Search

Background: Aortic valve repair is currently the only effective treatment for calcific aortic valve stenosis (CAVS), as no pharmacological therapies exist to prevent or slow its progression. Recent promising results showed that glucagon-like peptide-1 (GLP-1) attenuates the calcification of aortic valve interstitial cells. Therefore, we conducted a two-sample Mendelian randomization analysis to investigate the effect of GLP-1 receptor agonism (GLP-1Ra) on the risk of CAVS. Methods: The inverse variance weighted (IVW) method was used to obtain the primary causal inference, and several sensitivity analyses, including MR-Egger, were performed to assess the robustness of the results. Results: Based on the IVW estimates, the GLP-1Ra showed a neutral effect on the risk of CAVS (odds ratio [OR] per 1 mmol/mol decrease in glycated hemoglobin = 0.87, 95% CI = [0.69, 1.11], p = 0.259; I2 = 4.5%, Cohran's Q = 2.09, heterogeneity p = 0.35; F statistic = 16.8). A non-significant effect was also derived by the sensitivity analyses. No evidence of horizontal pleiotropy was identified. Conclusions: GLP-1Ra was not significantly associated with the risk of CAVS. Furthermore, pragmatically designed studies are required to evaluate the effect of GLP-1Ra on the clinical course of CAVS in different patient subgroups. [ABSTRACT FROM AUTHOR]

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]

Chronic kidney disease (CKD) is a major global health problem, affecting about 9.5% of the population and 850 million people worldwide. In primary care, most CKD is caused by diabetes and/or hypertension, but a substantial proportion of cases may have alternative causes. During the early stages, CKD is asymptomatic, and many people are unaware that they are living with the disease. Despite the lack of symptoms, CKD is associated with elevated risks of cardiovascular disease, progressive kidney disease, kidney failure and premature mortality. Risk reduction strategies are effective and cost‐effective but require early diagnosis through testing of the estimated glomerular filtration rate and albuminuria in high‐risk populations. Once diagnosed, the treatment of CKD centres around lifestyle interventions, blood pressure and glycaemic control, and preventative treatments for cardiovascular disease and kidney disease progression. Most patients with CKD should be managed with statins, renin‐angiotensin‐aldosterone system inhibitors and sodium‐glucose cotransporter‐2 inhibitors. Additional treatment options to reduce cardiorenal risk are available in patients with diabetes, including glucagon‐like peptide‐1 receptor agonists and non‐steroidal mineralocorticoid receptor antagonists. The Kidney Failure Risk Equation is a new tool that can support the identification of patients at high risk of progressive kidney disease and kidney failure and can be used to guide referrals to nephrology. This review summarizes the latest guidance relevant to managing adults with, or at risk of, CKD and provides practical advice for managing patients with CKD in primary care. [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]

Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis. This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞) and maximal plasma concentration (C max). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. In the single-dose cohorts (n = 41), mean AUC 0-∞ and C max were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH—including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted. NCT05296733. [Display omitted] • Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist under investigation for MASH. • This multinational phase I trial of survodutide included people with compensated or decompensated cirrhosis. • The pharmacokinetics of survodutide were not affected by cirrhosis. • Survodutide was generally tolerable and was associated with improvements in liver-related non-invasive tests. • These are the first safety and efficacy data for a dual agonist in people with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Background Results and Conclusion Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus and insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular and cerebrovascular diseases and chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such comorbidities, though such therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies and potential implications for managing fatty kidney and chronic kidney disease.Glucagon‐like peptide‐1 agonists and sodium‐glucose cotransporter‐2 inhibitors are two novel classes of glucose‐lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon‐like peptide‐1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well‐established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity. [ABSTRACT FROM AUTHOR]

Background: Alcohol and drug dependence are major health and economic burdens to society. One of the major challenges to reducing this burden will be to develop more effective and better tolerated medications that target alternative mechanisms in the brain. While the dopamine system has been well characterized for mediating the reward value of drugs, there is evidence that the endocrine system also conveys signals to the same neural systems using gut hormones. Summary: These gut hormones, produced in the stomach and intestine and that regulate food intake, have also been shown to control the use of other substances, such as alcohol and drugs of abuse. Examples of such hormones are ghrelin and glucagon-like peptide-1, which exert their effects on dopamine transmission in parts of the brain known to be involved in some of the core features of addiction, such as reward sensitivity. Key Messages: This raises the possibility that gut hormone systems may play a pivotal role in addictive disorders. This review will briefly outline emerging evidence that the ghrelin and glucagon-like peptide-1 hormones are contrasting mediators of alcohol and drug use and may present a promising alternative target for treatment intervention in addictive disorders. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy (DN), a complication of diabetes, is the most leading cause of end-stage renal disease. Bariatric surgery functions on the remission of diabetes and diabetes-related complications. One anastomosis gastric bypass (OAGB), one of popular bariatric surgery, can improve diabetes and its complications by regulating the glucagon-like peptide-1 (GLP-1) level. Meanwhile, GLP-1 can alleviate renal damage in high-fat-diet-induced obese rats. However, the effect of OAGB on renal injury remains uncertain in DN. Methods: A diabetes model was elicited in rats via HFD feeding and STZ injection. The role and mechanism of OAGB were addressed in DN rats by the body and kidney weight and blood glucose supervision, oral glucose tolerance test (OGTT), enzyme-linked immunosorbent assay (ELISA), biochemistry detection, histopathological analysis, and western blot assays. Results: OAGB surgery reversed the increase in body weight and glucose tolerance indicators in diabetes rats. Also, OAGB operation neutralized the DN-induced average kidney weight, kidney weight/body weight, and renal injury indexes accompanied with reduced glomerular hypertrophy, alleviated mesangial dilation and decreased tubular and periglomerular collagen deposition. In addition, OAGB introduction reduced the DN-induced renal triglyceride and renal cholesterol with the regulation of fatty acids-related proteins expression. Mechanically, OAGB administration rescued the DN-induced expression of Sirt1/AMPK/PGC1α pathway mediated by GLP-1. Pharmacological block of GLP-1 receptor inverted the effect of OAGB operation on body weight, glucose tolerance, renal tissue damage, and fibrosis and lipids accumulation in DN rats. Conclusion: OAGB improved renal damage and fibrosis and lipids accumulation in DN rats by GLP-1-mediated Sirt1/AMPK/PGC1α pathway. [ABSTRACT FROM AUTHOR]

