the free fatty acid receptors (FFARs) located at the basolateral membrane of enteroendocrine cells. Aim: To evaluate FFAR3 expression in enteroendocrine cells of the small intestine under different circumstances, such as diet and bariatric surgery, as well as explore the link between ketone bodies and GLP-1 secretion. Materials and methods: FFAR3 and enteroendocrine cell expression was analyzed using Western blot and immunohistochemistry in biopsies from healthy volunteers, obese patients undergoing RYGB and mice. GLUTag cells were used to study GLP-1 secretion and FFAR3 signaling pathways. Results: The expression of FFAR3 is markedly influenced by diet, especially high fat diet, which increased FFAR3 protein expression. Lack of substrate such as free fatty acids in the alimentary limb after RYGB, downregulate FFAR3 expression. The number of enteroendocrine cells was affected by diet in the normal weight individuals but not in the subjects with obesity. In GLUTag cells, we show that the ketone bodies exert its blocking effect on GLP-1 secretion via the FFAR3, and the Gαi/o signaling pathway. Conclusion: Our findings that ketone bodies via FFAR3 inhibits GLP-1 secretion bring important insight into the pathophysiology of T2D. This highlights the role of FFAR3 as a possible target for future anti-diabetic drugs and treatments.

The article examines whether the Incretin hype should be the same for older adults. Topics discussed include lifestyle interventions that have demonstrated significant improvements in physical function, the classes of incretins that are increasingly valid and widely covered in persons with diabetes, and actions that can help in the identification of the right candidate for these medications.

Background: Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake. Both glucose homeostasis and food intake have been reported to be affected by circadian rhythms and vice versa. In this study, we investigated whether the secretion of glucagon, GLP-1 and GIP was affected by circadian rhythms. Methods: A total of 24 healthy men with regular sleep schedules were examined for 24 h at the hospital ward with 15 h of wakefulness and 9 h of sleep. Food intake was standardized, and blood samples were obtained every third hour. Plasma concentrations of glucagon, GLP-1 and GIP were measured, and data were analyzed by rhythmometric statistical methods. Available data on plasma glucose and plasma C-peptide were also included. Results: Plasma concentrations of glucagon, GLP-1, GIP, C-peptide and glucose fluctuated with a diurnal 24-h rhythm, with the highest levels during the day and the lowest levels during the night: glucagon (p < 0.0001, peak time 18:26 h), GLP-1 (p < 0.0001, peak time 17:28 h), GIP (p < 0.0001, peak time 18:01 h), C-peptide (p < 0.0001, peak time 17.59 h), and glucose (p < 0.0001, peak time 23:26 h). As expected, we found significant correlations between plasma concentrations of C-peptide and GLP-1 and GIP but did not find correlations between glucose concentrations and concentrations of glucagon, GLP-1 and GIP. Conclusions: Our results demonstrate that under meal conditions that are similar to that of many free-living individuals, plasma concentrations of glucagon, GLP-1 and GIP were observed to be higher during daytime and evening than overnight. These findings underpin disturbed circadian rhythm as a potential risk factor for diabetes and obesity. Trial registration: ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023. [ABSTRACT FROM AUTHOR]

Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes. Plain Language Summary: Impact of peptides from the gut on bone health in obesity and diabetes mellitus Obesity and related type 2 diabetes (T2D) are prevalent diseases. Unfortunately, there is now a clear link between obesity and related T2D and poor bone health, leading to increased bone fracture risk. However, we know that peptides derived from the gut following a meal can possess positive effects on bone health and reduce bone fracture risk. These peptides are called glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). Moreover, some of these peptides, GLP-1 and GIP, are already being used to treat obesity and T2D, whilst GLP-2 is used to treat people with short bowel syndrome. In other words, drugs that mimic the action of GLP-1, GLP-2 and GIP are available for human use. This current review article aims to provide an initial appraisal of the relationship between obesity, diabetes and bone health, with a focus on the positive impact of peptide hormones like GLP-1, GLP-2 and GIP for bone health in obesity/diabetes. The take home message is that drugs engineered to promote GIP, GLP-1 and GLP-2 action may have potential to offer therapeutic promise for improving bone health in obesity and diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Nephrotoxicity represents amajor complication of using doxorubicin (DOX) in themanagement of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 μg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO-or SEMtreated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy. [ABSTRACT FROM AUTHOR]

Summary: Background: Obesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements. Aims: To conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA‐approved and upcoming anti‐obesity medications (AOMs). Methods: We conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms 'neurohormonal', 'obesity', 'incretin', and 'weight loss'. Next, we searched for clinical trial data of all FDA‐approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide ‐ medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions. Results: We reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA‐approved medications for weight loss are presented, including placebo‐controlled or, when available, head‐to‐head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration. Conclusion: AOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction‐associated steatotic liver disease. [ABSTRACT FROM AUTHOR]

