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ABSTRACT Background and Aims Methods Results Conclusions Glucagon‐like peptide‐1 receptor (GLP1R) agonists and glucose‐dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction‐associated steatotic liver disease (MASLD) and metabolic dysfunction‐associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty.We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP‐1/GIP concentrations and MASLD and its related traits. Next, we conducted drug‐target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD‐related traits.Circulating 2‐h GLP‐1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (ORGLP‐1 = 0.168 [95% CI 0.033–0.839], p = 0.030; ORGIP = 0.331 [95% CI 0.222–0.494], p = 6.31 × 10−8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531–0.849], p = 9.07 × 10−4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD‐related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index.GLP‐1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a devastating neurodegenerative condition that exerts a significant global burden. Despite recent efforts, disease modifying therapies remain extremely limited, with a tremendous proportion of patients having to rely on symptomatic treatment only. Epidemiological and pathological overlaps exist between Alzheimer's disease and diabetes mellitus type 2, with people with diabetes mellitus type 2 at a significantly increased risk of developing Alzheimer's disease in the future. Incretin mimetics, also known as GLP-1/GIP receptor agonists, are useful tools licensed for the treatment of diabetes mellitus type 2 which have recently been the subject of news coverage for their off-label use as weight loss medications. Emerging evidence highlights the possible neuroprotective function of incretin mimetics in models of Alzheimer's disease as well as in clinical studies. This review details the pre-clinical and clinical studies that have explored the effectiveness of incretin mimetics to alleviate Alzheimer's disease associated pathology and cognitive impairment, while also highlighting the progress made to examine the effectiveness of these molecules in Parkinson's disease. Should clinical trials prove effective, incretin mimetics may be able to be repurposed and become useful novel tools as disease-modifying treatments for Alzheimer's disease and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

A study published in the journal Diabetes, Obesity & Metabolism explores the potential benefits of using a long-acting glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) to offset gastrointestinal adverse effects associated with glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy. The study involved healthy participants who received a single dose of the GIPRA along with daily doses of liraglutide, a selective GLP-1 RA. The results showed that co-exposure to the GIPRA reduced the incidence of gastrointestinal adverse events commonly seen with GLP-1 RA treatment. These findings suggest that GIPRA may improve the tolerability and adherence to GLP-1 RA therapy. [Extracted from the article]

Type 2 diabetes (T2D) and obesity are prevalent metabolic disorders affecting millions of individuals worldwide. A new effective therapeutic drug called tirzepatide for the treatment of obesity and T2D is a dual agonist of the GIP receptor and GLP-1 receptor. Tirzepatide is clinically more effective than GLP-1 receptor agonists but the reasons why are not well understood. Tirzepatide reportedly stimulates the GIP receptor more potently than the GLP-1 receptor. However, tirzepatide signaling has not been thoroughly investigated at the E354 (wildtype) or Q354 (E354Q) GIP receptor variants. The E354Q variant is associated increased risk of T2D and lower body mass index. To better understand GIP receptor signaling we characterized the activity of endogenous agonists and tirzepatide at both GIP receptor variants. Using Cos7 cells we examined wildtype and E354Q GIP receptor signaling, analyzing cAMP and IP¹ accumulation as well as AKT, ERK1/2 and CREB phosphorylation. GIP(1-42) and GIP(1-30)NH2 displayed equipotent effects on these pathways excluding CREB phosphorylation where GIP(1-30)NH2 was more potent than GIP(1-42) at the E354Q GIP receptor. Tirzepatide favored cAMP signaling at both variants. These findings indicate that tirzepatide is a biased agonist towards Gas signaling and suggests it equally activates the wildtype and E354Q GIP receptor variants. We also observed differences between the pharmacology of the GIP receptor variants with endogenous peptides, which may help to explain differences in phenotype. These findings contribute to a comprehensive understanding of GIP receptor signaling, and will aid development of therapies combating T2D and obesity. [ABSTRACT FROM AUTHOR]

Obesity is a major public health crisis in the United States (US) affecting 42% of the population, exacerbating a spectrum of other diseases and contributing significantly to morbidity and mortality overall. Recent advances in pharmaceutical interventions, particularly glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, liraglutide) and dual gastric inhibitory polypeptide and GLP-1 receptor agonists (e.g., tirzepatide), have shown remarkable efficacy in weight-loss. However, limited access to these medications due to high costs and insurance coverage issues restricts their utility in mitigating the obesity epidemic. We quantify the annual mortality burden directly attributable to limited access to these medications in the US. By integrating hazard ratios of mortality across body mass index categories with current obesity prevalence data, combined with healthcare access, willingness to take the medication, and observed adherence to and efficacy of the medications, we estimate the impact of making these medications accessible to all those eligible. Specifically, we project that with expanded access, over 42,000 deaths could be averted annually, including more than 11,000 deaths among people with type 2 diabetes. These findings underscore the urgent need to address barriers to access and highlight the transformative public health impact that could be achieved by expanding access to these novel treatments. [ABSTRACT FROM AUTHOR]

Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen have been awarded the 2024 Lasker-DeBakey Clinical Medical Research Award for their work on GLP-1 receptor agonists and their applications to obesity. GLP-1 receptor agonists have revolutionized the treatment of metabolic disorders like diabetes and obesity, and have shown potential for treating other disorders as well. These drugs have been studied in cardiovascular trials and have shown significant reductions in cardiovascular outcomes, as well as beneficial effects on blood pressure, lipoproteins, and inflammation. However, they do come with side effects such as nausea, vomiting, pancreatitis, and injection site reactions. Longer-acting forms of GLP-1 receptor agonists have been developed to improve convenience for patients. [Extracted from the article]