Upon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon‐like peptide‐1 (GLP‐1) secretion from enteroendocrine L cells by activating Toll‐like receptor 4 (TLR4). Because GLP‐1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell‐derived GLP‐1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.9% saline, peristaltic wall motion was video recorded and converted into spatio‐temporal maps. Fluorescence immunohistochemistry was also carried out. Intraluminal administration of LPS (100 or 1 µg mL−1 but not 100 ng mL−1) increased the frequency of oro‐aboral propagating peristaltic contractions. The LPS‐induced acceleration of colonic peristalsis was blocked by TAK‐242 (the TLR4 antagonist), exendin‐3 (the GLP‐1 receptor antagonist) or BIBN4096 (the calcitonin gene‐related peptide receptor antagonist). GLP‐1‐positive epithelial cells co‐expressed TLR4 immunoreactivity. In aspirin‐pretreated preparations where epithelial barrier function had been impaired, a lower dose of LPS (100 ng mL−1) became capable of accelerating peristalsis. By contrast, luminally applied dimethyl sulphoxide, a reactive oxygen species scavenger that protects epithelial integrity, attenuated the prokinetic effects of a higher dose of LPS (100 µg mL−1). In colonic segments of a stress rat model leading to a leaky gut, LPS induced more pronounced prokinetic effects. Colonic L cells may well sense luminal LPS via TLR4 triggering the release of GLP‐1 that stimulates calcitonin gene‐related peptide‐containing neurons. The resultant acceleration of peristalsis would facilitate excretion of Gram‐negative bacteria from the intestine, and thus L cells may have a protective role against intestinal bacterial infections. Key points: Colonic epithelial cells form a barrier against bacterial invasion but also may contribute more actively to the exclusion of luminal pathogen by stimulating colonic motility.Luminal lipopolysaccharide (LPS) accelerated colonic peristalsis by stimulating calcitonin gene‐related peptide‐containing neurons.The prokinetic effect of LPS was mediated by the secretion of glucagon‐like peptide‐1 from enteroendocrine L cells in which Toll‐like receptor 4 was expressed.The LPS‐mediated acceleration of peristalsis depended on epithelial barrier integrity.L cells have a defensive role against Gram‐negative bacterial infections by facilitating faecal excretion, and could be a potential therapeutic target for gastrointestinal infections. [ABSTRACT FROM AUTHOR]

Objectives: Glucagon-like peptide-1 (GLP-1) has a cardiovascular protective effect by preventing abdominal aortic aneurysm (AAA) formation. However, it is unclear at what point the agent should be administered to achieve the optimal effect. In this study, we aimed to determine whether administering the GLP-1 receptor agonist liraglutide during the earlier stages would more efficiently inhibit AAA progression in mice. Methods: Depending on the group, mice were given a daily dose of 300 μg/kg liraglutide for 28 days at 7, 14, and 28 days after aneurysm induction. The morphology of the abdominal aorta was monitored using 7.0 T magnetic resonance imaging (MRI) during the administration of liraglutide. After 28 days of administration, the AAA dilatation ratio was calculated, and histopathological examination was performed. Oxidative stress levels were evaluated by the expression of malondialdehyde (MDA) and matrix metalloproteinases (MMPs). The inflammatory response was also evaluated. Results: Liraglutide treatment led to a decrease in AAA formation, including a reduction in abdominal aorta expansion, elastin degradation in the elastic laminae, and vascular inflammation caused by leukocyte infiltration. The expression of MDA and the activity of MMPs (MMP-2, MMP-9) also decreased. Notably, administering liraglutide during the early stages resulted in a significant reduction in the dilatation rate of the aortic wall, as well as in MDA expression, leukocyte infiltration, and MMP activity in the vascular wall. Conclusions: The GLP-1 receptor agonist liraglutide was found to inhibit AAA progression in mice by exerting anti-inflammatory and antioxidant effects, particularly during the early stages of AAA formation. Therefore, liraglutide may represent a potential pharmacological target for the treatment of AAA. [ABSTRACT FROM AUTHOR]

The text discusses the emergence of tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, as a promising therapeutic option for diabetes and obesity, collectively known as diabesity. Tirzepatide has shown exceptional potential in clinical trials, offering significant improvements in glycemic control and weight loss compared to traditional therapies. The dual agonism of tirzepatide targets multiple metabolic dysfunctions simultaneously, providing a more comprehensive approach to managing diabetes and obesity. Further research is needed to explore the long-term safety and efficacy of tirzepatide, as well as its potential benefits in diverse patient populations. [Extracted from the article]

Aims/Introduction: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α‐cells. Materials and Methods: Experiments were carried out in high‐fat, high‐sucrose diet‐fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme‐linked immunosorbent assay; the latter eliminates cross‐reactivities with other proglucagon‐derived peptides. Results: Plasma glucagon, insulin and glucagon‐like peptide‐1 levels were increased by imeglimin administration in high‐fat, high‐sucrose diet‐fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long‐term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long‐term administration of imeglimin did not alter α‐cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein‐1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. Conclusions: Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Abstract Aims/Introduction Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α‐cells. Materials and Methods Experiments were carried out in high‐fat, high‐sucrose diet‐fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme‐linked immunosorbent assay; the latter eliminates cross‐reactivities with other proglucagon‐derived peptides. Results Plasma glucagon, insulin and glucagon‐like peptide‐1 levels were increased by imeglimin administration in high‐fat, high‐sucrose diet‐fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long‐term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long‐term administration of imeglimin did not alter α‐cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein‐1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. Conclusions Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation.

