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Abstract Background In idiopathic intracranial hypertension (IIH), sustained weight loss is the main pillar in modifying disease course, whereby glucagon-like peptide-1 receptor agonists (GLP-1-RAs) could present an attractive treatment option. Methods In this open-label, single-center, case–control pilot study, patients with IIH (pwIIH) and a body mass index (BMI) of ≥ 30 kg/m2 were offered to receive a GLP-1-RA (semaglutide, liraglutide) in addition to the usual care weight management (UCWM). Patients electing for UCWM only served as a control group matched for age-, sex- and BMI (1:2 ratio). The primary endpoint was the percentage weight loss at six months (M6) compared to baseline. Secondary endpoints included the rate of patients with a weight loss of ≥ 10%, monthly headache days (MHD), the rate of patients with a ≥ 30% and ≥ 50% reduction in MHD, visual outcome parameters, and adverse events (AEs). Results We included 39 pwIIH (mean age 33.6 years [SD 8.0], 92.3% female, median BMI 36.3 kg/m2 [IQR 31.4–38.3]), with 13 patients being treated with GLP-1-RAs. At M6, mean weight loss was significantly higher in the GLP-1-RA group (–12.0% [3.3] vs. –2.8% [4.7]; p

ABSTRACT Aims/Introduction Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose‐stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin. Materials and Methods Blood glucose and plasma insulin, GIP, and GLP‐1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK‐Ay/TaJcl (KK‐Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase‐4 inhibitor sitagliptin or the GLP‐1 receptor antagonist exendin‐9. The effects of imeglimin, with or without GIP or GLP‐1, on GSIS were examined in C57BL/6 mouse islets. Results Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK‐Ay mice, whereas it also increased the plasma levels of GIP and GLP‐1 in KK‐Ay mice and the GLP‐1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP‐1 levels during the OGTT in KK‐Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP‐1, but not with GIP, in mouse islets. Exendin‐9 had only a minor inhibitory effect on the glucose‐lowering action of imeglimin during the OGTT in KK‐Ay mice. Conclusions Our data suggest that the imeglimin‐induced increase in plasma GLP‐1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.

Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management 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 SEM-treated 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.

Background: Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analog, and its pharmacokinetic and pharmacodynamic properties as a GLP-1 receptor (GLP-1R) agonist make it an important therapeutic option for many patients with type 2 diabetes mellitus. This study compared the bioequivalence and safety of liraglutide with the originator product in healthy Chinese adult subjects.Methods: Subjects (N = 36, both sexes) were randomized in a 1:1 ratio into two groups (18 cases each) for a two-cycle, self-crossover trial. Each cycle involved a single subcutaneous injection of the test and reference drugs, with a washout period of 14 days. The plasma drug concentration was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main pharmacokinetic parameters were statistically analyzed to assess drug bioequivalence. Furthermore, the safety of the drugs was assessed throughout the trial.Results: The geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ were 103.73%, 103.01%, and 103.03%, respectively, and their 90% confidence intervals (CIs) were consistent with the range of 80.00%–125.00%, indicating that the two formulations had similar pharmacokinetics. Meanwhile, safety results showed that both drugs were well tolerated.Conclusion: Studies have shown that the test drug has similar bioequivalence and safety to the reference drug.Clinical trial registration: (http://www.chinadrugtrials.org.cn/index.html), identifier (CTR20171303).

Glucagon like peptide-1 (GLP-1) receptor agonists are well established drugs for the treatment of type 2 diabetes (T2D). In addition to glycemic control, GLP-1 receptor agonists have beneficial other effects. They act by binding to GLP-1 receptors, which are widely distributed in the body, including cardiomyocytes and blood vessels. The aim of this article is to provide a comprehensive review of GLP-1 receptor agonists impact on cardiovascular outcomes and risk reduction. In the last decade, several cardiovascular outcomes trials (CVOT) have been conducted in order to explore cardiovascular benefit of GLP-1 receptor agonists. CVOTs primarily proved cardiovascular safety and tolerability of different GLP-1 receptor agonists, but also showed cardiovascular benefit of specific drugs. CVOTs have shown that GLP-1 receptor agonists reduce MACE in patients with T2D compared to placebo. In addition, they have positive impact on several cardiovascular risk factors such as obesity by promoting weight loss, blood pressure and blood lipid levels. Also, they stimulate the endothelium to produce nitric oxide, reduce oxidative stress, and have antiatherogenic and antiinflammatory effects. Studies have shown their positive impact on kidney outcomes in patients with T2D compared to placebo. The results of previous trials are encouraging in terms of multiple positive effects of GLP-1 receptor agonists. However, further research is needed to understand their full potential and all details of their mechanism of action, which will enable to expand the therapeutic indications and to determine their optimal use in clinical practice.

Objective: Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Methods: Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N = 99) received NN1177 (on an escalating dose regimen of 200, 600, 1300, 1900, 2800, 4200 and 6000 μg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N = 49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1100 μg) or placebo, and a drug–drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-μg dose of NN1177, following administration of a Cooperstown 5 + 1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed. Results: For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 μg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids. Conclusion: Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

Abstract Introduction: A growing number of studies have thus far showed the association between type 2 diabetes mellitus (DM) and the intestinal microbiome homoeostasis. As reported, the gut microflora can be significantly different in patients with type 2 DM (T2DM) compared to those in healthy individuals. Methods: The authors collected the relevant articles published until 2022 and these are carefully selected from three scientific databases based on keywords. Discussion: This review highlights research on the anti-diabetic properties of berberine (BBR)-induced glucagon-like peptide-1 (GLP-1), as a glucose-lowering factor and a balance regulator in the microbial flora of the intestines, which plays an important role in adjusting the signalling pathways affecting insulin secretion. Results: Considering the anti-diabetic characteristics of the BBR-induced GLP-1, BBR makes a promising complementary treatment for reducing the clinical symptoms of DM by reducing the hyperglycaemia. Berberin might be a safe and effective drug for T2DM with little or no adverse effects. Highlights Berberine induces GLP-1 insulin secretion by PLC2 pathway in the intestinal Berberine-induced GLP-1 decreases mitochondrial stress and relocates cytochrome c out of the mitochondria. Berberine induces GLP-1 secretion in the intestine by altering the bacterial profile, thus could possibly lighten diabetes symptoms Berberine-induced SCFA production, SCFA causes GLP-1 secretion from the intestinal L-Cell. Preventing mitochondrial damage, reducing adipose tissue fat, and reducing oxidative stress are thus among the results of BBR-induced GLP-1. The lower costs of BBR, and its limited side effects and higher availability, make it a promising supplementary medicine for DM Berberine induces GLP-1 insulin secretion by PLC2 pathway in the intestinalBerberine-induced GLP-1 decreases mitochondrial stress and relocates cytochrome c out of the mitochondria.Berberine induces GLP-1 secretion in the intestine by altering the bacterial profile, thus could possibly lighten diabetes symptomsBerberine-induced SCFA production, SCFA causes GLP-1 secretion from the intestinal L-Cell.Preventing mitochondrial damage, reducing adipose tissue fat, and reducing oxidative stress are thus among the results of BBR-induced GLP-1.The lower costs of BBR, and its limited side effects and higher availability, make it a promising supplementary medicine for DM [ABSTRACT FROM AUTHOR]

