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Background Weight gain and associated metabolic complications are increasingly prevalent among people with human immunodeficiency virus (PWH). Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited. Methods A retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at the University of California, San Diego Owen Clinic between 1 February 2021 and 1 February 2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss. Results A total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a weight loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI (odds ratio [OR], 1.10 [95% confidence interval {CI}, 1.03–1.16]), treatment duration of GLP-1RA therapy >6 months (OR, 3.12 [95% CI, 1.49–6.49]), and use of tirzepatide (OR, 5.46 [95% CI, 1.44–20.76]) were significantly more likely to be associated with >5% weight loss. Conclusions Use of GLP-1RAs led to declines in weight, BMI, and A1C among PWH and offers an additional strategy to address weight gain and diabetes. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), which is a global public health concern, can take various forms, from mild concussions to blast injuries, and each damage type has a particular mechanism of progression. However, TBI is a condition with complex pathophysiology and heterogenous clinical presentation, which makes it difficult to model for in vitro and in vivo studies and obtain relevant results that can easily be translated to the clinical setting. Accordingly, the pharmacological options for TBI management are still scarce. Since a wide spectrum of processes, such as glucose homeostasis, food intake, body temperature regulation, stress response, neuroprotection, and memory, were demonstrated to be modulated after delivering glucagon-like peptide 1 (GLP-1) or GLP-1 receptor agonists into the brain, we aimed to speculate on their potential role in TBI management by comprehensively overviewing the preclinical and clinical body of evidence. Based on promising preclinical data, GLP-1 receptor agonists hold the potential to extend beyond metabolic disorders and address unmet needs in neuroprotection and recovery after TBI, but also other types of central nervous system injuries such as the spinal cord injury or cerebral ischemia. This overview can lay the basis for tailoring new research hypotheses for future in vitro and in vivo models in TBI settings. However, large-scale clinical trials are crucial to confirm their safety and efficacy in these new therapeutic applications. [ABSTRACT FROM AUTHOR]

Cardiovascular outcome trials (CVOTs) in people living with type 2 diabetes mellitus and obesity have confirmed the cardiovascular benefits of glucagon-like peptide 1 receptor agonists (GLP-1RAs), including reduced cardiovascular mortality, lower rates of myocardial infarction, and lower rates of stroke. The cardiovascular benefits observed following GLP-1RA treatment could be secondary to improvements in glycemia, blood pressure, postprandial lipidemia, and inflammation. Yet, the GLP-1R is also expressed in the heart and vasculature, suggesting that GLP-1R agonism may impact the cardiovascular system. The emergence of GLP-1RAs combined with glucose-dependent insulinotropic polypeptide and glucagon receptor agonists has shown promising results as new weight loss medications. Dual-agonist and tri-agonist therapies have demonstrated superior outcomes in weight loss, lowered blood sugar and lipid levels, restoration of tissue function, and enhancement of overall substrate metabolism compared to using GLP-1R agonists alone. However, the precise mechanisms underlying their cardiovascular benefits remain to be fully elucidated. This review aims to summarize the findings from CVOTs of GLP-1RAs, explore the latest data on dual and tri-agonist therapies, and delve into potential mechanisms contributing to their cardioprotective effects. It also addresses current gaps in understanding and areas for further research. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D. [ABSTRACT FROM AUTHOR]

Obesity is a disease of epidemic proportions in the United States and contributes to morbidity and mortality for a large part of the population. In addition, the financial costs of this disease to society are high. Lifestyle modifications are key to prevention and treatment but adherence and long‐term success have been challenging. Bariatric surgery has been available and pharmacologic approaches, first developed in the 1950s, continue to be an option; however, existing formulations have not provided optimal clinical efficacy and have had many concerning adverse effects. Over the last decade, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, a novel group of medications for the treatment of type 2 diabetes, were found to produce significant weight loss. Several formulations, at higher doses, received FDA approval for the treatment of obesity or those overweight with weight‐related co‐morbidities. More hormone‐based therapies were and are being developed, some with dual or triple‐receptor agonist activity. Their use, however, is not without questions and concerns as to long‐term safety and efficacy, problems with cost and reimbursement, and how their use may intersect with public health efforts to manage the obesity epidemic. This review will focus on the GLP‐1 receptor agonists currently used for weight loss and discuss their pharmacology, pertinent research findings establishing their benefits and risks, issues with prescribing these medications, and a perspective from a public health point of view. [ABSTRACT FROM AUTHOR]