Aim: To compare weight and glucometabolic outcomes of semaglutide and metabolic and bariatric surgery (MBS) for patients with type 2 diabetes and obesity. Materials and Methods: Patients treated with either semaglutide for a duration of ≥2 years or MBS in Sweden were identified within the Scandinavian Obesity Surgery Registry and the National Diabetes Registry and matched in a 1:1–2 ratio using a propensity score matching with a generalized linear model, including age, sex, glycated haemoglobin before treatment, duration of type 2 diabetes, use of insulin, presence of comorbidities and history of cancer, with good matching results but with a remaining imbalance for glomerular filtration rate and body mass index, which were then adjusted for in the following analyses. Main outcomes were weight loss and glycaemic control. Results: The study included 606 patients in the surgical group matched to 997 controls who started their treatment from 2018 until 2020. Both groups improved in weight and glucometabolic control. At 2 years after the intervention, mean glycated haemoglobin was 42.3 ± 11.18 after MBS compared with 50.7 ± 12.48 after semaglutide treatment (p < 0.001) with 382 patients (63.0%) and 139 (13.9%), respectively, reaching complete remission without other treatment than the intervention (p < 0.001). Mean total weight loss reached 26.4% ± 8.83% after MBS compared with 5.2% ± 7.87% after semaglutide (p < 0.001). Conclusion: Semaglutide and MBS were both associated with improvements in weight and improved glycaemic control at 2 years after the start of the intervention, but MBS was associated with better weight loss and glucometabolic control. [ABSTRACT FROM AUTHOR]

Metabolic health is highly dependent on intestinal and hepatic handling of dietary and endogenous lipids and lipoproteins. Disorders of lipid and lipoprotein metabolism are commonly observed in patients with insulin resistant states such as obesity, metabolic syndrome, and type 2 diabetes. Evidence from both animal models and human studies indicates that a major underlying factor in metabolic or diabetic dyslipidemia is the overproduction of hepatic and intestinal apolipoprotein (apo)B-containing lipoprotein particles. These particles are catabolized down into highly proatherogenic remnants, which can be taken up into the arterial intima and promote plaque development. Several gut-derived peptides have been identified as key regulators of energy metabolism; one such peptide is the incretin hormone glucagon-like peptide (GLP)-1. Our laboratory has previously demonstrated that GLP-1 can signal both centrally and peripherally to reduce postprandial and fasting lipoprotein secretion. Moreover, we have demonstrated that GLP-1 receptor (GLP-1R) agonists can ameliorate diet-induced dyslipidemia. Recently, we published evidence for a novel vagal neuroendocrine signalling pathway by which native GLP-1 may exert its anti-lipemic effects. Furthermore, we demonstrated a novel role for other gut-derived peptides in regulating intestinal lipoprotein production. Overall, ample evidence supports a key role for GLP-1R on the portal vein afferent neurons and nodose ganglion in modulating intestinal fat absorption and lipoprotein production and identifies other gut-derived peptides as novel regulators of postprandial lipemia. Insights from these data may support identification of potential drug targets and the development of new therapeutics targeting treatment of diabetic dyslipidemia.

Type 2 diabetes mellitus (T2DM), a chronic metabolic disease caused by an imbalance between carbohydrate intake and metabolism, is one of the most difficult metabolic diseases to treat worldwide. The main symptoms of T2DM include hyperglycemia, insufficient insulin secretion, insulin resistance, polydipsia and polyuria. T2DM is often accompanied by many complications such as atherosclerosis, renal function injury and non-alcoholic fatty liver disease. Glucagon-like peptide-1 (GLP-1) is a polypeptide composed of 31 amino acids, which is mainly used to maintain glucose homeostasis in vivo and relieve T2DM. However, its half-life is short and it is easily degraded in vivo. This article introduces probiotics and their metabolites that regulate GLP-1 in the host, and also discusses the alleviative effect of GLP-1 on T2DM, including the association between GLP-1 and T2DM, the clinical application of metformin and GLP-1 agonists, the insufficiency of GLP-1 in alleviating T2DM and the regulation of the GLP-1 content by related prebiotics. Finally, the regulatory mechanisms of probiotics and their metabolites on GLP-1, including short-chain fatty acids, bile acids (BAs), tryptophan and its derivatives and extracellular polysaccharides, are summarized in order to provide some references for studies on the regulatory effects of probiotics and their metabolites on GLP-1 production and release in the host as well as their alleviative effects on T2DM.

Xi-Ding Yang,1,2 Yong-Yu Yang1,3 1Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2Phase I Clinical Trial Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 3Hunan Provincial Engineering Research Central of Translational Medical and Innovative Drug, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Yong-Yu Yang, Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China, Email yongyuyang@csu.edu.cnPurpose: The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use.Methodology: The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies.Results: Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug–drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this.Conclusion: This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.Keywords: Pharmacokinetics, semaglutide, curve plasma concentrations, type 2 diabetes, obesity, glucagon-like peptide-1, drug–drug interaction

Some neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that encompasses memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative diseases that are characterized by deficits of cognition and alterations of behavior. Despite the huge efforts against Alzheimer's disease, there has yet been no successful treatment for this disease. Interestingly, several possible risk genes for cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes, and/or caveolae formation, suggesting that caveolae may be a therapeutic target for cognitive dysfunctions. Interestingly, the modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptor signaling may offer a novel approach to preventing and alleviating cognitive dysfunction. A paradigm showing that both GLP-1 and NMDA receptors at caveolae sites may be promising and crucial targets for the treatment of cognitive dysfunctions has been presented here, which may also be able to modify the progression of Alzheimer's disease. This research direction may create the potential to move clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease. [ABSTRACT FROM AUTHOR]