Objective(s): The detrimental effects of high fructose consumption on metabolic health have been extensively studied. However, limited research has focused on the impact of fructose intake on neuroprotective mechanisms, specifically the expression of insulin receptor (INSR) and glucagonlike peptide-1 receptor (GLP-1R) in the hippocampus. Understanding the effects of fructose on these neuroprotective molecules can provide valuable insights into the potential role of fructose in hippocampal dysfunction. The goal of this study is to aim at the basal plasma levels of lipid profile, insulin, GLP-1, and HOMA-IR, as well as the mRNA and protein expression of neuroprotective molecules such as INSR and GLP-1R in Wistar rats fed a high fructose diet. Materials and Methods: Rats were separated into control (C) and high fructose (HF) groups. The HF group was given 20% fructose water to drink for 16 weeks. Results: Fructose ingestion significantly increased abdominal fat (C=1.24±0.08 g, HF=1.79±0.19 g, P<0.05) and plasma triglyceride levels (C=179.22±22.85 µg/ml, HF=242.45±14.45 µg/ml, P<0.05), but had no statistically significant effect on body weight and plasma HDL, LDL, total cholesterol, insulin, and GLP-1 levels (P>0.05). Although INSR mRNA expression in the hippocampus was significantly lower in the HF group compared to the control group (P<0.05), GLP-1R mRNA expression did not differ significantly across the groups (P>0.05). Furthermore, whereas INSR and GLP-1R protein levels in the experimental group were on a declining trend, this trend was not substantially different (P>0.05). Conclusion: These data suggest that fructose consumption may be harmful to the hippocampus by lowering the expression of INSR. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. Methods: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. Results: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. Conclusions: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically. [ABSTRACT FROM AUTHOR]

Background: Obesity treatment based on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) proved to limit morbidity and mortality in adult population. In children, optimizing lifestyle intervention (LSI) and reducing culpable environmental exposures represent the mainstay strategy for obesity prevention and management. However, there remains a subset of children and adolescents whose obesity is resistant to lifestyle approach. For these poor responders, the need for safe and effective weight-reducing agents is apparent. The purpose of this review is to provide an overview of the efficacy and safety of approved GLP-1 RA in the management of adult and pediatric obesity. Summary: We presented the main outcomes of clinical trial programs called SCALE and STEP that supported a market authorization approval for liraglutide and semaglutide for the treatment of obesity in adult population. Then, we summarized the studies on the efficacy of GLP-1 RA in pediatric obesity that have been accumulating from 2 larger studies with liraglutide and few other smaller studies with exenatide and liraglutide. The results indicate that GLP-1 RA is safe, tolerable, and effective in reducing weight and also in improving cardiometabolic profile in children with obesity and poor response to LSI alone. At present, liraglutide is the first and so far the only GLP-1 RA that received FDA approval in 2020 for use in children aged 12–17 years with obesity. New trials including semaglutide for pediatric obesity are ongoing. Key Messages: There is a strong interest in current use and further development of obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism. In adolescents with obesity, who are poor responders to lifestyle approach, the use of GLP-1 RA as an adjunct to LSI is effective and safe. Due to limited experience, a general recommendation is to prioritize long acting over short acting GLP-1 RA because they are approved for the treatment of obesity and have better tolerability, safety, and treatment response effect. In the future research, more high-grade evidence including novel iterations of GLP-1 agonism and long-term follow-ups are needed in pediatric population. [ABSTRACT FROM AUTHOR]

In recent years, we have witnessed the many beneficial effects of glucagon‐like peptide (GLP)‐1 receptor agonists, including the reduction in cardiovascular risk in patients with type 2 diabetes, and the reduction of body weight in those with obesity. Increasing evidence suggests that these agents differ considerably from endogenous GLP‐1 when it comes to their routes of action, although their clinical effects appear to be the same. Given the limitations of the GLP‐1 receptor agonists, could it be useful to develop agents which stimulate GLP‐1 release? Here we will discuss the differences and similarities between GLP‐1 receptor agonists and endogenous GLP‐1, and will detail how endogenous GLP‐1—when stimulated appropriately—could have clinically relevant effects. [ABSTRACT FROM AUTHOR]

Metabolic diseases, such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, and liver disease, have become increasingly prevalent around the world. As an alternative to bariatric surgery, glucagon-like peptide 1 (GLP-1) receptor agonists have been at the forefront of weight loss medication to combat these metabolic complications. Recently, there has been an exciting rapid emergence of new weight loss medications that combine GLP-1 receptor (GLP-1R) agonists with other gut- and pancreatic-derived hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) receptor agonists. Dual-agonist (GLP-1/GIP and GLP-1/GCG) and tri-agonist (GLP-1/GIP/GCG) administration generally result in greater weight loss, reduction of blood sugar and lipid levels, restoration of tissue function, and improvement in whole-body substrate metabolism compared to when GLP-1R agonists are used alone. The aim of this review is to summarize the recent literature of both preclinical and clinical studies on how these emerging gut-peptide therapies further improve weight loss and metabolic health outcomes for various metabolic diseases. [ABSTRACT FROM AUTHOR]