Objective: The intestinal luminal pH profile varies from stomach to rectum and becomes disrupted in diseases. However, little is known about the pH dependence of incretin hormone secretion, with most in vitro studies having failed to consider this modulatory factor or having used nonphysiological buffer systems. Here, we report the extracellular pH (pHe) dependence of glucagon‐like peptide‐1 (GLP‐1) exocytosis from L cells. Methods: The pHe dependence of GLP‐1 release from GLUTag cells and murine ex vivo primary gut cultures was detected by ELISA. GLP‐1 release was measured over a range of pHe under a physiological (CO2/HCO3−) buffering regime and in its absence (HEPES buffer). The relationship between intracellular pH (pHi) and pHe was mapped given that at least some component of pH sensitivity is likely to be intracellular. Results: GLP‐1 secretion from L cells was pHe‐dependent and stimulated under alkaline conditions. In the absence of glucose or extracellular calcium, secretion remained at a pHe‐insensitive baseline. pHi followed changes in pHe, but the relationship was offset to more alkaline levels in the absence of CO2/HCO3− buffer and became shallower if [Cl−] changes that normally accompany [HCO3−] changes were compensated iso‐osmotically with gluconate. Conclusions: GLP‐1 secretion is sensitive to pHe and the buffer present. Exploiting this mechanism therapeutically may benefit patients with obesity. [ABSTRACT FROM AUTHOR]

The rapidly rising incidence of obesity, coupled with type 2 diabetes mellitus (T2DM), is a growing concern. Glucagonlike peptide 1 (GLP-1), an endogenous peptide secreted by enteroendocrine L-cells, demonstrates exceptional pharmacological potential for the treatment of T2DM and obesity, primarily through its pivotal roles in regulating glucose homeostasis, stimulating glucose-dependent insulin secretion, and promoting satiety. Considering its proven efficacy in glucoregulation and weight loss, GLP-1 receptor agonists (GLP-1RAs) have emerged as a revolutionary breakthrough in the arena of diabetes management and weight control. Additional gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon, exhibit structural similarities to GLP-1 and work synergistically to lower blood glucose levels or aid in weight loss. Today, various classes of gut hormone receptor multiple agonists are steadily progressing through development and clinical trials, including dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist, tirzepatide, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM, outperforming basal insulin or selective GLP-1RAs by providing superior HbA1c reductions. Remarkably, tirzepatide also facilitated unprecedented weight loss of up to 22.5% in non-diabetic individuals living with obesity. This result is comparable to those achieved with certain types of bariatric surgery. Therefore, the advent of gut hormone multi-agonists signifies the dawn of an exciting new era in peptide-based therapy for obesity and T2DM. This review offers a comprehensive summary of the various types of gut hormone multiple agonists, including their discovery, development, action of mechanisms, and clinical effectiveness. We further delve into potential hurdles, limitations, and prospective advancements in the field. [ABSTRACT FROM AUTHOR]

Objectives: We characterized blood glucose fluctuations in patients with myotonic dystrophy type 1 (DM1). After confirming the incretin secretion capacity of patients with DM1, we intended to clarify whether dipeptidyl peptidase 4 (DPP-4) inhibitor administration was appropriate in cases of DM1 with diabetes mellitus. Methods: A 48 h continuous glucose monitoring (CGM) was performed in 29 Japanese patients with DM1. An oral glucose tolerance test (OGTT) was performed in patients with DM1 and five disease controls, and levels of blood glucose, insulin, and incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) were measured. DPP-4 inhibitors were administered to patients with diabetes mellitus complicated by DM1, and the CGM results were compared. Results: The CGM showed distinct patterns of blood glucose variability among patients classified by an OGTT pattern with significant differences in glucose parameters such as time above 140 mg/dL and mean amplitude of glycemic excursions between the groups. High sensor glucose values were observed in a certain number of patients who were classified as having normal or impaired glucose tolerance by the OGTT. The CGM confirmed the presence of low glucose levels in several patients. Incretin secretion, the target of DPP-4 inhibitors, was preserved in patients with DM1. DPP-4 inhibitor treatment resulted in lower glucose levels and improved insulin secretion in some patients. Conclusions: This is the first CGM study for DM1 patients. The CGM identified potential early abnormalities in glucose metabolism in DM1. In the future, it will be crucial to explore effective methods for harnessing CGM and assessing it quantitatively in DM1. [ABSTRACT FROM AUTHOR]

Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role of leucine, a well-known β-cell fuel, in the α-cell–intrinsic regulation of glucagon release. In islet perifusion assays, physiologic concentrations of leucine strongly inhibited alanine- and arginine-stimulated glucagon secretion from human and mouse islets under hypoglycemic conditions. Mechanistically, leucine dose-dependently reduced α-cell cAMP, independently of Ca2+, ATP/ADP, or fatty acid oxidation. Leucine also reduced α-cell cAMP in islets treated with somatostatin receptor 2 antagonists or diazoxide, compounds that limit paracrine signaling from β/δ-cells. Studies in dispersed mouse islets confirmed an α-cell–intrinsic effect. The inhibitory effect of leucine on cAMP was mimicked by glucose, α-ketoisocaproate, succinate, and the glutamate dehydrogenase activator BCH and blocked by cyanide, indicating a mechanism dependent on mitochondrial metabolism. Glucose dose-dependently reduced the impact of leucine on α-cell cAMP, indicating an overlap in function; however, leucine was still effective at suppressing glucagon secretion in the presence of elevated glucose, amino acids, and the incretin GIP. Taken together, these findings show that leucine plays an intrinsic role in limiting the α-cell secretory tone across the physiologic range of glucose levels, complementing the inhibitory paracrine actions of β/δ-cells. Article Highlights: Despite the critical role of pancreatic islets as nutrient sensors, the mechanisms by which amino acids regulate glucagon release remain incompletely understood. We show that leucine, a well-known β-cell fuel, regulates glucagon secretion via a combination of α-cell–intrinsic and islet paracrine signaling. Leucine intrinsically suppresses α-cell cAMP, independently of α-cell Ca2+, ATP/ADP, or fatty acid oxidation. Our findings demonstrate complementary roles of leucine and glucose in the regulation of α-cell cAMP and glucagon secretion. [ABSTRACT FROM AUTHOR]