Introdroduction: 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. Methods: The objective of this narrative review was to summarize the available data on approved and emerging incretin‐based agents for the treatment of obesity. Results: 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. Conclusions: 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]

Forty percent of Americans are obese and 20% are overweight. Until recently, notwithstanding great efforts to combat this chronic, worsening epidemic, the only therapy that "worked" was surgery. However, recently, a new class of safe drugs (incretins) have been developed that cause obese patients to lose ∼20 to 25% of their body weight. Herein we recount this revolution and its implications. [ABSTRACT FROM AUTHOR]

While linagliptin is the most potent dipeptidyl peptidase 4 inhibitor, its use is limited due to poor bioavailability and the potential risk of pancreatic injury. Here, we investigated whether the sustained weekly administration of linagliptin could provide better effect compared to frequent daily oral administration. Type 2 diabetes was induced by feeding rats a high fructose/fat/salt diet followed by STZ injection. Compared to the partial glycemic control achieved with daily oral linagliptin, a weekly subcutaneous injection containing about one-fourth of the oral dose produced superior glycemic control, as evidenced by the 4-week postprandial glucose follow-up and oral glucose tolerance test. This was confirmed by the significant increase in serum insulin in the case of the sustained linagliptin administration. Higher levels of the anti-inflammatory cytokine adiponectin and lower triglyceride levels were observed after sustained linagliptin administration compared with daily oral linagliptin. In addition, sustained linagliptin displayed a significant increase in β-cells' insulin immunoreactivity when compared with daily linagliptin. More reduction in collagen deposition and caspase-3 immunoreactivity in pancreatic tissue were observed in sustained linagliptin compared with oral linagliptin. In conclusion, sustained linagliptin administration provided superior glycemic control, which seems to be mediated by more reduction in pancreatic injury. [ABSTRACT FROM AUTHOR]

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]

In recent years, there has been a growing emphasis on the relationship between obesity and diabetes. An analysis of Korean data revealed that more than 75% of diabetic patients were overweight or obese, with two-thirds having abdominal obesity. Traditional treatment goals for diabetes have primarily focused on lowering blood glucose levels to prevent and treat microvascular and macrovascular complications, which is known as the glucocentric approach. However, with the recognition of the shared pathophysiology of insulin resistance in both diabetes and obesity, a weight-centric approach has emerged, particularly beneficial for patients in whom insulin resistance is a primary driver of type 2 diabetes. Of note, the overlap of various physiological aspects in diabetic patients necessitates a multicentric approach for effective type 2 diabetes management. Recent guidelines now recommend weight loss as a primary treatment goal alongside blood glucose control for overweight and obese diabetic patients, highlighting the significance of weight management in diabetes care. Medications such as glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist with weight-loss effects are recommended for this patient population. Ongoing research is exploring the potential of various gut hormone-based therapies, offering hope for effective weight management and improved diabetes outcomes in the growing population of obese diabetic individuals. [ABSTRACT FROM AUTHOR]

INTRODUCTION: After colectomy with ileoanal pouch anastomosis (IPAA), many patients develop high bowel frequency (BF) refractory to antimotility agents, despite normal IPAA morphology. Low circulating levels of glucagon-like protein-1 (GLP-1), a modulator of gastroduodenal motility, have been reported after colectomy. METHODS: Double-blind crossover study of 8 IPAA patients with refractory high BF treated with daily administration of the GLP-1 receptor agonist liraglutide or placebo. RESULTS: Liraglutide, but not placebo, reduced daily BF by more than 35% (P < 0.03). DISCUSSION: Larger randomized controlled studies are warranted to delineate the treatment potential of GLP-1 receptor agonists in IPAA patients suffering from noninflammatory high BF. [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]

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.

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]

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]

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]

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.