Neurolysin oligopeptidase (E.C.3.4.24.16; Nln), a member of the zinc metallopeptidase M3 family, was first identified in rat brain synaptic membranes hydrolyzing neurotensin at the Pro-Tyr peptide bond. The previous development of C57BL6/N mice with suppression of Nln gene expression (Nln-/-), demonstrated the biological relevance of this oligopeptidase for insulin signaling and glucose uptake. Here, several metabolic parameters were investigated in Nln-/- and wild-type C57BL6/N animals (WT; n = 5–8), male and female, fed either a standard (SD) or a hypercaloric diet (HD), for seven weeks. Higher food intake and body mass gain was observed for Nln-/- animals fed HD, compared to both male and female WT control animals fed HD. Leptin gene expression was higher in Nln-/- male and female animals fed HD, compared to WT controls. Both WT and Nln-/- females fed HD showed similar gene expression increase of dipeptidyl peptidase 4 (DPP4), a peptidase related to glucagon-like peptide-1 (GLP-1) metabolism. The present data suggest that Nln participates in the physiological mechanisms related to diet-induced obesity. Further studies will be necessary to better understand the molecular mechanism responsible for the higher body mass gain observed in Nln-/- animals fed HD. [ABSTRACT FROM AUTHOR]

The rising incidence of health‐endangering obesity constantly calls for more effective treatments. Gastric intramural injection of botulinum neurotoxin A (BTX‐A) as a new modality carries great promise yet inconsistent therapeutic efficacy. A layer‐specific delivery strategy enabled by dissolving microneedles is hence pioneered to investigate the working site of BTX‐A and the resulting therapeutic effects. The drug‐loaded tips of the layer‐specific gastric paralysis microneedles (LGP‐MN) rapidly release and achieve uniform distribution of BTX‐A within the designated gastric wall layers. In an obesity rat model, the LGP‐MNs not only prove safer than conventional injection, but also demonstrate consistently better therapeutic effects with muscular layer delivery, including 16.23% weight loss (3.06‐fold enhancement from conventional injection), 55.20% slower gastric emptying rate, improved liver steatosis, lowered blood lipids, and healthier gut microbiota. Further hormonal study reveals that the elevated production of stomach‐derived glucagon‐like peptide‐1 due to the muscularis‐targeting LGP‐MN treatment is an important contributor to its unique glucose tolerance‐improving effect. This study provides clear indication of the gastric muscularis as the most favorable working site of BTX‐A for weight loss and metabolic improvement purposes, and meanwhile suggests that the LGP‐MNs could serve as a novel clinical approach to treat obesity and metabolic syndromes. [ABSTRACT FROM AUTHOR]

Introduction: The CAPTURE study estimated the global prevalence of established cardiovascular disease (CVD) and characterized the usage of glucose-lowering agents (GLAs) in adults with type 2 diabetes (T2D) across 13 countries. The purpose of this secondary analysis of data from the Japanese sites within CAPTURE (NCT03786406, NCT03811288) was to provide data about medication usage stratified by CVD status among Japanese participants with T2D. Materials and methods: Data on GLA usage (including those with proven cardiovascular [CV] benefits) in Japanese participants with T2D managed in clinics or hospitals were collected and stratified by CVD subgroups. Results: There were 800 Japanese participants in the CAPTURE study (n = 502 [no CVD group], n = 298 [CVD group], n = 268 [atherosclerotic CVD subgroup]). Oral antidiabetic agents and insulin were used by 88.5% and 23.4%, respectively, of participants overall. Among participants with established CVD, dipeptidyl peptidase-4 inhibitors (65.1%) were most frequently used, followed by biguanides (50.7%) and insulins (26.2%). The pattern was similar among participants with atherosclerotic CVD. A lower proportion of participants in the CVD group used glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) with proven CV benefits versus the no CVD group (GLP-1 RAs: 7.0% vs. 8.6%; SGLT-2is: 13.4% vs. 19.1%). Conclusion: This analysis of the CAPTURE study provided a comprehensive overview of prescription patterns for the treatment of T2D in Japan. Use of GLAs with proven CV benefit was low, even in participants with established CVD, which was comparable to the findings from the global cohort. [ABSTRACT FROM AUTHOR]

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases. [ABSTRACT FROM AUTHOR]

Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 (GLP‐1) can improve cardiac function and cardiovascular outcomes in diabetic cardiomyopathy; however, the beneficial effect of GLP‐1 on human diabetic cardiomyocytes (DCMs) and its mechanism have not been fully elucidated. Here, the DCMs model by human‐induced pluripotent stem cells‐derived cardiomyocytes is developed. Two subtypes of GLP‐1, GLP‐17–36 and GLP‐19‐36, are evaluated for their efficacy on the DCMs model. Diabetogenic condition is sufficient to induce most characteristics of diabetic cardiomyopathy in vitro, such as cardiac hypertrophy, lipid accumulation, impaired calcium transients, and abnormal electrophysiological properties. GLP‐17−36 and GLP‐19–36 can restore cardiomyocyte hypertrophic phenotype, impaired calcium transient frequency, abnormal action potential amplitude, depolarization, and repolarization velocity. Interestingly, RNA‐seq reveals different pathways altered by GLP‐17–36 and GLP‐19–36, respectively. Differentially expressed gene analysis reveals that possible targets of GLP‐17–36 involve the regulation of mitotic nuclear division and extracellular matrix–receptor interaction, while possible targets of GLP‐19–36 involve kinetochore assembly, and the complement and coagulation cascades. This study demonstrates the therapeutic effects of GLP‐1 on human DCMs and provides a novel platform to unveil the cellular mechanisms of diabetic cardiomyopathy, shedding light on discovering better targets for novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Abstract The maintenance of glucose homeostasis is obligatory for health and survival. It relies on peripheral glucose sensing and signalling between the brain and peripheral organs via hormonal and neural responses that restore euglycaemia. Failure of these mechanisms causes hyperglycaemia or diabetes. Current anti‐diabetic medications control blood glucose but many patients remain with hyperglycemic condition. Diabetes is often associated with hypertension; the latter is more difficult to control in hyperglycaemic conditions. We ask whether a better understanding of the regulatory mechanisms of glucose control could improve treatment of both diabetes and hypertension when they co‐exist. With the involvement of the carotid body (CB) in glucose sensing, metabolic regulation and control of sympathetic nerve activity, we consider the CB as a potential treatment target for both diabetes and hypertension. We provide an update on the role of the CB in glucose sensing and glucose homeostasis. Physiologically, hypoglycaemia stimulates the release of hormones such as glucagon and adrenaline, which mobilize or synthesize glucose; however, these counter‐regulatory responses were markedly attenuated after denervation of the CBs in animals. Also, CB denervation prevents and reverses insulin resistance and glucose intolerance. We discuss the CB as a metabolic regulator (not just a sensor of blood gases) and consider recent evidence of novel ‘metabolic’ receptors within the CB and putative signalling peptides that may control glucose homeostasis via modulation of the sympathetic nervous system. The evidence presented may inform future clinical strategies in the treatment of patients with both diabetes and hypertension, which may include the CB.