Tirzepatide (Mounjaro®), a first-in-class dual incretin agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, is approved for use as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM) in the USA, EU, Japan and other countries. It comes as single-dose prefilled pens and single-dose vials. In phase III SURPASS trials, once-weekly subcutaneous tirzepatide, as monotherapy or add-on-therapy to oral glucose-lowering medications and insulin, was superior to the GLP-1 receptor agonists (RAs) dulaglutide 0.75 mg and semaglutide 1 mg as well as basal and prandial insulin for glycaemic control and weight loss in adults with inadequately controlled T2DM. Tirzepatide was generally well tolerated, with a safety profile consistent with that of GLP-1 RAs. Tirzepatide was associated with a low risk of clinically significant or severe hypoglycaemia and no increased risk of major adverse cardiovascular events. Adverse events were mostly mild to moderate in severity, with the most common being gastrointestinal events including nausea, diarrhoea, decreased appetite and vomiting. In conclusion, tirzepatide is a valuable addition to the treatment options for T2DM. Plain Language Summary: Many people with type 2 diabetes mellitus (T2DM) do not achieve and maintain glycaemic and weight management goals using currently available treatments. Tirzepatide (Mounjaro®) is the first incretin-based glucose-lowering medication to be approved as an add-on to diet and exercise in adults with T2DM that targets both the glucose-dependent insulinotropic polypeptide receptor (GIP) and the glucagon-like peptide-1 (GLP-1) receptor. In patients with inadequately controlled T2DM, tirzepatide improved glycaemic control and body weight more so than dulaglutide 0.75 mg, semaglutide 1 mg and insulin when used on its own or in combination with other medications. Tirzepatide was generally well tolerated and had a low risk of hypoglycaemia. The most common adverse events were usually short-lived gastrointestinal-related events, which were generally mild to moderate in nature, including nausea, diarrhoea, decreased appetite and vomiting. Tirzepatide is a valuable addition to the treatment options for people with inadequately controlled T2DM. [ABSTRACT FROM AUTHOR]

Context Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. Objective This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. Methods ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. Results TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA– patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. Conclusion Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity. [ABSTRACT FROM AUTHOR]

Context Efficacy and safety of tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, have been studied in patients with type 2 diabetes in the global phase 3 SURPASS program. Objective This work aimed to assess the efficacy and safety of tirzepatide in Hispanic/Latino and non-Hispanic/Latino patients in SURPASS-1 to -4 clinical trials. Methods A total of 5679 patients were included, 2895 of self-reported Hispanic/Latino ethnicity, in this exploratory analysis of SURPASS-1 to -4 trial data. Interventions included tirzepatide 5, 10, or 15 mg, placebo, or active comparator (semaglutide 1 mg, insulin degludec, and insulin glargine). Change in glycated hemoglobin A1c (HbA1c) and body weight from baseline to week 40 (SURPASS-1 and -2) and to week 52 (SURPASS-3 and -4), and other efficacy and safety outcomes were evaluated within Hispanic/Latino and non-Hispanic/Latino subgroups. Results Among Hispanic/Latino and non-Hispanic/Latino patients treated with tirzepatide, respectively, HbA1c decreased significantly from baseline, ranging from 1.9% to 2.7% and 1.7% to 2.5%, and body weight decreased significantly from baseline, ranging from 5.3 kg to 12.4 and 6.5 kg to 17.1 kg (both P <.05) vs comparators across all trials. Subgroup trends were consistent with the overall trial populations. Treatment-emergent adverse events were reported in similar proportions across the subgroups and were primarily gastrointestinal disorders. The incidence of hypoglycemia was low. Conclusion Tirzepatide significatively reduced HbA1c and body weight in Hispanic/Latino and non-Hispanic/Latino patients. Tirzepatide was generally well tolerated in both subgroups. Efficacy and safety trends were comparable between subgroups and within the overall trial populations. [ABSTRACT FROM AUTHOR]