Duodenal mucosal resurfacing (DMR) by thermal ablation of the duodenal mucosa is a minimally invasive endoscopic procedure for controlling metabolic syndrome (MS). However, thermal energy can cause adverse effects due to deep mucosal injury, necessitating an additional mucosal lifting process, which complicate the procedures. Therefore, we aimed to develop a similar procedure using non-thermal photodynamic therapy (PDT) for DMR using a highly functional metal stent covered with photosensitizers (PSs) to minimize the potential risks of thermal ablation injury. We developed a novel PS stent enabling the controlled release of radical oxygen species with specific structures to prevent stent migration and duodenal stricture after ablation and performed an animal study (n = 8) to demonstrate the feasibility and safety of PDT for DMR. The stents were placed for 7 days to prevent duodenal strictures after PDT. To confirm PDT efficacy, we stained for gastric inhibitory polypeptide (GIP) and glucose transporter isoform 1. The PS stents were deployed, and PDT was applied without evidence of duodenal stricture, pancreatitis, or hemorrhage in any of the pigs. Microscopic evaluation indicated apoptosis of the mucosal cells in the irradiated duodenum on days 7 and 14, which recovered after day 28. Immunohistochemistry revealed suppressed GIP expression in the mucosal wall of the irradiated duodenum. Endoscopic PDT for DMR using PS stents could be applied safely in a porcine model and may result in decreased GIP secretion, which is a crucial mechanism in MS treatment. Further clinical studies are required to explore its safety and efficacy in patients with MS. [ABSTRACT FROM AUTHOR]

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

Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes mellitus (T2DM) are widespread, non-communicable diseases that are responsible for considerable levels of morbidity and mortality globally, primarily in the form of cardiovascular disease (CVD). Changes to lifestyle and behaviour have insufficient long-term efficacy in most patients with these diseases; metabolic surgery, although effective, is not practically deliverable on the scale that is required. Over the past two decades, therapies based on incretin hormones, spearheaded by glucagon-like peptide 1 (GLP1) receptor agonists (GLP1RAs), have become the treatment of choice for obesity and T2DM, and clinical evidence now suggests that these agents have benefits for CVD. We review the latest advances in incretin-based pharmacotherapy. These include 'GLP1 plus' agents, which combine the known advantages of GLP1RAs with the activity of additional hormones, such as glucose-dependent insulinotropic peptide, glucagon and amylin, to achieve desired therapeutic goals. Second-generation non-peptidic oral GLP1RAs promise to extend the benefits of GLP1 therapy to those who do not want, or cannot have, subcutaneous injection therapy. We conclude with a discussion of the knowledge gaps that must be addressed before incretin-based therapies can be properly deployed for maximum benefit in the treatment of obesity and T2DM. This article reviews advances in incretin-based pharmacotherapy, including the latest glucagon-like peptide 1 (GLP1) receptor agonists (GLP1RAs), 'GLP1 plus' agents, which combine the benefits of these agonists with the activity of additional hormones, and oral GLP1RAs, which promise to extend the benefits of GLP1 therapy. Key points: The incretins glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) and related hormones such as glucagon and amylin regulate metabolism, gastrointestinal motility, appetite and body weight. GLP1 receptor agonists (GLP1RAs) are established treatments for type 2 diabetes mellitus (T2DM) and obesity, with data that support positive effects on hard clinical end points such as cardiovascular events and renal outcomes. 'GLP1 plus' treatments go beyond GLP1RAs by combining GLP1 activity with complementary activities such as those of GIP, glucagon and amylin; these treatments are beginning to reach clinical practice. People with T2DM and obesity have varying presentations with differing metabolic and organ involvement, so 'GLP1 plus' treatments might offer differential advantages, depending on the clinical picture. Oral GLP1RAs are also beginning to reach clinical practice, and will open up access for those who do not want, or cannot have, injections; oral GLP1RAs can also be made at lower cost. Evidence on the duration of treatment for obesity, on the treatment of children <12 years of age and women of reproductive age, on rare adverse effects and on how we can target treatment to subgroups needs to be developed. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to investigate the effects of glucagon-like peptide-1 receptor (GLP-1) agonists on the lipid profiles of patients with type 2 diabetes. Methods: We retrieved the data of phase 3 randomized controlled trials on GLP-1 agonists in patients with type 2 diabetes from the PubMed, Embase, and Cochrane library up to 11 February 2024. We extracted % changes in low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol/total cholesterol (T-CHO) and triglycerides levels from baseline. Using Bayesian network meta-analysis, mean differences and 95% credible intervals for lipid changes were estimated as a unit of percentage points (%p) by class. Results: Twenty-six studies covering 22,290 participants were included. The glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 dual agonist showed significant differences in LDL-C (range of mean differences: −11.61 to −6.77%p), triglycerides (−19.94 to −13.31%p), and T-CHO (−7.94 to −5.09%p) levels compared to placebo, insulin, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. The GLP-1 agonist significantly reduced T-CHO (−5.20%p; −6.39%p) and LDL-C (−4.32%p; −8.17%p) levels compared to placebo and SGLT2 inhibitors, respectively. Conclusions: The GIP/GLP-1 dual agonist positively affects the lipid profiles of patients with type 2 diabetes. This may contribute to a lower risk of cardiovascular disease in patients with type 2 diabetes. Protocol registration: PROSPERO (CRD42021282668) [ABSTRACT FROM AUTHOR]

Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut−/−) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut−/− mice, and was similar in plasma, pancreas, and kidney in NEPGut−/− vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut−/− displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction. [ABSTRACT FROM AUTHOR]

Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure. [ABSTRACT FROM AUTHOR]