Abstract Background Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D. Methods Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo. Results Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was − 2.6 mmHg (95% CI − 3.8, − 1.5; p

Abstract Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that has been utilized for the treatment of type 2 diabetes mellitus. Liraglutide at a higher dose also shows beneficial effects in weight loss, which prompted its widespread use as an anti-obesity drug. The potential of liraglutide to treat Alzheimer’s disease and cognitive impairment has also been suggested. Nevertheless, the pharmacokinetics of liraglutide, including its distribution to the brain, has not been fully characterized. Therefore, this study aimed to develop a simple and sensitive bioanalytical method using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and determine the pharmacokinetics and brain distribution of liraglutide in rats. Liraglutide in the rat plasma and brain tissue homogenates was extracted by protein precipitation using methanol. A gradient elution profile was used for chromatographic separation with mobile phases comprising 0.3% formic acid in water and 0.3% formic acid in acetonitrile. The mass spectrometry was operated in the positive electrospray ionization with multiple reaction monitoring mode. The lower limit of quantification of the present LC–MS/MS was 1 ng/mL in the plasma and 2 ng/mL in the brain tissue. Following intravenous injection (0.05 mg/kg, n = 5), plasma concentrations of liraglutide decreased monoexponentially with an average half-life of 3.67 h. The estimated absolute bioavailability of liraglutide after subcutaneous injection was 13.16%. Brain distribution of liraglutide was not significant, with the tissue-to-plasma partition coefficient (K p) of liraglutide less than 0.00031. However, the concentrations of liraglutide were significantly different in the different brain regions following IV injection. In the brain, liraglutide concentrations were the highest in the hypothalamus, followed by the cerebellum and cerebrum. The present LC–MS/MS assay and the pharmacokinetic results may be helpful to understand better the effect of liraglutide in the brain for further preclinical and clinical studies of liraglutide.

Abstract Aims/Introduction Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are important incretin hormones. They are released from the gut after meal ingestion and potentiate glucose‐stimulated insulin secretion. Their release after meal ingestion and oral glucose are well established and have been characterized previously. During recent years, knowledge of other regulatory aspects that potentially may affect GIP and GLP‐1 secretion after meal ingestion have also begun to emerge. Here, the results of human studies on these novel aspects of meal‐ and nutrient‐stimulated incretin hormone secretion are reviewed. Materials and Methods The human literature was revisited by identifying articles in PubMed using key words GIP, GLP‐1, secretion, meal, and nutrients. Results The results show that all macronutrients individually stimulate GIP and GLP‐1 secretion. However, there was no synergistic action when given in combination. A pre‐load 30 min before a meal augments the GIP and GLP‐1 response. GIP and GLP‐1 secretion have a diurnal variation with a higher response to an identical meal in the morning than in the afternoon. There is no difference in GIP and GLP‐1 secretion whether a meal is ingested slowly or rapidly. GIP and GLP‐1 secretion after dinner are the same whether or not breakfast and lunch have been ingested. The temperature of the food may be of importance for the incretin hormone response. Conclusions These novel findings have increased our knowledge on the regulation of the complexity of the incretin system and are also important knowledge when designing future studies.

Liraglutide (LIRA) is a glucagon-like peptide-1 (GLP-1) receptor agonist renowned for its efficacy in treating type 2 diabetes mellitus (T2DM) and is typically administered via subcutaneous injections. Oral delivery, although more desirable for being painless and potentially enhancing patient adherence, is challenged by the peptide’s low bioavailability and vulnerability to digestive enzymes. This study aimed to develop LIRA-containing zein-based nanoparticles stabilized with eudragit RS100 and chitosan for oral use (Z-ERS-CS/LIRA). These nanoparticles demonstrated a spherical shape, with a mean diameter of 238.6 nm, a polydispersity index of 0.099, a zeta potential of +40.9 mV, and an encapsulation efficiency of 41%. In vitro release studies indicated a prolonged release, with up to 61% of LIRA released over 24 h. Notably, the nanoparticles showed considerable resistance and stability in simulated gastric and intestinal fluids, suggesting protection from pH and enzymatic degradation. Pharmacokinetic analysis revealed that orally administered Z-ERS-CS/LIRA paralleled the pharmacokinetic profile seen with subcutaneously delivered LIRA. Furthermore, in vivo tests on a diabetic rat model showed that Z-ERS-CS/LIRA significantly controlled glucose levels, comparable to the results observed with free LIRA. The findings underscore Z-ERS-CS/LIRA nanoparticles as a promising approach for oral LIRA delivery in T2DM management.

The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide. We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors. We also assessed liraglutide-mediated phosphorylation of the PKA substrate RRXS*/T* motif in CHO-Glp1r cells expressing Myc-tagged wild-type (WT) Raptor or a PKA-resistant (Ser791Ala) Raptor mutant. Finally, we measured the body weight response to liraglutide in WT mice and mice with a targeted knock-in of PKA-resistant Ser791Ala Raptor. Liraglutide increased phosphorylation of S6 and the PKA motif in WT Raptor in a PKA-dependent manner but failed to stimulate phosphorylation of the PKA motif in Ser791Ala Raptor in CHO-Glp1r cells. Lean Ser791Ala Raptor knock-in mice were resistant to liraglutide-induced weight loss but not setmelanotide-induced (melanocortin-4 receptor-dependent) weight loss. Diet-induced obese Ser791Ala Raptor knock-in mice were not resistant to liraglutide-induced weight loss; however, there was weight-dependent variation such that there was a tendency for obese Ser791Ala Raptor knock-in mice of lower relative body weight to be resistant to liraglutide-induced weight loss compared to weight-matched controls. Together, these findings suggest that PKA-mediated phosphorylation of Raptor at Ser791 contributes to liraglutide-induced weight loss.