Aim: Studies examining the safety and effectiveness of sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) versus glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) among community‐dwelling adults may not generalize to nursing home (NH) residents, who are typically older and more multimorbid. We compared the safety and cardiovascular effectiveness of SGLT2is and GLP‐1RAs among US NH residents. Materials and Methods: Eligible individuals were aged ≥66 years with type 2 diabetes mellitus and initiated an SGLT2i or GLP‐1RA in an NH between 2013 and 2018. Safety outcomes included fall‐related injuries, hypoglycaemia, diabetic ketoacidosis (DKA), urinary tract infection or genital infection, and acute kidney injury in the year following treatment initiation. Cardiovascular effectiveness outcomes included death, major adverse cardiovascular events and hospitalization for heart failure. Per‐protocol adjusted hazard ratios (HR) were calculated using stabilized inverse probability of treatment and censoring weighted cause‐specific hazard regression models accounting for 127 covariates. Results: The study population included 7710 residents (31.08% SGLT2i, 68.92% GLP‐1RA). Compared with GLP‐1RA initiators, SGLT2i initiators had higher rates of DKA (HR 1.95, 95% confidence limits 1.27, 2.99) and death (HR 1.18, 95% confidence limits 1.02, 1.36). Rates of urinary tract infection or genital infection, acute kidney injury, major adverse cardiovascular events, and heart failure were also elevated, while rates of fall‐related injuries and hypoglycaemia were reduced, but all estimates were imprecise and highly compatible with no difference. Conclusions: SGLT2is do not have superior, and may have inferior, effectiveness compared with GLP‐1RAs for cardiovascular and mortality outcomes in NH residents. Residents initiating SGLT2is should be monitored closely for DKA. [ABSTRACT FROM AUTHOR]

Idiopathic intracranial hypertension (IIH) is a disorder that primarily affects obese women of reproductive age. The exact pathogenesis of IIH is unknown though multiple etiologies have been proposed. We report a case of IIH triggered by first-time Ramadan intermittent fasting (RIF) in an 18-year-old woman. Our patient developed new onset headaches, diplopia, and pulsatile tinnitus with examination notable for bilateral papilledema and lumbar puncture revealing an elevated opening pressure. Her symptoms resolved after cessation of RIF, apart from persistent left sided tinnitus which later resolved with acetazolamide administration. This case report uniquely illustrates that RIF may provoke symptomatic IIH. We hypothesize that a decreased concentration of glucagon-like peptide-1 (GLP-1) induced by fasting results in decreased GLP-1 receptor activation in the choroid plexus, allowing for increased CSF secretion into the ventricles invoking increased intracranial pressure (ICP). This theoretical mechanism provides further insight as to the possible underlying pathophysiology of IIH. [ABSTRACT FROM AUTHOR]

Processing of proglucagon into glucagon-like peptide-1 (GLP-1) and GLP-2 in intestinal L cells is mediated by the prohormone convertase 1/3 (PC1/3) while PC2 is responsible for the synthesis of glucagon in pancreatic alpha cells. While GLP-1 is also produced by alpha cells, the identity of the convertase involved in its synthesis is still unsettled. It also remains to be determined whether all alpha cells produce the incretin. The aims of this study were first, to elucidate the identity of the proconvertase responsible for GLP-1 production in human alpha cells, and second, to ascertain whether the number of glucagon cells expressing GLP-1 increase during diabetes. To answer these questions, sections of pancreas from donors' non-diabetic controls, type 1 and type 2 diabetes were processed for double-labelled immunostaining of glucagon and GLP-1 and of each hormone and either PC1 or PC2. Stained sections were examined by confocal microscopy. It was found that all alpha cells of islets from those three groups expressed GLP-1 and PC2 but not PC1/3. This observation supports the view that PC2 is the convertase involved in GLP-1 synthesis in all human glucagon cells and suggests that the regulation of its activity may have important clinical application in diabetes. [ABSTRACT FROM AUTHOR]

Purpose: Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism. Methods: Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR. Results: Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice. Conclusion: Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity. [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]

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

Background: One anastomosis gastric bypass (OAGB) has been proposed as an effective alternative to the current standard procedure in Switzerland, Roux-en-Y gastric bypass (RYGB). Prospective data comparing both procedures are scarce. Therefore, we performed a non-inferiority randomized controlled trial assessing the effectiveness and safety of these 2 operative techniques. Method: Eighty patients were randomized 1:1. OAGB consisted of a very long gastric pouch with a 200 cm biliopancreatic limb, RYGB of a 150 cm ante-colic alimentary and a 60 cm biliopancreatic limb, respectively. Primary endpoint was the percent excess weight loss (%EWL) at 12 months after surgery. Results: Mean %EWL at 12 months was 87.9% (SD24.4) in the RYGB group and 104.1% (SD24.6) in the OAGB group (p = 0.006). There was no mortality. The rate of marginal ulcers was higher in patients with OAGB compared to those with RYGB (p = 0.011), while the total number of late complications did not statistically differ between the two groups. Except for the remission of GERD, which was higher in the RYGB group compared to OAGB, there was no difference between the groups regarding the remission of comorbidities. OAGB showed improved glucose control compared to the RYGB after 1 year (p = 0.001). Furthermore, glucagon-like peptide-1 increase was significantly higher in OAGB at 6 weeks (p = 0.041) and 1 year after surgery (p = 0.029). Quality of life improved after both surgeries, without differences between the groups. Conclusions: %EWL 1 year after surgery was higher in OAGB than in RYGB. A better glycemic control with a higher increase in GLP-1 was observed after OAGB compared to RYGB. Trial registration: This trial is registered on ClinicalTrials.gov under the identifier NCT02601092. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1(GLP-1) is an incretin hormone secreted primarily from the intestinal L-cells in response to meals. GLP-1 is a key regulator of energy metabolism and food intake. It has been proven that P9 protein from A. muciniphila could increase GLP-1 release and improve glucose homeostasis in HFD-induced mice. To obtain an engineered Lactococcus lactis which produced P9 protein, mature polypeptide chain of P9 was codon-optimized, fused with N-terminal signal peptide Usp45, and expressed in L. lactis NZ9000. Heterologous secretion of P9 by recombinant L. lactis NZP9 were successfully detected by SDS-PAGE and western blotting. Notably, the supernatant of L. lactis NZP9 stimulated GLP-1 production of NCI-H716 cells. The relative expression level of GLP-1 biosynthesis gene GCG and PCSK1 were upregulated by 1.63 and 1.53 folds, respectively. To our knowledge, this is the first report on the secretory expression of carboxyl-terminal processing protease P9 from A. muciniphila in L. lactis. Our results suggest that genetically engineered L. lactis which expressed P9 may have therapeutic potential for the treatment of diabetes, obesity and other metabolic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have shown encouraging results regarding cardiovascular outcomes mainly in patients with diabetes. In the present study, we compared the efficacy of GLP‐1 RAs in cardiovascular events between patients with and without diabetes. Methods: After finding eligible studies assessing the impact of GLP‐1 RAs on cardiovascular events in patients with and without diabetes using a systematic search, we performed a meta‐analysis on randomized‐controlled trials (RCTs) comparing cardiovascular outcomes between patients taking GLP‐1 RAs and placebo stratified by the presence or absence of diabetes. Relative risk (RR) and its 95% confidence interval (CI) were set as the reporting effect size using the random‐effects model. Results: A total of 24 RCTs (50 033 with GLP‐1 RAs and 44 514 with placebo) were included. Patients on GLP‐1 RAs had lower risk of major adverse cardiovascular events (MACE) (RR 0.87, 95% CI 0.82−0.93), cardiovascular death (RR 0.88, 95% CI 0.82−0.94), myocardial infarction (MI) (RR 0.87, 95% CI 0.77−0.97), stroke (RR 0.86, 95% CI 0.80−0.92), and hospitalization for heart failure (RR 0.90, 95% CI 0.83−0.98). Both subgroups were shown to be effective in terms of MACE and mortality. Nondiabetic patients had decreased risk of hospitalization for heart failure and MI, whereas the diabetic subgroup had marginally nonsignificant efficacy. Conclusion: The findings of this meta‐analysis indicated that patients who are overweight/obese but do not have diabetes have a comparable reduction in the risk of adverse cardiovascular events as those with diabetes. These results need to be confirmed further by large‐scale randomized trials in the future. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. Methods: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = −60, −30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0–60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = −60 min and t = 120 min. Results: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = −60 or −30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = −60 or −30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. Conclusions/interpretation: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. Trial registration: www.anzctr.org.au ACTRN12621000878875 Funding: The study was not funded by a specific research grant. [ABSTRACT FROM AUTHOR]