Background: Tirzepatide--a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist--is used to treat type 2 diabetes. However, the efficacy and safety of tirzepatide in patients undergoing hemodialysis remain unclear. Methods: We conducted a single-center retrospective study of patients with type 2 diabetes undergoing hemodialysis who were transitioned from dulaglutide to tirzepatide. We continuously monitored glucose levels in patients undergoing hemodialysis before and after switching from dulaglutide to tirzepatide. Results: Fourteen patients (mean age: 61.9 ± 9.9 years, male: female = 11:3) were included in this study. After switching to tirzepatide, time in range increased to 50.8% from 42.7% (p = 0.02), time above range decreased to 37.8% from 48.4% (p = 0.02), and mean glucose levels decreased to 137.4 mg/dL from 156.6 mg/dL (p = 0.006). In contrast, there was no significant difference in time below range before and after tirzepatide administration (11.3% and 8.9%) (p = 0.75). Three patients experienced dyspepsia (21.4%), and one patient experienced nausea (7.1%); however, no critical adverse events were reported. Conclusion: Transitioning from dulaglutide to tirzepatide improved glycemic control without increasing hypoglycemia in patients undergoing hemodialysis for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic β‐cells plays a pivotal role in the maintenance of the mass, structure and function of β‐cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and β‐cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon‐like peptide‐1 receptor agonists enhance the autophagic activity of β‐cells, which might contribute to the profound effects of glucagon‐like peptide‐1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in β‐cells and their implication in the development of diabetes are discussed. In addition to non‐selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in β‐cells are discussed. As β‐cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of β‐cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy. [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]

Sildenafil, a phosphodiesterase‐5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic effects remain poorly investigated. This study examines the impact of sildenafil on insulin secretion in MIN6‐K8 mouse clonal β cells. Sildenafil amplified insulin secretion by enhancing Ca2+ influx. These effects required other depolarizing stimuli in MIN6‐K8 cells but not in KATP channel‐deficient β cells, which were already depolarized, indicating that sildenafil‐amplified insulin secretion is depolarization‐dependent and KATP channel‐independent. Interestingly, sildenafil‐amplified insulin secretion was inhibited by pharmacological inhibition of R‐type channels, but not of other types of voltage‐dependent Ca2+ channels (VDCCs). Furthermore, sildenafil‐amplified insulin secretion was barely affected when its effect on cyclic GMP was inhibited by PDE5 knockdown. Thus, sildenafil stimulates insulin secretion and Ca2+ influx through R‐type VDCCs independently of the PDE5/cGMP pathway, a mechanism that differs from the known pharmacology of sildenafil and conventional insulin secretory pathways. Our results reposition sildenafil as an insulinotropic agent that can be used as a potential antidiabetic medicine and a tool to elucidate the novel mechanism of insulin secretion. [ABSTRACT FROM AUTHOR]

This article explores the relationship between insulin hypersecretion and impaired insulin action on glucose metabolism. It presents two competing hypotheses regarding the role of insulin hypersecretion in promoting obesity and insulin resistance. The study conducted by Tricò et al. focuses on individuals with insulin hypersecretion and finds that they have higher rates of de novo lipogenesis and increased adipose tissue. The article also discusses the limitations of current methods used to assess insulin sensitivity and highlights the complexity of glucose homeostasis. Overall, this research provides important insights into the regulation of plasma glucose concentration and raises questions about the traditional understanding of the relationship between insulin sensitivity, insulin secretion, and plasma glucose levels. Further research is needed to better understand the mechanisms underlying insulin hypersecretion and its impact on metabolic health. [Extracted from the article]

Aim: Glucose‐dependent insulinotropic polypeptide (GIP) is a ligand of glucose‐dependent insulinotropic polypeptide receptor (GIPR) that plays an important role in the digestive system. In recent years, GIP has been regarded as a hormone‐like peptide to regulate the local metabolic environment. In this study, we investigated the antioxidant role of GIP on the neuron and explored the possible mechanism. Methods: Cell counting Kit‐8 (CCK‐8) was used to measure cell survival. TdT‐mediated dUTP Nick‐End Labeling (TUNEL) was used to detect apoptosis in vitro and in vivo. Reactive oxygen species (ROS) levels were probed with 2', 7'‐Dichloro dihydrofluorescein diacetate (DCFH‐DA), and glucose intake was detected with 2‐NBDG. Immunofluorescence staining and western blot were used to evaluate the protein level in cells and tissues. Hematoxylin‐eosin (HE) staining, immunofluorescence staining and tract‐tracing were used to observe the morphology of the injured spinal cord. Basso‐Beattie‐Bresnahan (BBB) assay was used to evaluate functional recovery after spinal cord injury. Results: GIP reduced the ROS level and protected cells from apoptosis in cultured neurons and injured spinal cord. GIP facilitated wound healing and functional recovery of the injured spinal cord. GIP significantly improved the glucose uptake of cultured neurons. Meanwhile, inhibition of glucose uptake significantly attenuated the antioxidant effect of GIP. GIP increased glucose transporter 3 (GLUT3) expression via up‐regulating the level of hypoxia‐inducible factor 1α (HIF‐1α) in an Akt‐dependent manner. Conclusion: GIP increases GLUT3 expression and promotes glucose intake in neurons, which exerts an antioxidant effect and protects neuronal cells from oxidative stress both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) and obesity are prevalent metabolic disorders affecting millions of individuals worldwide. A new effective therapeutic drug called tirzepatide for the treatment of obesity and T2D is a dual agonist of the GIP receptor and GLP-1 receptor. Tirzepatide is clinically more effective than GLP-1 receptor agonists but the reasons why are not well understood. Tirzepatide reportedly stimulates the GIP receptor more potently than the GLP-1 receptor. However, tirzepatide signaling has not been thoroughly investigated at the E354 (wildtype) or Q354 (E354Q) GIP receptor variants. The E354Q variant is associated increased risk of T2D and lower body mass index. To better understand GIP receptor signaling we characterized the activity of endogenous agonists and tirzepatide at both GIP receptor variants. Using Cos7 cells we examined wildtype and E354Q GIP receptor signaling, analyzing cAMP and IP1 accumulation as well as AKT, ERK1/2 and CREB phosphorylation. GIP(1-42) and GIP(1-30)NH2 displayed equipotent effects on these pathways excluding CREB phosphorylation where GIP(1-30)NH2 was more potent than GIP(1-42) at the E354Q GIP receptor. Tirzepatide favored cAMP signaling at both variants. These findings indicate that tirzepatide is a biased agonist towards Gαs signaling and suggests it equally activates the wildtype and E354Q GIP receptor variants. We also observed differences between the pharmacology of the GIP receptor variants with endogenous peptides, which may help to explain differences in phenotype. These findings contribute to a comprehensive understanding of GIP receptor signaling, and will aid development of therapies combating T2D and obesity.