Abstract The rising incidence of health‐endangering obesity constantly calls for more effective treatments. Gastric intramural injection of botulinum neurotoxin A (BTX‐A) as a new modality carries great promise yet inconsistent therapeutic efficacy. A layer‐specific delivery strategy enabled by dissolving microneedles is hence pioneered to investigate the working site of BTX‐A and the resulting therapeutic effects. The drug‐loaded tips of the layer‐specific gastric paralysis microneedles (LGP‐MN) rapidly release and achieve uniform distribution of BTX‐A within the designated gastric wall layers. In an obesity rat model, the LGP‐MNs not only prove safer than conventional injection, but also demonstrate consistently better therapeutic effects with muscular layer delivery, including 16.23% weight loss (3.06‐fold enhancement from conventional injection), 55.20% slower gastric emptying rate, improved liver steatosis, lowered blood lipids, and healthier gut microbiota. Further hormonal study reveals that the elevated production of stomach‐derived glucagon‐like peptide‐1 due to the muscularis‐targeting LGP‐MN treatment is an important contributor to its unique glucose tolerance‐improving effect. This study provides clear indication of the gastric muscularis as the most favorable working site of BTX‐A for weight loss and metabolic improvement purposes, and meanwhile suggests that the LGP‐MNs could serve as a novel clinical approach to treat obesity and metabolic syndromes.

Objective: Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog. Methods: We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775). Results: In vitro, ecnoglutide potently induced cAMP (EC50 = 0.018 nM) but not GLP-1 receptor internalization (EC50 > 10 μM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing. Conclusions: Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.

The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide- 1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health. [ABSTRACT FROM AUTHOR]

Background: Enterochromaffin (EC) cell‐derived 5‐hydroxytryptamine (5‐HT) is a mediator of toxin‐induced reflexes, initiating emesis via vagal and central 5‐HT3 receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5‐HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5‐HT signaling, local 5‐HT levels and pharmacology in discrete regions of the mouse small and large intestine. We also investigated the inter‐relationships between incretin hormones, glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory polypeptide (GIP) and endogenous 5‐HT in mucosal and motility assays. Methods: Adult mouse GI mucosae were mounted in Ussing chambers and area‐specific studies were performed to establish the 5‐HT3 and 5‐HT4 pharmacology, the sidedness of responses, and the inter‐relationships between incretins and endogenous 5‐HT. Natural fecal pellet transit in vitro and full‐length GI transit in vivo were also measured. Key Results: We observed the greatest level of tonic and exogenous 5‐HT‐induced ion transport and highest levels of 5‐HT in ascending colon mucosa. Here both 5‐HT3 and 5‐HT4 receptors were involved but elsewhere in the GI tract epithelial basolateral 5‐HT4 receptors mediate 5‐HT's prosecretory effect. Exendin‐4 and GIP induced 5‐HT release in the ascending colon, while L cell‐derived PYY also contributed to GIP mucosal effects in the descending colon. Both peptides slowed colonic transit. Conclusions & Inferences: We provide functional evidence for paracrine interplay between 5‐HT, GLP‐1 and GIP, particularly in the colonic mucosal region. Basolateral epithelial 5‐HT4 receptors mediated both 5‐HT and incretin mucosal responses in healthy colon. [ABSTRACT FROM AUTHOR]

In Covid-19, variations in fasting blood glucose are considered a distinct risk element for a bad prognosis and outcome in Covid-19 patients. Tirazepatide (TZT), a dual glucagon-like peptide-1 (GLP-1)and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist may be effective in managing Covid-19-induced hyperglycemia in diabetic and non-diabetic patients. The beneficial effect of TZT in T2DM and obesity is related to direct activation of GIP and GLP-1 receptors with subsequent improvement of insulin sensitivity and reduction of body weight. TZT improves endothelial dysfunction (ED) and associated inflammatory changes through modulation of glucose homeostasis, insulin sensitivity, and pro-inflammatory biomarkers release. TZT, through activation of the GLP-1 receptor, may produce beneficial effects against Covid-19 severity since GLP-1 receptor agonists (GLP-1RAs) have anti-inflammatory and pulmoprotective implications in Covid-19. Therefore, GLP-1RAs could effectively treat severely affected Covid-19 diabetic and non-diabetic patients. Notably, using GLP-1RAs in T2DM patients prevents glucose variability, a common finding in Covid-19 patients. Therefore, GLP-1RAs like TZT could be a therapeutic strategy in T2DM patients with Covid-19 to prevent glucose variability-induced complications. In Covid-19, the inflammatory signaling pathways are highly activated, resulting in hyperinflammation. GLP-1RAs reduce inflammatory biomarkers like IL-6, CRP, and ferritin in Covid-19 patients. Therefore, GLP-1RAs like TZ may be effective in Covid-19 patients by reducing the inflammatory burden. The anti-obesogenic effect of TZT may reduce Covid-19 severity by ameliorating body weight and adiposity. Furthermore, Covid-19 may induce substantial alterations in gut microbiota. GLP-1RA preserves gut microbiota and prevents intestinal dysbiosis. Herein, TZT, like other GLP-1RA, may attenuate Covid-19-induced gut microbiota alterations and, by this mechanism, may mitigate intestinal inflammation and systemic complications in Covid-19 patients with either T2DM or obesity. As opposed to that, glucose-dependent insulinotropic polypeptide (GIP) was reduced in obese and T2DM patients. However, activation of GIP-1R by TZT in T2DM patients improves glucose homeostasis. Thus, TZT, through activation of both GIP and GLP-1, may reduce obesity-mediated inflammation. In Covid-19, GIP response to the meal is impaired, leading to postprandial hyperglycemia and abnormal glucose homeostasis. Therefore, using TZT in severely affected Covid-19 patients may prevent the development of glucose variability and hyperglycemia-induced oxidative stress. Moreover, exaggerated inflammatory disorders in Covid-19 due to the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α may lead to systemic inflammation and cytokine storm development. Besides, GIP-1 inhibits expression of IL-1β, IL-6, MCP-1, chemokines and TNF-α. Therefore, using GIP-1RA like TZT may inhibit the onset of inflammatory disorders in severely affected Covid-19 patients. In conclusion, TZT, through activation of GLP-1 and GIP receptors, may prevent SARS-CoV-2-induced hyperinflammation and glucose variability in diabetic and non-diabetic patients. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) and chronic pancreatitis (CP) often represent parts of the spectrum of disease. While growing evidence indicates that intra-pancreatic fat deposition (IPFD) plays an important role in the pathogenesis of pancreatitis, no study of living individuals has investigated IPFD in both AP and CP. Further, the associations between IPFD and gut hormones remain to be elucidated. The aims were to investigate the associations of IPFD with AP, CP, and health; and to study whether gut hormones affect these associations. Magnetic resonance imaging on the same 3.0 Tesla scanner was used to determine IPFD in 201 study participants. These participants were arranged into the health, AP, and CP groups. Gut hormones (ghrelin, glucagon-like peptide-1, gastric inhibitory peptide, peptide YY, and oxyntomodulin) were measured in blood, both after an 8-hour overnight fasting and after ingestion of a standardised mixed meal. A series of linear regression analyses was run, accounting for age, sex, ethnicity, body mass index, glycated haemoglobin, and triglycerides. Both the AP group and CP group had significantly higher IPFD in comparison with the health group, consistently across all models (p for trend 0.027 in the most adjusted model). Ghrelin in the fasted state had a significant positive association with IPFD in the AP group (but not the CP or health group), consistently across all models (p = 0.019 in the most adjusted model). None of the studied gut hormones in the postprandial state was significantly associated with IPFD. Fat deposition in the pancreas is similarly high in individuals with AP and those with CP. The gut-brain axis, and more specifically overexpression of ghrelin, may contribute to increased IPFD in individuals with AP. [ABSTRACT FROM AUTHOR]