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Pancreatitis is characterized by inflammation of the pancreas and significantly affects quality of life. Less than 5% of pancreatitis cases are drug-induced, but recent evidence suggests a substantial risk associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The aim of this study was to compare the risk of developing pancreatitis between those using GLP-1 RAs and those using sodium-glucose transport protein 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. Methods: This study was done using the FDA Adverse Event Reporting System (FAERS) database from 2019 to 2021. This database contains information from diverse submissions from healthcare providers, patients, and manufacturers. To ensure fairness and accuracy, the risk of pancreatitis associated with other hypoglycemic agents (SGLT2 inhibitors and DPP-4 inhibitors) was also investigated. Traditional and Bayesian statistical analysis methods were used to identify disproportionate statistics and included the reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM), and information component (IC). A drug–adverse-event combination that met the criteria of all four indices was deemed a signal. Results: The analysis of 2,313 pancreatitis reports linked to hypoglycemic agents revealed a predominant association with GLP-1 RA (70.2%) compared to DPP-4 inhibitors (15%) and SGLT2 (14.7%). Most of these reports involved female patients (50.4%), and the highest incidence occurred in those over 50 years old (38.4%). Additionally, 17.7% of the reports were associated with serious events. The ROR was significant for the risk of pancreatitis when using DPP-4 (13.2, 95% confidence interval (CI) 11.84-14.70), while the ROR for GLP-1 was 9.65 (95% CI 9.17-10.16). The EBGM was highest with DPP-4 (12.25), followed by GLP-1 (8.64), while IC was highest with DPP-4 inhibitors (3.61). Liraglutide had the greatest association with pancreatitis among the GLP-1 RAs (ROR: 6.83, 95% CI 6.60-7.07). Conclusion: The findings show that pancreatitis has a strong link with DPP-4 inhibitors and GPL1 agonists, which pose a greater risk. Among the GLP-1 agonist medications, liraglutide has been found to have an association with pancreatitis. [ABSTRACT FROM AUTHOR]

Aim: To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon‐like peptide‐1 receptor (GLP‐1R) agonists for in‐depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. Materials and Methods: Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)‐K1 cells stably expressing human GCGR and GLP‐1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP‐1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP‐1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor‐21 (FGF21) and liver nicotinamide N‐methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight‐ and glucose‐lowering efficacies were investigated in diet‐induced obese (DIO) mice and diabetic db/db mice, respectively. Results: Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP‐1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP‐1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in‐depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15‐ to 17‐fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight‐lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%–0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). Conclusions: Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP‐1R pharmacology, engaging the GCGR for robust body weight‐lowering efficacy exceeding that of selective GLP‐1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP‐1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity. [ABSTRACT FROM AUTHOR]

Despite its considerable and growing burden, there are currently no Food and Drug Administration‐approved treatments for metabolic dysfunction‐associated steatotic liver disease or its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Several glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all‐cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction‐associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP‐1RAs are Food and Drug Administration‐approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP‐1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP‐1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP‐1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta‐analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP‐1RAs. Large‐scale, phase 3 trials, which will provide definitive data on GLP‐1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH. [ABSTRACT FROM AUTHOR]