A recent study published in the European Heart Journal analyzed the effects of the antidiabetic drug semaglutide on blood pressure (BP) and body weight. The study found that participants who received semaglutide experienced a greater decline in systolic BP (SBP) compared to those who received a placebo, largely due to a decline in body weight. The study also noted that individuals with obesity are at a higher risk of cardiovascular disease and hypertension, and weight loss through caloric restriction or metabolic surgery can significantly lower BP. The findings suggest that the BP-lowering effects of semaglutide may contribute to its protective effects on cardiovascular health. [Extracted from the article]

The prevalence of obesity with various complications is increasing rapidly in Korea. Although lifestyle modification is fundamental in obesity treatment, more effective treatment tools are required. Many advances in obesity treatment have been reported recently, including lifestyle modifications and pharmacological, endoscopic, and surgical treatments. Drugs with proven long-term efficacy and safety are preferred because management for obesity treatment is a long-term process. Currently, four medications are available for long-term use in Korea: Orlistat, Naltrexone/bupuropion NR, Phentermine/topiramate capsule, and Liraglutide. Recently, semaglutide and tirzepatide have been attracting attention because of their effectiveness and convenience, but they are not yet available in Korea. In addition, there are limitations such as the yo-yo effect when discontinuing the drug, long-term safety, and cost. Patients and medical staff must be aware of the advantages and side effects of each medication to ensure the successful treatment of obesity.

Background: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. Methods: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. Results: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. Conclusion: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946. [ABSTRACT FROM AUTHOR]

The article explores the physiological integration of taste and metabolism, emphasizing recent advancements in understanding taste perception, taste receptors, and their implications for health, particularly in the context of added sugars and nonnutritive sweeteners. It discusses the intricate mechanisms of taste transduction, debunking myths such as the tongue taste map, and sheds light on the role of extraoral taste receptors in regulating physiological balance beyond conscious gustation.

This systematic review of cost-effectiveness analyses of newer antidiabetes medications for type 2 diabetes was done to inform the ACP clinical guideline on newer pharmacologic treatments in adults with type 2 diabetes. It evaluates the nonindustry-funded cost-effectiveness analyses that estimate the cost per quality-adjusted life-years gained for SGLT2 inhibitors, GLP1 agonists, DPP4 inhibitors, and long-acting insulins as monotherapy or combination therapy in treating adults with type 2 diabetes mellitus. Background: In the United States, costs of antidiabetes medications exceed $327 billion. Purpose: To systematically review cost-effectiveness analyses (CEAs) of newer antidiabetes medications for type 2 diabetes. Data Sources: Bibliographic databases from 1 January 2010 through 13 July 2023, limited to English. Study Selection: Nonindustry-funded CEAs, done from a U.S. perspective that estimated cost per quality-adjusted life-year (QALY) gained for newer antidiabetic medications. Two reviewers screened the literature; disagreements were resolved with a third reviewer. Data Extraction: Cost-effectiveness analyses were reviewed for treatment comparisons, model inputs, and outcomes. Risk of bias (RoB) of the CEAs was assessed using Drummond criteria and certainty of evidence (CoE) was assessed using GRADE (Grading of Recommendations Assessment, Development, and Evaluations). Certainty of evidence was determined using cost per QALY thresholds predetermined by the American College of Physicians Clinical Guidelines Committee; low (>$150 000), intermediate ($50 to $150 000), or high (<$50 000) value per QALY compared with the alternative. Data Synthesis: Nine CEAs were eligible (2 low, 1 high, and 6 some concerns RoB), evaluating glucagon-like peptide-1 agonists (GLP1a), dipeptidyl peptidase-4 inhibitors (DPP4i), sodium–glucose cotransporter-2 inhibitors (SGLT2i), glucose-dependent insulinotropic peptide agonist (GIP/GLP1a), and insulin. Comparators were metformin, sulfonylureas, neutral protamine Hagedorn (NPH) insulin, and others. Compared with metformin, GLP1a and SGLT2i are low value as first-line therapy (high CoE) but may be of intermediate value when added to metformin or background therapy compared with adding nothing (low CoE). Insulin analogues may be similarly effective but more expensive than NPH insulin (low CoE). The GIP/GLP1a value is uncertain (insufficient CoE). Limitations: Cost-effectiveness analyses varied in methodological approach, assumptions, and drug comparisons. Risk of bias and GRADE method for CEAs are not well established. Conclusion: Glucagon-like peptide-1 agonists and SGLT2i are of low value as first-line therapy but may be of intermediate value when added to metformin or other background therapy compared with adding nothing. Other drugs and comparisons are of low or uncertain value. Results are sensitive to drug effectiveness and cost assumptions. Primary Funding Source: American College of Physicians. (PROSPERO: CRD42022382315) [ABSTRACT FROM AUTHOR]

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut–brain communication can be leveraged to achieve sustained body weight loss without adverse effects. [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]

Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes and obesity are momentous risk factors threatening people's lives and health. Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss. Co-agonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss. Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it. Methods: The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro. The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys. The OGTTs were performed in Sprague‑Dawley (SD) rats. The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic (db/db) mice for 4 weeks. The effects of anti-obesity and improving metabolism of DR10627 were evaluated by repeated administration of DR10627 in diet-induced obesity (DIO) mice for 57 days. Results: DR10627 had the capacity to activate both GLP-1R and GIPR in vitro. The terminal half-life of DR10627 was found to be approximately 4.19– 5.8 h in cynomolgus monkeys. DR10627 had a great improvement in oral glucose tolerance in SD rats. Moreover, DR10627 had a potent glucose-lowering effect in db/db mice, and the hypoglycemic effect of 18 nmol/kg DR10627 was better than that of 50 nmol/kg liraglutide. In addition, 10 and 30 nmol/kg DR10627 possessed the ability of potentiating the weight-loss, lipid-lowing efficacy and improving metabolism to a greater extent than 80 nmol/kg liraglutide. Conclusion: Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and db/db mice, and substantial body weight reduction and metabolism improvement in DIO mice. DR10627 is a promising agent deserving further investigation for the treatment of type 2 diabetes and obesity. [ABSTRACT FROM AUTHOR]

In this study, we investigated how Roux‐en‐Y gastric bypass (RYGB) enhances glucagon‐like peptide 1 (GLP‐1) response in GK rats and explored the potential link between RYGB‐stimulated BAs/FXR signalling and GLP‐1R‐linked signalling in β‐cells, a key pathway that regulates glucose‐stimulated insulin secretion (GSIS). Here we show that RYGB restores GLP‐1R expression in GK rat islets. This involves increased total BAs as well as chenodeoxycholic acid (CDCA), leading to FXR activation, increasing FXR binding to the promoter of Glp‐1r and enhancing occupancy of histone acetyltransferase steroid receptor coactivator‐1 (SRC1), thus increasing histone H3 acetylation at the promoter. These coordinated events bring about increased GLP‐1R expression, resulting in greater GLP‐1 response in β‐cells. Moreover, ablation of FXR suppressed the stimulatory effects of GLP‐1. Thus, this study unravels the crucial role of the BAs/FXR/SRC1 axis‐controlled GLP‐1R expression in β‐cells, which results in enhanced incretin effect and normalized blood glucose of GK rats after RYGB. [ABSTRACT FROM AUTHOR]

This article is a comment on a systematic review and meta-analysis conducted by Yang et al. on the impact of tirzepatide (TZP) on heart rate compared to glucagon-like peptide-1 receptor agonists (GLP-1RAs). GLP-1RAs have been shown to increase heart rate, and there is evidence that glucose-dependent insulinotropic polypeptide (GIP) may also increase heart rate. The comment discusses the inclusion of the SURPASS-2 study in the analysis, which was not included by Yang et al. due to missing data. The addition of SURPASS-2 to the analysis showed no significant difference in heart rate change between TZP and GLP-1RAs, except in Japanese individuals. However, more studies are needed to fully understand the impact of TZP on heart rate compared to GLP-1RAs. [Extracted from the article]

Helicobacter pylori (H. pylori) seems to play causative roles in gastric cancers. H. pylori has also been detected in established gastric cancers. How the presence of H. pylori modulates immune response to the cancer is unclear. The cytotoxicity of natural killer (NK) cells, toward infected or malignant cells, is controlled by the repertoire of activating and inhibitory receptors expressed on their surface. Here, we studied H. pylori‐induced changes in the expression of ligands, of activating and inhibitory receptors of NK cells, in the gastric adenocarcinoma AGS cells, and their impacts on NK cell responses. AGS cells lacked or had low surface expression of the class I major histocompatibility complex (MHC‐I) molecules HLA‐E and HLA‐C—ligands of the major NK cell inhibitory receptors NKG2A and killer‐cell Ig‐like receptor (KIR), respectively. However, AGS cells had high surface expression of ligands of activating receptors DNAM‐1 and CD2, and of the adhesion molecules LFA‐1. Consistently, AGS cells were sensitive to killing by NK cells despite the expression of inhibitory KIR on NK cells. Furthermore, H. pylori enhanced HLA‐C surface expression on AGS cells. H. pylori infection enhanced HLA‐C protein synthesis, which could explain H. pylori‐induced HLA‐C surface expression. H. pylori infection enhanced HLA‐C surface expression also in the hepatoma Huh7 and HepG2 cells. Furthermore, H. pylori‐induced HLA‐C surface expression on AGS cells promoted inhibition of NK cells by KIR, and thereby protected AGS cells from NK cell cytotoxicity. These results suggest that H. pylori enhances HLA‐C expression in host cells and protects them from the cytotoxic attack of NK cells expressing HLA‐C‐specific inhibitory receptors. [ABSTRACT FROM AUTHOR]

Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions.

A study published in the Journal of Diabetes Investigation by Wang et al. explores the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the gut microbiome. The researchers found that clinical DPP-4 inhibitors have little effect on microbial DPP-4 produced by the Bacteroides genus. Additionally, oral administration of microbial DPP-4 to mice on a high-fat diet resulted in reduced levels of active glucagon-like peptide-1 (GLP-1), leading to decreased insulin levels and worsened glucose tolerance. However, the study also discovered that daurisoline-d4, a natural alkaloid found in medical herbs, inhibited microbial DPP-4 activity and improved glycemic control. These findings suggest the potential for developing drugs that target microbial DPP-4 for individuals with diabetes who do not respond well to conventional DPP-4 inhibitors. [Extracted from the article]