The HERG ion channel belongs to the voltage-gated potassium (Kv) channel family and is involved in potassium efflux during cellular repolarization. Mutations in HERG have been linked to long QT syndrome, which is associated with elevated secretion of glucagon-like peptide-1 (GLP-1). However, the precise contribution of HERG to GLP-1 secretion remains unclear. In this study, we demonstrate the expression of HERG in GLP-1-producing L-cells within the intestinal epithelium of rodents. Using a mouse L-cell model (GLUTag cell line), we observed that downregulation of HERG led to a significant prolongation of action potential duration, an increase in intracellular calcium concentration, and a stimulation of GLP-1 secretion following exposure to nutrients. These findings provide evidence that HERG plays a direct role in regulating GLP-1 secretion in the intestine and may hold promise as a potential target for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Background: In idiopathic intracranial hypertension (IIH), sustained weight loss is the main pillar in modifying disease course, whereby glucagon-like peptide-1 receptor agonists (GLP-1-RAs) could present an attractive treatment option. Methods: In this open-label, single-center, case–control pilot study, patients with IIH (pwIIH) and a body mass index (BMI) of ≥ 30 kg/m2 were offered to receive a GLP-1-RA (semaglutide, liraglutide) in addition to the usual care weight management (UCWM). Patients electing for UCWM only served as a control group matched for age-, sex- and BMI (1:2 ratio). The primary endpoint was the percentage weight loss at six months (M6) compared to baseline. Secondary endpoints included the rate of patients with a weight loss of ≥ 10%, monthly headache days (MHD), the rate of patients with a ≥ 30% and ≥ 50% reduction in MHD, visual outcome parameters, and adverse events (AEs). Results: We included 39 pwIIH (mean age 33.6 years [SD 8.0], 92.3% female, median BMI 36.3 kg/m2 [IQR 31.4–38.3]), with 13 patients being treated with GLP-1-RAs. At M6, mean weight loss was significantly higher in the GLP-1-RA group (–12.0% [3.3] vs. –2.8% [4.7]; p < 0.001). Accordingly, weight loss of ≥ 10% was more common in this group (69.2% vs. 4.0%; p < 0.001). Median reduction in MHD was significantly higher in the GLP-1-RA group (–4 [–10.5, 0.5] vs. 0 [–3, 1]; p = 0.02), and the 50% responder rate was 76.9% vs. 40.0% (p = 0.04). Visual outcome parameters did not change significantly from baseline to M6. Median reduction in acetazolamide dosage was significantly higher in the GLP-1-RA group (–16.5% [–50, 0] vs. 0% [–25, 50]; p = 0.04). AEs were mild or moderate and attributed to gastrointestinal symptoms in 9/13 patients. None of the AEs led to premature treatment discontinuation. Conclusions: This open-label, single-center pilot study suggests that GLP-1-RAs are an effective and safe treatment option for achieving significant weight loss with a favorable effect on headache, leading to reduced acetazolamide dosage in pwIIH. [ABSTRACT FROM AUTHOR]

Objective: Bariatric surgery is currently the most effective treatment for obesity, and procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy (SG) also result in rapid improvements in insulin sensitivity and glucose tolerance. In addition, these procedures cause changes in the secretion of various gut-derived hormones. The role these hormones play in the mechanism of the beneficial effects of bariatric surgery is still debated, but nonetheless, their importance provides inspiration for novel obesity-targeted pharmacotherapies. Methods: Male Sprague-Dawley rats were fed either regular chow or a cafeteria diet to induce obesity. A sub-group of the obese animals then underwent either sham surgery or SG. Results: Following a 4-week recovery period, SG rats weighed significantly less than obese or sham-operated rats. Improvements in glucose tolerance and insulin sensitivity also occurred in the SG group, but these were not always statistically significant. We measured the intracellular lipid content of liver samples and found that obese rats showed signs of non-alcoholic fatty liver disease, which were significantly ameliorated by SG. There were significantly higher glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide responses to a standard mixed meal in the SG group, as well as paradoxically higher glucagon secretion. Conclusion: These data highlight the need for more specific anti-glucagon antibodies to characterize the changes in proglucagon-derived peptide concentrations that occur following SG. Further studies are required to determine whether these peptides contribute to the therapeutic effects of SG. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of gastric distension, induced using a gastric 'barostat', on the secretion of glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) in the presence and absence of small intestinal nutrients in healthy individuals. Materials and Methods: Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m2) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure. Results: Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP‐1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P =.99 for glucose infusion). Conclusions: Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans. [ABSTRACT FROM AUTHOR]