Prediabetes is an intermediate state of glucose homeostasis whereby plasma glucose concentrations are above normal but below the threshold of diagnosis for diabetes. Over the last several decades, criteria for prediabetes have changed as the cut points for normal glucose concentration and diagnosis of diabetes have shifted. Global consensus does not exist for prediabetes criteria; as a result, the clinical course and risk for type 2 diabetes vary. At present, we can identify individuals with prediabetes based on three glycemic tests (hemoglobin A1c, fasting plasma glucose, and 2‐h plasma glucose during an oral glucose tolerance test). The majority of individuals diagnosed with prediabetes meet only one of these criteria. Meeting one, two, or all glycemic criteria changes risk for type 2 diabetes, but this information is not widely known and does not currently guide intervention strategies for individuals with prediabetes. This review summarizes current epidemiology, prognosis, and intervention strategies for individuals diagnosed with prediabetes and suggests a call for more precise risk stratification of individuals with prediabetes as elevated (one prediabetes criterion), high risk (two prediabetes criteria), and very high risk (three prediabetes criteria). In addition, the roles of oral glucose tolerance testing and continuous glucose monitoring in the diagnostic criteria for prediabetes need reassessment. Finally, we must reframe our goals for prediabetes and prioritize intensive interventions for those at high and very high risk for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Nutritional, endocrine, and neurological signals converge in multiple brain centres to control feeding behaviour and food intake as part of the allostatic regulation of energy balance. Among the several neuroendocrine systems involved, the leptin, glucocorticoid, and glucagon‐like peptide 1 (GLP1) systems have been extensively researched. Leptin is at the top hierarchical level since its complete absence is sufficient to trigger severe hyperphagia. Glucocorticoids are key regulators of the energy balance adaptation to stress and their sustained excess leads to excessive adiposity and metabolic perturbations. GLP1 participates in metabolic adaptation to food intake, regulating insulin secretion and satiety by parallel central and peripheral signalling systems. Herein, we review the brain and peripheral targets of these three hormone systems that integrate to regulate food intake, feeding behaviour, and metabolic homeostasis. We examine the functional relationships between leptin, glucocorticoids, and GLP1 at the central and peripheral levels, including the cross‐regulation of their circulating levels and their cooperative or antagonistic actions at different brain centres. The pathophysiological roles of these neuroendocrine systems in dysregulated intake are explored in the two extremes of body adiposity – obesity and lipodystrophy – and eating behaviour disorders. [ABSTRACT FROM AUTHOR]

Probiotics have garnered increasing attention as a potential therapeutic approach for type 2 diabetes mellitus (T2DM). Previous studies have confirmed that Bifidobacterium animalis subsp. lactis MN-Gup (MN-Gup) could stimulate the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells, but whether MN-Gup has a hypoglycemic effect on T2DM in vivo remains unclear. In this study, a T2DM mouse model was constructed, with a high-fat diet and streptozotocin in mice, to investigate the effect of MN-Gup on diabetes. Then, different doses of MN-Gup (2 × 109 CFU/kg, 1 × 1010 CFU/kg) were gavaged for 6 weeks to investigate the effect of MN-Gup on glucose metabolism and its potential mechanisms. The results showed that a high-dose of MN-Gup significantly reduced the fasting blood glucose (FBG) levels and homeostasis model assessment-insulin resistance (HOMA-IR) of T2DM mice compared to the other groups. In addition, there were significant increases in the short-chain fatty acids (SCFAs), especially acetate, and GLP-1 levels in the MN-Gup group. MN-Gup increased the relative abundance of Bifidobacterium and decreased the number of Escherichia-Shigella and Staphylococcus. Moreover, the correlation analysis revealed that Bifidobacterium demonstrated a significant positive correlation with GLP-1 and a negative correlation with the incremental AUC. In summary, this study demonstrates that Bifidobacterium animalis subsp. lactis MN-Gup has significant hypoglycemic effects in T2DM mice and can modulate the gut microbiota, promoting the secretion of SCFAs and GLP-1. [ABSTRACT FROM AUTHOR]

Background: Anti‐obesity medications (AOMs) have historically had limited weight‐loss efficacy. However, newer glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA)–based therapies seem to be more effective, including dual agonists of GLP‐1R and the glucagon receptor (GCGR) or glucose‐dependent insulinotropic polypeptide receptor. Objective: To explore healthcare professionals' (HCPs) experience in obesity treatment and their understanding of agonists of GCGR, glucose‐dependent insulinotropic polypeptide (GIP) RA, and GLP‐1 RA. Methods: This cross‐sectional online survey of HCPs prescribing AOMs was conducted in the United States in 2023 with a questionnaire designed to evaluate prescribing behavior and understanding of GCGR, GIP RA, and GLP‐1 RA. Results: The 785 respondents (251 primary‐care physicians [PCPs], 263 endocrinologists, and 271 advanced practice providers [APPs]) reported 55% of their patients had obesity (body mass index ≥30 kg/m2 or ≥27 with weight‐related complications) and recommended AOMs to 49% overall, significantly more endocrinologists (57% of patients, p < 0.0005) than PCPs (43%) or APPs (46%). The greatest barriers to treatment were medication cost/lack of insurance (mean 4.2 on 1–5 scale [no barrier–extreme barrier]), low patient engagement/adherence (3.3), and inadequate time/staff (3.1). Metformin was the type 2 diabetes (T2D) medication most commonly prescribed to treat obesity in T2D patients (92.5% of respondents). Most HCPs (65%) were very/extremely familiar with GLP‐1 RA, but only 30% with GIP RA and 16% with GCGR. Most HCPs expected dual GCGR/GLP‐1 RA to benefit many obesity‐related conditions; however, only a minority of HCPs perceived that they would benefit non‐cardiometabolic complications of obesity. Conclusions: Among HCPs prescribing AOMs, gaps exist in the management of people living with obesity as <50% are prescribed AOMs. Barriers to treatment indicate a need to improve access to AOMs. HCPs were less familiar with GCGR or GIP RA than GLP‐1 RA but expect dual GCGR/GLP‐1 RA may offer additional benefits, potentially addressing treatment barriers and access. Thus, there is a need for greater education among HCPs regarding the mechanism of action and therapeutic effects of GCGR agonists, and dual GCGR/GLP‐1 RA, so that the full range of obesity‐related complications can be effectively treated. [ABSTRACT FROM AUTHOR]

Along with social development and lifestyle changes, the number of overweight and obese patients worldwide is rising annually. Obesity is a chronic metabolic disease with complex etiology. Dipeptidyl peptidase IV (DPP-IV) is a novel adipokine with significantly elevated expression in the visceral fat of obese patients. DPP-IV is a molecule that regulates metabolic homeostasis and inflammatory processes. Through its enzymatic activity, it plays a significant part in achieving hypoglycemic and weight loss effects through various pathways. DPP-IV and DPP-IV inhibitors also have pleiotropic effects in modulating obesity-related diseases by reducing obesity-related inflammation, ameliorating inflammatory bowel disease (IBD), improving hepatic steatosis and lowering cardiovascular risk, and even decreasing the risk of novel coronavirus disease-19 (COVID-19). This paper reviews the mechanisms of action based on DPP-IV targets in obesity and metabolic homeostasis, as well as their active role in the treatment of chronic diseases associated with obesity.