Stevia rebaudiana Bertoni water extracts have been used as a natural sweetener and customary medicine by the indigenous inhabitants of South America for several hundred years. This plant was sent to Europe in the 16th century and was described by Peter Jacob Esteve in Spain. Recently the food industry has started to employ S. rebaudiana as sweetener using its glycosides after purification. Advertisement claims that Stevia glycosides is good for controling body mass and reducing glycemia. This study's objective was to evaluate the effect of S. rebaudiana leaf extract on Wistar rats as animal model to prove its effectiveness on body mass control, glycemia reduction, and other biochemical parameters. Three groups were randomly formed with 24 males and 24 females: A blank group without any sweetener, a control group drinking water with 10% glucose, and the test group ingesting a 0.94% water extract of S. rebaudiana. Body mass measurements as well as food and drink consumption were daily performed. The experiment lasted 120 days after the specimens were weaned and got used to eating solid food. Euthanasia was done and blood serum was collected to evaluate the following biochemical parameters: Glucose, triglycerides, cholesterol, insulin, glucagon, leptin, ghrelin, and glucose-dependent insulinotropic peptide, GIP. Results indicated that only female rats had statistical differences in body mass gain. No relevant effects either positive or negative were found in the biochemical parameters measured. The crude extracts of S. rebaudiana did not show any relevant changes in biochemical and hormonal profiles, changes nor body mass with respect to the blank and control groups of young and healthy rats in the age range of infancy to youth. According to the results obtained, the therapeutic properties that have been associated to S. rebaudiana consumption especially for body mass control and glycemia reduction, did not occur in young and healthy male and female rats in equivalent age to infants, young children, and youths. [ABSTRACT FROM AUTHOR]

Periodontitis is a common condition affecting the tissues surrounding and supporting teeth. In addition to oral health concerns, periodontal disease increases the chance of developing systemic illnesses including type 2 diabetes mellitus. Porphyromonas gingivalis, a key-stone pathogen that has been linked to the pathophysiology of periodontal disease, can generate a series of dipeptide producing exopeptidases, dipeptidyl peptidases (DPP). DPP-4 levels in gingival crevicular fluid have been shown to increase during active periodontal disease, which may lead to their association with the disease's progression. Following oral glucose administration, mice injected with DPP-4 had higher blood glucose than the control group. DPP-4 inhibitors are used to treat patients with type 2 diabetes mellitus in order to extend the half-life of incretins. Elevated glucagon-like peptide-1 (GLP-1) levels following periodontal therapy could be considered new and applicable real-world evidence confirming the experimental findings of a beneficial interaction between oral microbiota and incretin axis. GLP-1 receptor agonist exendin-4 enhanced the osteoblast proliferation and development of these stem cells and inhibited the effects of glucose on the cells. In addition to lowering blood sugar, liraglutide, a GLP-1 receptor agonist, also possesses anti-inflammatory and bone-protective properties. These findings support the use of GLP-1 in the management and prevention of diabetic periodontitis. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the impact of a dual glucose‐dependent insulinotropic peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist tirzepatide (TZP), and its potential dose‐response effect, on heart rate. Methods: Articles were searched from PubMed, Web of Science, Embase, Cochrane Library, and clinical trials registries (ClinicalTrials.gov) databases. Randomized controlled trials (RCTs) comparing TZP at doses of 5, 10 and 15 mg in adults with type 2 diabetes were included. Six study arms were summarized from original research (TZP 5, 10 and 15 mg, GLP‐1 receptor agonists [GLP‐1RAs], insulin, placebo). The GLP‐1RA and non‐GLP‐1RA groups were combined to form a control group. Two reviewers independently extracted data and assessed the quality of each study. Mean differences (MDs) were calculated as effect estimates for continuous outcomes. Pairwise meta‐analyses and network meta‐analyses were conducted. The study protocol was prospectively registered (PROSPERO ID: CRD42023418551). Results: Eight articles were included in this systematic review and meta‐analysis. The mean baseline heart rate ranged from 65.2 to 75.7 beats per minute. Pairwise meta‐analysis showed that, compared with combined the control group, there were significantly greater increases in heart rates in the TZP group (MD 1.82, 95% confidence interval [CI] 0.75, 2.89). Similar significant rises were identified when comparing TZP with GLP‐1RAs and non‐GLP‐1RAs (GLP‐1 RAs: MD 2.29, 95% CI 1.00, 3.59; non‐GLP‐1RAs: MD 1.58, 95% CI 0.26, 2.91). TZP 5 mg was associated with smaller increases in heart rates compared to TZP 10 mg and TZP 15 mg (TZP 10 mg: MD −0.97, 95% CI −1.79, −0.14; TZP 15 mg: MD −2.57, 95% CI −3.79, −1.35). TZP 10 mg increased heart rate less than TZP 15 mg (MD −1.5, 95% CI −2.38, −0.82). Network meta‐analysis indicated that TZP 15 mg was associated with significant increases in heart rate compared with TZP 5 mg (MD 2.53, 95% CI 1.43, 3.62), TZP 10 mg (MD 1.44, 95% CI 0.35, 2.53), GLP‐1RAs (MD 3.46, 95% CI 1.67, 5.25), insulin (MD 2.86, 95% CI 1.32, 4.41) and placebo (MD 2.96, 95% CI 1.36, 4.57). Conclusions: Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP‐1RA and non‐GLP‐1RA groups, but also that the 15‐mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose‐response impact on heart rate. Further research on the effects of TZP treatment‐related increases in heart rate is required. [ABSTRACT FROM AUTHOR]

Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions. [ABSTRACT FROM AUTHOR]