A study published in the European Heart Journal explores the effects of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on weight loss in patients with heart failure with preserved ejection fraction (HFpEF). The study found that dapagliflozin treatment resulted in greater weight loss in obese individuals compared to lean individuals, with most of the weight loss being fat rather than water or lean tissue. The study also discovered that dapagliflozin increased levels of peptide YY (PYY), a hormone that promotes satiety and decreases appetite. The increase in PYY was correlated with weight loss, particularly in adipose tissue, and favorable haemodynamic effects during exercise. These findings suggest that SGLT2i-mediated increases in PYY may contribute to weight loss in obese HFpEF patients through increased satiety, with secondary haemodynamic benefits. [Extracted from the article]

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.

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: 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]

Modern approaches to the treatment of type 2 diabetes mellitus (T2DM) are aimed not only at glycemic control, but also at reducing cardiovascular risks. The increasing prevalence of the disease and the need for effective treatment options highlight the importance of glucagon-like peptide-1 (GLP-1) receptor agonists in the pharmacotherapy structure.The aim of the work was to review the literature regarding the physiology of GLP-1 and the therapeutic potential and development trends of its agonists.Materials and methods. The search for the review materials was carried out using the abstract databases of PubMed, Google Scholar and e-Library. The search was carried out for publications from 2000 to 2023, using the following keywords: “GLP-1”; “GLP-1R agonists”; “GIP”; “exenatide”; “liraglutide”; “dulaglutide”; “semaglutide”; “lixisenatide”; “albiglutide”; “taspoglutide” taking into account various spellings.Results. The interaction of almost all food components with enteroendocrine cells of the intestine leads to the secretion of incretins (primarily GLP-1) into the blood, triggering a complex of physiological reactions aimed primarily at the rapid utilization of incoming glucose (regulation of insulin and glucagon secretion), as well as the central regulation of dietary behavior (slowing gastric emptying and the formation of a feeling of satiety). A wide distribution of the GLP-1 receptor in various tissues and organs, its connection with intracellular signaling cascades aimed at launching energy-consuming remodeling (recovery) processes in endothelial cells, heart, neurons, beta cells, etc., is the basis for a wide range of pleiotropic effects of GLP-1 unrelated to its hypoglycemic effect. The discovery of synthetic GLP-1 receptor agonists with a long period of action has made it possible not only to therapeutically influence various parts of carbohydrate metabolism disorders, but also to increase the functional reserves of the target diabetes organs, reducing the risk of developing complications of the disease. Incretin-like drugs are well tolerated, with nausea being the most common side effect. The factors limiting a wider use of the drugs include their high cost and the preferred form of a subcutaneous solution. The current research is focused on the development of long-acting, oral, dual and triple agonists, fixed-dose combinations, and small molecule drugs.Conclusion. GLP-1 receptor agonists are a class of effective and safe drugs for the treatment of diabetes and obesity, which is rapidly developing in the most advanced areas of pharmacy. A further development of this group and the solution of the identified problems will open up new opportunities for the treatment of diabetes and its complications.

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.

Traumatic brain injury (TBI), which is a global public health concern, can take various forms, from mild concussions to blast injuries, and each damage type has a particular mechanism of progression. However, TBI is a condition with complex pathophysiology and heterogenous clinical presentation, which makes it difficult to model for in vitro and in vivo studies and obtain relevant results that can easily be translated to the clinical setting. Accordingly, the pharmacological options for TBI management are still scarce. Since a wide spectrum of processes, such as glucose homeostasis, food intake, body temperature regulation, stress response, neuroprotection, and memory, were demonstrated to be modulated after delivering glucagon-like peptide 1 (GLP-1) or GLP-1 receptor agonists into the brain, we aimed to speculate on their potential role in TBI management by comprehensively overviewing the preclinical and clinical body of evidence. Based on promising preclinical data, GLP-1 receptor agonists hold the potential to extend beyond metabolic disorders and address unmet needs in neuroprotection and recovery after TBI, but also other types of central nervous system injuries such as the spinal cord injury or cerebral ischemia. This overview can lay the basis for tailoring new research hypotheses for future in vitro and in vivo models in TBI settings. However, large-scale clinical trials are crucial to confirm their safety and efficacy in these new therapeutic applications.

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]