The widespread adoption of glucagon‐like peptide‐1 (GLP‐1) agonists in treating type 2 diabetes mellitus (T2DM) and obesity has sparked investigations into their impact on hair health, an area characterized by diverse conjectures. Some propose potential risks such as disrupted hair growth cycles or premature androgenetic alopecia (AGA), while others suggest benefits linked to improved insulin sensitivity and enhanced scalp blood circulation. However, despite these theoretical underpinnings, clinical evidence linking GLP‐1 agonists to hair loss remains sparse. The necessity for vigilant patient monitoring and collaborative efforts cannot be overstressed in comprehensively addressing any potential consequences of GLP‐1 agonist therapy on hair health as their use continues to expand. [ABSTRACT FROM AUTHOR]

Objective To explore the effect of chenodeoxycholic acid (CDCA) on the expression of glucagon-like peptide-1 (GLP-1) in the intestine of mice induced by high-fat diet (HFD) through farnesoid X receptor (FXR), and investigate the related mechanism. Methods Forty C57BL/6 mice were divided into control group, HFD group, HFD+CDCA group, HFD+Z-Gug (FXR antagonist) group, and HFD+CDCA+Z-Gug group, with 8 animals in each group. During intervention for 8 weeks, body weight and 24-hour food intake were measured every week. At the 8th week, oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were conducted. After the mice were sacrificed, the serum levels of GLu, TG, CHO, LDL-C and HDL-C were detected; the expression levels of GLP-1 and FXR in intestinal tissues were detected by immunofluorescence assay; and the mRNA levels of TNF-α, IL-6, IL-1β, Gcg and FXR were detected by RT-qPCR; the serum level of GLP-1 was detected by ELISA, and the proportion of intraepithelial lymphocytes (IELs) subsets and the expression of CD26/DPP4 were detected by flow cytometry. Results Compared with the control group, the HFD group had increased body weight, abnormal serum glucose and lipid metabolism, impaired oral glucose tolerance, and weakened secretion of gastrointestinal hormones (P < 0.05), enhanced FXR expression at mRNA and protein levels, declined Gcg mRNA level and GLP-1 secretion level (P < 0.05), increased mRNA levels of intestinal inflammatory factors TNF-α, IL-6 and IL-1β (P < 0.05), raised proportions of TCRαβ+ IELs, TCRαβ+CD8αα+ IELs, and TCRαβ+CD8αβ+ IELs but reduced proportion of TCRγδ+IELs, and increased total CD26/DPP4 expression in IELs (P < 0.05). Compared with the HFD group, HFD+CDCA treatment resulted in significantly increased body weight, impaired oral glucose tolerance, decreased secretion of gastrointestinal hormones, increased FXR mRNA and protein expression, and decreased Gcg mRNA expression and GLP-1 secretion (P < 0.05); decreased proportions of TCRαβ+ IELs, TCRαβ+CD8αα+ IELs and TCRααβ+CD8αβ+ IELs but increased proportion of TCRγδ+ cells in IELs, and increased expression of total CD26/DPP4 in IELs (P < 0.05), which were significantly improved after Z-Gug intervention (P < 0.05). Conclusion CDCA may inhibit the expression and secretion of GLP-1 in intestinal tissue by activating FXR, and reduce the secretion of GLP-1. At the same time, CDCA may inhibit the expression of related inflammatory factors, regulate the proportions of IELs subsets, up-regulate the expression level of CD26/DPP4, promote the degradation of GLP-1 and aggravate insulin resistance. [Key words] chenodeoxycholic acid , glucagon-like peptide-1, farnesoid X receptor , intraepithelial lymphocytes , CD26 ,

Diabetes, characterized by hyperglycemia, is a major cause of death and disability worldwide. Peptides, such as insulin and glucagon-like peptide-1 (GLP-1) analogs, have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body. Compared to subcutaneous injection, oral administration of anti-diabetic peptides is a preferred approach. However, biological barriers significantly reduce the efficacy of oral peptide therapeutics. Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes. This review will highlight (1) the benefits of oral anti-diabetic peptide therapeutics; (2) the biological barriers for oral peptide delivery, including pH and enzyme degradation, intestinal mucosa barrier, and biodistribution barrier; (3) the delivery platforms to overcome these biological barriers. Additionally, the review will discuss the prospects in this field. The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

ABSTRACT: The purpose of this study was to investigate if consumption of a high-protein, low-carbohydrate breakfast (PRO) leads to a lower subsequent ad libitum energy intake at lunch and the rest of the day compared with ingestion of an isocaloric low-protein, high-carbohydrate breakfast (CHO) or no breakfast (CON). The study was designed as a randomized controlled 3-period crossover study. Thirty young (18–30 yr) females with overweight to obesity (body mass index >25 kg/m2) in random order completed 3 separate experimental days where they consumed either a PRO, CHO, or CON breakfast test meal followed by an ad libitum lunch meal 3 h after breakfast. Participants were allocated to a sequence group by their inclusion number. The PRO and CHO breakfasts were matched in dietary fiber and fat content. Energy intake at lunch was calculated and dietary records were obtained for the rest of the day to calculate the total daily energy intake and macronutrient intake. Ratings of appetite sensations between meals and palatability of the test meals were assessed using visual analog scale sheets in intervals ranging from 10 to 30 min. In addition, blood samples were obtained at multiple time points separated by 10 to 60 min intervals between breakfast and lunch and were analyzed for appetite-regulating gut hormones, insulin, and glucose. Finally, performance in a cognitive concentration test was tested 150 min after breakfast. Compared with CHO and CON, the area under the curves for satiety, fullness, and satisfaction in the 3 h after breakfast were significantly higher after PRO, whereas the areas under the curve for hunger, desire to eat, and prospective eating were significantly lower after PRO. The appetite-regulating gut hormones cholecystokinin, glucagon-like peptide-1, and ghrelin in the hours after breakfast, energy intake during the ad libitum lunch meal, and the total daily energy intake did not differ significantly between PRO, CHO, and CON. However, the cognitive concentration test score was 3.5 percentage points higher for PRO, but not CHO, versus CON. A dairy-based high-protein, low-carbohydrate breakfast increased satiety sensation in the hours after breakfast but did not reduce total daily energy intake compared with an isocaloric low-protein, high-carbohydrate breakfast or omitting breakfast. However, performance in a cognitive concentration test before lunch was enhanced after the high-protein, low-carbohydrate breakfast, but not the low-protein, high-carbohydrate breakfast, compared with omitting breakfast.