According to current statistics, the incidence of type 2 diabetes has increased significantly over the past few years. The number of drugs prescribed to correct carbohydrate metabolism is also increasing, and new groups of hypoglycemic drugs are appearing. This prompts a more detailed study and analysis of the possible side effects of the prescribed therapy. One of the modern groups of medications f or treating type 2 diabetes are analogues of glucagon-like peptide-1 receptor agonists, which, in addition to correcting carbohydrate metabolism, have a beneficial effect on the risk of developing cardiovascular events. Despite this, there is evidence that their use may be associated with the development of undesirable adverse effects from the pancreas, particularly acute pancreatitis, pancreatopathy, or asymptomatic hyperenzymemia. The aim of our work was the analysis of a clinical case of an asymptomatic increase in the level of pancreatic enzymes (Gullo's syndrome) in a patient with type 2 diabetes, who used a glucagon-like peptide-1 receptor analogue for treatment according to the usual scheme (dulaglutide 0.75 mg subcutaneously once a week during 2 years). As a result, the patient developed a side effect that could be related to taking this medicine. This did not lead to the withdrawal of the drug but required a more thorough examination of the patient and regular further screening for the timely detection of the development of possible organic pathology of the pancreas in the future. So, after analyzing this clinical case, it is possible to see the possibility of developing asymptomatic pancreatic hyperenzymopathy during the treatment of type 2 diabetes mellitus with glucagonlike peptide-1 receptor agonist analogues, which should be taken into account when determining the treatment tactics. [ABSTRACT FROM AUTHOR]

COVID-19 is a global pandemic with devastating economic and public health impacts, which is particularly associated with increased incidence of respiratory and cardiovascular disease together with inflammation and oxidative stress as essential underlying features. Glucagon-Like Peptide-1 (GLP-1) receptor agonists are now routinely used for the clinical management of type 2 diabetes due to their established glucose-dependent insulinotropic actions. However, these agents also display a variety of pleiotropic functions, including the promotion of anti-inflammatory and antioxidant responses, highlighting likely therapeutic applications beyond glycemic control. Given that COVID-19 is particularly linked with adverse modulation of inflammatory and oxidative signaling, which are known to be impacted by GLP1 receptor activation, it seems logical that GLP-1 receptor agonists may be beneficial for the clinical management of patients with SARS-CoV-2 infection. In this review, we discuss the specific role of inflammation and oxidative stress associated with COVID-19, including underlying pathogenic mechanisms, as the basis for the potential therapeutic application of GLP-1 receptor agonists to combat both acute and chronic complications of this devastating disease. [ABSTRACT FROM AUTHOR]

Objective: The objective of this article was to review pharmacology, efficacy, safety, and place in therapy of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Data Sources: PubMed/MEDLINE and ClinicalTrials.gov were searched through September 7, 2022, using the keyword "tirzepatide." Study Selection and Data Extraction: Clinical trials with available results were included. Data Synthesis: Seven published phase 3, multicenter, randomized, parallel-group trials investigated efficacy and safety of tirzepatide versus placebo, semaglutide, insulin degludec, and insulin glargine for type 2 diabetes mellitus (T2DM) treatment. Studies included adults with uncontrolled T2DM and body mass index above 23 or 25 kg/m2. Hemoglobin A1c reduction from baseline was greater with tirzepatide across all studies with absolute reductions up to 3.02% and relative reductions ranging 0.44% (vs semaglutide) to 2.11% (vs placebo). Weight loss was significant. Incidence of gastrointestinal adverse effects (AE) was similar to semaglutide, and major cardiovascular events was similar to insulin glargine. Relevance to Patient Care and Clinical Practice: Studies demonstrated greater A1c lowering and weight reduction versus placebo and active comparators with AE similar to semaglutide, suggesting tirzepatide will be a valuable addition to the growing list of antidiabetic medications. Although tirzepatide's effects on major cardiovascular events was not increased when compared with insulin glargine, further evidence is needed to assess long-term implications on cardiovascular outcomes compared with agents with proven cardiovascular benefits. Conclusions: Tirzepatide has the potential to significantly impact the clinical management of T2DM, and results of ongoing clinical trials will help to fully determine its place in therapy. [ABSTRACT FROM AUTHOR]

Dietary peptides potently stimulate glucagon-like peptide-1 (GLP-1) secretion, however, the underlying molecular mechanisms, such as structure-activity relationships and sensing mechanisms are only partly elucidated. In this study, we used a dipeptide library to identify dipeptides that potently stimulate GLP-1 release and to clarify the underlying structure-activity relationship. Murine enteroendocrine GLUTag cells were exposed to 339 dipeptides for 60 min, and the concentration of GLP-1 released into the supernatant was measured. Subsequently, selected dipeptides were examined for their reproducibility and dose responsiveness. In addition, we investigated the role of constituent amino acids in the secretion of GLP-1, and whether tripeptides containing the active dipeptide structures maintained their activity. In a concentration range of 1–5 mg/mL, twelve dipeptides had reproducible and concentration-dependent GLP-1-releasing activity. Among them, nine dipeptides (FY, KF, NI, PM, QL, QY, WF, WN, WY) were novel, with WY exhibiting the most potent activity. The reverse sequences and most free amino acids did not induce GLP-1 secretion, indicating that GLP-1-producing cells recognize the structure of each peptide to induce GLP-1 secretion. However, no apparent similarities were found between the active peptides. A comparison between the six tripeptides composed of F, W, and Y revealed the further potent tripeptides FWY and WYF, than WY. In the present study, a comprehensive analysis revealed nine novel dipeptides with high potential to stimulate GLP-1 secretion. Furthermore, the results indicate that 'WY' is a specific dipeptide sequence that potently stimulates GLP-1 secretion. • Structure-activity relationship in peptide-induced GLP-1 secretion is unknown. • Dipeptide library was used to identify potent GLP-1-releasing dipeptides. • Nine of 339 dipeptides had potent GLP-1 releasing activity, with Trp-Tyr (WY) most. • Addition of Phe to N- or C- terminus of WY further enhanced the potency of WY. • WY is a specific dipeptide sequence that potently stimulates GLP-1 secretion. [ABSTRACT FROM AUTHOR]