A poorly studied issue in women with breast cancer is the role of incretins (GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1)) in the quantity and quality of muscle mass in lean and obese individuals. The current report aims to analyze the patterns of association and the role of incretin in muscle functionality and body composition in women with cancer compared with healthy women (mammography BI-RADS I or II) to elucidate whether GIP and GLP-1 can be used to estimate the risk, in conjunction with overweight or obesity, for breast cancer. We designed a case–control study in women with a breast cancer diagnosis confirmed by biopsy in different clinical stages (CS; n = 87) and healthy women with a mastography BI-RADS I or II within the last year (n = 69). The women were grouped according to body mass index (BMI): lean (<25 kg/m2BS), overweight (≥25–<30 kg/m2BS), and obese (≥30 kg/m2BS). We found that GLP-1 and GIP levels over 18 pg/mL were associated with a risk of breast cancer (GIP OR = 36.5 and GLP-1 OR = 4.16, for the entire sample), particularly in obese women (GIP OR = 8.8 and GLP-1 OR = 6.5), and coincidentally with low muscle quality indexes, showed an association between obesity, cancer, incretin defects, and loss of muscle functionality. [ABSTRACT FROM AUTHOR]

Simple Summary: Diabetes affects patients with breast cancer. Women with diabetes and the comorbidities related to diabetes tend to receive less aggressive breast cancer treatments primarily because of the potential side effects of the treatment. Managing proper antidiabetic treatment should affect the patient's breast cancer prognosis in patients with both conditions. This review explores the link between diabetes and an elevated risk of breast cancer, highlighting the global prevalence of these conditions. It delves into the impact of antihyperglycemic therapy, including insulin, metformin, and novel groups: incretins and SGLT-2 inhibitors, on the prognosis of breast cancer in diabetic patients. The review also underscores the increased incidence and mortality rates of breast cancer in individuals with diabetes, along with the role of obesity and its connection to the metastasis process in those undergoing antidiabetic treatment. The role of obesity as a confounding variable is confirmed, highlighting the importance of considering obesity during hypoglycemic therapy selection in breast cancer patients. Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs. [ABSTRACT FROM AUTHOR]

An editorial focuses on the potential of small molecule GLP-1 agonists, specifically orforglipron and danuglipron, to become the next first-line drugs in the management of type-2 diabetes mellitus due to their enhanced efficacy and affordability compared to existing peptide GLP-1 agonists.

Compositional oscillations of the gut microbiome are essential for normal peripheral circadian rhythms, both of which are disrupted in diet-induced obesity (DIO). Although time-restricted feeding (TRF) maintains circadian synchrony and protects against DIO, its impact on the dynamics of the cecal gut microbiome is modest. Thus, other regions of the gut, particularly the ileum, the nexus for incretin and bile acid signaling, may play an important role in entraining peripheral circadian rhythms. We demonstrate the effect of diet and feeding rhythms on the ileal microbiome composition and transcriptome in mice. The dynamic rhythms of ileal microbiome composition and transcriptome are dampened in DIO. TRF partially restores diurnal rhythms of the ileal microbiome and transcriptome, increases GLP-1 release, and alters the ileal bile acid pool and farnesoid X receptor (FXR) signaling, which could explain how TRF exerts its metabolic benefits. Finally, we provide a web resource for exploration of ileal microbiome and transcriptome circadian data.

Obesity has emerged as a significant global health concern, with its prevalence escalating over recent decades. This surge has prompted the exploration of innovative pharmacotherapies, such as GLP-1 receptor agonists (GLP-1RA) and incretin-based treatments, to address associated health complications, including type 2 diabetes mellitus (T2DM), dyslipidemia, and hyperglycemia. These therapies have undergone rigorous clinical assessment for their effectiveness in mitigating obesity-related cardio-metabolic diseases and improving overall health outcomes. In this comprehensive review, we delve into the current landscape of obesity management, highlighting the pivotal role of emerging pharmaceutical interventions in combating the multifaceted challenges posed by this epidemic. By elucidating the latest advancements and therapeutic strategies, this review aims to provide insights into the ongoing efforts to tackle obesity and its associated health burdens on a global scale. [ABSTRACT FROM AUTHOR]

Features of the functional state of the enteropancreatic hormonal system in pregnant women with gestational diabetes mellitus© Fatima O. Ushanova1*, Tatiana Y. Demidova1, Tatiana N. Korotkova21Pirogov Russian National Research Medical University, Moscow, Russia2Federal Research Centre of Nutrition, Biotechnology and Food Safety, Moscow, RussiaBACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is growing rapidly, along with which the typical portrait of a pregnant woman with this disease is changing. Frequent detection of GDM in the early stages of pregnancy causes a high interest in the study of new mechanisms of its development.AIM: Evaluation of the state of the incretin response based on the analysis of the secretion of GLP-1, glucagon, insulin and c-peptide in pregnant women with different periods of GDM development.MATERIALS AND METHODS: A single-center prospective comparative uncontrolled study that included pregnant women with GSD, divided into 2 groups depending on the duration of the disease: group 1 — pregnant women who were diagnosed at