Yujian Shao,1,2 Yonglu Chen,2 Mingyue Zhu,3 Yuanyuan Liu,2 Chen Fang,3 Minjun Wang,2 Peng Sun,3 Weiling Fu,2 Jing Huang,3 Shimei Sheng,2 Yanshan Huang2 1Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd, Hangzhou, Zhejiang, People’s Republic of China; 3First Research Institute, Zhejiang Heze Pharmaceutical Technology Co., Ltd, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Yanshan Huang, Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd, Hangzhou, Zhejiang, People’s Republic of China, Email yanshanhuang@doerbio.comIntroduction: 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.Keywords: glucagon-like peptide-1, gastric inhibitory polypeptide receptor, obesity, type 2 diabetes, inflammation

Abstract Background The incidence of male reproductive dysfunction is increasing annually, and many studies have shown that obesity can cause severe harm to male reproductive function. The mechanism of male reproductive dysfunction caused by obesity is unclear, and there is no ideal treatment. Identification of effective therapeutic drugs and elucidation of the molecular mechanism involved in male reproductive health are meaningful. In this study, we investigated the effects of the GLP-1 receptor agonist liraglutide on sex hormones, semen quality, and testicular AC3/cAMP/PKA levels in high-fat-diet-induced obese mice. Methods Obese mice and their lean littermates were treated with liraglutide or saline for 12 weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), free testosterone (F-TESTO), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELISA. The sperm morphology and sperm count were observed after Pap staining. The mRNA and protein expression levels of testicular GLP-1R and AC3 were measured by RT-qPCR and Western blot, respectively. Testicular cAMP levels and PKA activity were detected using ELISA. Results Liraglutide treatment can decrease body weight, FBG, INS, HOMA-IR, E2 and SHBG levels; increase LH, FSH, T, and F-TESTO levels; increase sperm count; decrease the sperm abnormality rate; and increase GLP-1R and AC3 expression levels and cAMP levels and PKA activity in testicular tissue. Conclusions Liraglutide can improve the sex hormone levels and semen quality of obese male mice. In addition to its weight loss effect, liraglutide can improve the reproductive function of obese male mice, which may also be related to the upregulation of AC3/cAMP/PKA pathway in the testis. This work lays the groundwork for future clinical studies.

Purpose: To determine the relationship between gastrointestinal hormones (leptin, glucagon-like peptide-1), ghrelin, cholecystokinin, peptide YY, morphological characteristics, and physical performances in elite soccer players. Methods: Q2 Twenty-two elite male soccer players (age = 23.1 [2.7] y, height = 177.0 [0.1] cm, weight = 70.2 [2.9] kg, body mass index = 22.1 [1.8] kg/m2) completed 3-day food records each week during the 5-week training period. Blood samples were drawn after an overnight fast before and after preseason training to assess gastrointestinal hormones (leptin, glucagon-like peptide-1, ghrelin, cholecystokinin, and peptide YY). Continuous analysis of the training load was used during the training period. Preintervention and postintervention tests assessed jumping (countermovement jump), sprinting (10, 20, and 30 m), and endurance fitness (the Yo-Yo Intermittent Recovery Test Level 1 [YYIRT1]) levels. Results: Preseason training decreased body mass index (P =.001; effect size [ES] = 0.183) and body fat percentage (P =.001; ES = 0.516). There were increases in countermovement jump (P =.032; ES = 0.215), 20- (P =.016; ES = 0.195) and 30-m sprints (P =.001; ES = 0.188), and YYIRT1 performance (P =.001; ES = 0.9). Levels of cholecystokinin, peptide YY, and ghrelin did not change during preseason training, although changes in leptin (P =.001; ES = 0.41) and glucagon-like peptide-1 levels (P =.039; ES = 0.606) were recorded. Leptinemia correlated with anthropometric parameters (body mass index, r =.77, P =.001; percentage of body fat,r =.67, P =.006) and the total distance covered during the YYIRT1 (r = −.54; P =.03). Conclusion: Changes in morphological parameters and physical performance in elite-level male soccer players are related to variations in selected gastrointestinal hormones. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of subcutaneous injection of glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on serum sex hormone levels in obese male mice. Methods Eighteen male C57BL/6J mice were randomly divided into the normal group (n = 6) model group (n = 6), and intervention group (n = 6) Mice in the nor- mal group were fed with normal diet, and mice in the model group and intervention group were fed with high-fat diet to establish the obesity models. After 10 weeks, mice in the intervention group were subcutaneously injected with liraglutide at 100 µg/(kg.d), and mice in the normal group and model group were subcutaneously injected with the equal volume of nor- mal saline for 12 weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), free testosterone (FT), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELI-SA. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Results Compared with the normal group, the body weight of the model group increased at 0, 4, 8, and 12 weeks (all P < 0.01 ) ; compared with the model group, the body weight of the intervention group decreased at 4, 8, and 12 weeks (all P<0.01); there was no statistically significant difference in body weight between the intervention group and the normal group at 12 weeks (P > 0.05). After administration, compared with the normal group, the serum FBG, INS, and HOMA-IR levels increased in the model group (all P < 0.01 ) ; compared with the model group, the serum FBG, INS, and HOMA-IR levels decreased in the intervention group (all P < 0 ). Compared with the normal group, the levels of LH, FSH, T, and FT decreased and the levels of E2, and SHBG increased in the model group (all P < 0.05 ) ; compared with the model group, the levels of LH, FSH, T, and FT in the intervention group increased, and the levels of E, and SHBG decreased (all P < 0.05 ) . Conclusion The sex hormone levels of obese male mice are abnormal; liraglutide can improve the sex hormone levels of obese male mice, and its mechanism may be related to its significant effects of reducing blood glucose and body mass. [ABSTRACT FROM AUTHOR]

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition. [ABSTRACT FROM AUTHOR]