Background: Obesity has increased in recent years with consequences on diabetes and other comorbidities. Thus, 1 out of 3 diabetic patients suffers cardiovascular disease (CVD). The network among glucose, immune system, endothelium and epicardial fat has an important role on pro-inflammatory and thrombotic mechanisms of atherogenesis. Since semaglutide, long-acting glucagon like peptide 1- receptor agonist (GLP-1-RA), a glucose-lowering drug, reduces body weight, we aimed to study its effects on human epicardial fat (EAT), aortic endothelial cells and neutrophils as atherogenesis involved-cardiovascular cells. Methods: EAT and subcutaneous fat (SAT) were collected from patients undergoing cardiac surgery. Differential glucose consumption and protein cargo of fat-released exosomes, after semaglutide or/and insulin treatment were analyzed by enzymatic and TripleTOF, respectively. Human neutrophils phenotype and their adhesion to aortic endothelial cells (HAEC) or angiogenesis were analyzed by flow cytometry and functional fluorescence analysis. Immune cells and plasma protein markers were determined by flow cytometry and Luminex-multiplex on patients before and after 6 months treatment with semaglutide. Results: GLP-1 receptor was expressed on fat and neutrophils. Differential exosomes-protein cargo was identified on EAT explants after semaglutide treatment. This drug increased secretion of gelsolin, antithrombotic protein, by EAT, modulated CD11b on neutrophils, its migration and endothelial adhesion, induced by adiposity protein, FABP4, or a chemoattractant. Monocytes and neutrophils phenotype and plasma adiposity, stretch, mesothelial, fibrotic, and inflammatory markers on patients underwent semaglutide treatment for 6 months showed a 20% reduction with statistical significance on FABP4 levels and an 80% increase of neutrophils-CD88. Conclusion: Semaglutide increases endocrine activity of epicardial fat with antithrombotic properties. Moreover, this drug modulates the pro-inflammatory and atherogenic profile induced by the adiposity marker, FABP4, which is also reduced in patients after semaglutide treatment. [ABSTRACT FROM AUTHOR]

Introduction/Aim. Despite the fact that proton pump inhibitors are widely used for the inhibition of gastric acid secretion, recent studies have revealed certain long-term side effects. Due to acidic environment in the stomach, it is challenging to design new competitive inhibitors of gastric proton pump with more potent inhibition of gastric acid secretion to conventional drugs. The aim of this in silico study was to assess the potential of designed vonoprazan derivatives to inhibit the gastric proton pump using molecular docking study. Methods. The distribution-based design of the vonoprazan derivatives was carried out by optimization of the distribution coefficient at physiological pH and pKa values. A molecular docking study was performed using the protein structure of gastric proton pump (PDB ID: 5YLU) in complex with vonoprazan in AutoDock Vina software. Results. According to the estimated values of docking scores, derivatives 11, 21, and 25 showed the highest binding affinity to gastric proton pump. Compounds 3, 13, 14, 16, 17, 20, 22, and 23 formed the highest number of significant binding interactions with the active site of proton pump. Conclusion. Based on the obtained binding parameters, it can be concluded that derivatives 14 and 23 achieved the highest number of significant binding interactions (16 and 15, respectively) with concomitant lower values of the docking scores (-9.2 and -9.3 kcal/mol) compared to vonoprazan as a binding control. Based on the binding assessment criteria, these two compounds represent the molecules with the strongest inhibitory potential towards gastric proton pump. [ABSTRACT FROM AUTHOR]

In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the "skeleton" structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon, and glucose simultaneously in humans. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is "drug-independent", our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on the glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system. [ABSTRACT FROM AUTHOR]

Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss–independent, GLP-1R–dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss–independent, GLP-1R–dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. Article Highlights: Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss–independent, GLP-1 receptor (GLP-1R)–dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R–dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss–independent, GLP-1R–dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1. [ABSTRACT FROM AUTHOR]

The article discusses the importance of enteroendocrine cells (EECs) in the human gut, which secrete hormones that regulate various bodily functions. The differentiation of EECs from intestinal stem cells is controlled by a network of transcription factors, with NEUROG3 being a key regulator. The study used an in vitro model of human gut organoids combined with CRISPR screening to identify genes involved in EEC differentiation. The researchers discovered that the ZNF800 gene acts as a repressor of EEC differentiation and identified downstream targets of ZNF800, including other transcription factors. The study highlights the usefulness of organoid models for understanding gut physiology and provides insights into the regulation of endocrine cell development. [Extracted from the article]

Metabolic illnesses, including obesity and type 2 diabetes, have become worldwide epidemics that have an effect on public health. Clinical investigations and further exploration of these mechanisms could lead to innovative, effective, and personalized treatment strategies for individuals. It is important to screen biomarkers in previous studies to discover what is missing. Glucagon-like peptide-1′s role in insulin secretion and glucose control highlights its diagnostic and therapeutic potential. Glucose-dependent insulinotropic peptide's influence on postprandial satiety and weight management signifies its importance in understanding metabolic processes. Monocyte chemoattractant protein-1′s involvement in inflammation and insulin resistance underlines its value as a diagnostic marker. Insulin-like growth factor-binding protein-7's association with insulin sensitivity and kidney function presents it as a potential target for these diseases' management. In validating these biomarkers, it will be easier to reflect pathophysiological processes, and clinicians will be able to better assess disease severity, monitor disease progression, and tailor treatment strategies. The purpose of the study was to elucidate the significance of identifying novel biomarkers for type 2 diabetes mellitus and obesity, which can revolutionize early detection, risk assessment, and personalized treatment strategies. Standard literature searches of PubMed (MEDLINE), EMBASE, and Cochrane Library were conducted in the year 2023 to identify both original RCTs and recent systematic reviews that have explored the importance of identifying novel biomarkers for T2D and obesity. This search produced 1964 results, and then was reduced to randomized controlled trial and systematic reviews, producing 145 results and 44 results, respectively. Researchers have discovered potential associations between type 2 diabetes mellitus and obesity and the biomarkers glucagon-like peptide-1, glucose-dependent insulinotropic peptide, monocyte chemoattractant protein-1, and insulin-like growth factor-binding protein-7. Understanding the role of those biomarkers in disease pathogenesis offers hope for improving diagnostics, personalized treatment, and prevention strategies. [ABSTRACT FROM AUTHOR]