Rationale: Nicotine cessation is associated with increased consumption of highly palatable foods and body weight gain in most smokers. Concerns about body weight gain are a major barrier to maintaining long-term smoking abstinence, and current treatments for nicotine use disorder (NUD) delay, but do not prevent, body weight gain during abstinence. Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects of GLP-1R agonist monotherapy on nicotine seeking and withdrawal-induced hyperphagia are unknown. Objectives: We screened the efficacy of the long-lasting GLP-1R agonist liraglutide to reduce nicotine-mediated behaviors including voluntary nicotine taking, as well as nicotine seeking and hyperphagia during withdrawal. Methods: Male and female rats self-administered intravenous nicotine (0.03 mg/kg/inf) for ~21 days. Daily liraglutide administration (25 μg/kg, i.p.) started on the last self-administration day and continued throughout the extinction and reinstatement phases of the experiment. Once nicotine taking was extinguished, the reinstatement of nicotine-seeking behavior was assessed after an acute priming injection of nicotine (0.2 mg/kg, s.c.) and re-exposure to conditioned light cues. Using a novel model of nicotine withdrawal-induced hyperphagia, intake of a high fat diet (HFD) was measured during home cage abstinence in male and female rats with a history of nicotine self-administration. Results: Liraglutide attenuated nicotine self-administration and reinstatement in male and female rats. Repeated liraglutide attenuated withdrawal-induced hyperphagia and body weight gain in male and female rats at a dose that was not associated with malaise-like effects. Conclusions: These findings support further studies investigating the translational potential of GLP-1R agonists to treat NUD. [ABSTRACT FROM AUTHOR]

A polysaccharide LDOP‐A with a molecular weight of 9.9 kDa was isolated and purified from Dendrobium officinale leaves by membrane separation, cellulose column, and dextran gel column. The Smith degradable products, methylation products, and nuclear magnetic resonance analysis showed that LDOP‐A may be composed of →4)‐Glc‐(1→, →3,6)‐Man‐(1→, and →6)‐Glc‐(1→sugar residues. In vitro, simulated digestion assays showed that LDOP‐A could be partially digested in the stomach and small intestine, and produced a large amount of acetic acid and butyric acid during colonic fermentation. Further cell experiment results illustrated that LDOP‐A‐I (LDOP‐A digested by gastrointestinal tract) could induce glucagon‐like peptide‐1 (GLP‐1) secretion in NCI‐H716 cells without showing any cytotoxicity. [ABSTRACT FROM AUTHOR]

Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 hours were measured using a thermocouple thermometer before and after an oral administration of nutrients. Oxygen consumption after oral protein administration was also measured in rats. Rectal temperature measurements in rats confirmed an increase in core body temperature after refeeding, and the thermic effect of the oral administration of protein was greater than that of a representative carbohydrate or lipid. Among the five dietary proteins examined (casein, whey, rice, egg, and soy), soy protein had the highest thermic effect. The thermic effect of soy protein was also demonstrated by increased oxygen consumption. Studies using a nonselective β-adrenergic receptor antagonist and thermal camera suggested that brown adipose tissue did not contribute to soy protein–induced increase in rectal temperature. Furthermore, the thermic effect of soy protein was completely abolished by antagonism and knockout of the GLP-1 receptor, yet potentiated via augmentation of intact GLP-1 levels through inhibition of dipeptidyl peptidase-4 activity. These results indicate that GLP-1 signaling is essential for the thermic effects of dietary proteins in rats and mice, and extend the metabolic actions of GLP-1 ensuing from nutrient ingestion to encompass the thermic response to ingested protein. [ABSTRACT FROM AUTHOR]

Xing Chen,1 Shuchun Chen,2,3 Qingjuan Ren,3 Shu Niu,3 Xiaoyu Pan,3 Lin Yue,3 Zelin Li,3 Ruiyi Zhu,3 Zhuoya Jia,3 Xiaoyi Chen,3 Ruoxi Zhen,3 Jiangli Ban3 1Department of Nephrology, Hebei General Hospital, Shijiazhuang, 050051, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, 050051, People’s Republic of China; 3Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel/Fax +86 311 85988406, Email chenshuchunwork88@163.comPurpose: Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury.Methods: Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples.Results: Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P< 0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD+) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury.Conclusion: Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD+ and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.Keywords: semaglutide, glucagon-like peptide-1, metabolomics, obesity, kidney

Abstract Background Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy balance. In the brain, Glucagon-like peptide 1 (GLP-1), encoded by the proglucagon ‘Gcg’ gene, produced in a distinct population of neurons in the nucleus tractus solitarius (NTS), has been shown to regulate feeding behavior leading to the suppression of appetite. However, neuronal networks that mediate endogenous GLP-1 action in the CNS on feeding and energy balance are not well understood. Results We analyzed the distribution of GLP-1R-expressing neurons and axonal projections of NTS GLP-1-producing neurons in the mouse brain. GLP-1R neurons were found to be broadly distributed in the brain and specific forebrain regions, particularly the hypothalamus, including the arcuate nucleus of the hypothalamus (ARC), a brain region known to regulate energy homeostasis and feeding behavior, that receives dense NTSGcg neuronal projections. The impact of GLP-1 signaling in the ARC GLP-1R-expressing neurons and the impact of activation of ARC GLP-1R on food intake was examined. Application of GLP-1R specific agonist Exendin-4 (Exn-4) enhanced a proportion of the ARC GLP-1R-expressing neurons and pro-opiomelanocortin (POMC) neuronal action potential firing rates. Chemogenetic activation of the ARC GLP-1R neurons by using Cre-dependent hM3Dq AAV in the GLP-1R-ires-Cre mice, established that acute activation of the ARC GLP-1R neurons significantly suppressed food intake but did not have a strong impact on glucose homeostasis. Conclusions These results highlight the importance of central GLP-1 signaling in the ARC that express GLP-1R that upon activation, regulate feeding behavior.