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Foxo-1 and Sirt1 mediate the effect of exendin-4 on adiponectin expression (A) Suppression of Foxo-1 expression impaired exenin-4-induced adiponectin expression. (B) Exendin-4 suppresses phosphorylation of Foxo-1. (C) Exendin-4 triggered nuclear translocation of Foxo-1. (D) Suppression of Sirt1 expression impaired exenin-4-induced adiponectin expression.
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Glucagon-like peptide-1 (GLP-1) receptor plays an essential role in regulating glucose metabolism. GLP-1 receptor agonists have been widely used for treating diabetes and other insulin resistance-related diseases. However, mechanisms underlying the anti-diabetic effects of GLP-1 receptor agonists remain largely unknown. In this study, we investigat...
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Objective:
Tirzeptide is a novel glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) drug, which shows good efficiency for weight loss. Therefore, we aim to investigate the efficacy and safety of tirzepatide for weight loss in type 2 diabetes mellitus (T2DM) and obesity patients in this meta-analysis stu...
According to the World Health Organization (WHO), the prevalence of type 2 diabetes mellitus (T2DM) and obesity has increased globally over the past 50 years, affecting over 500 million adults worldwide in 2023. A novel class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a beacon of hope in treating the pandemi...
Background
Glucagon‐like peptide‐1 receptor agonists ( GLP ‐1 RAs ) and sodium‐glucose cotransporter‐2 inhibitors ( SGLT 2is) have shown their beneficial effects on cardiovascular outcomes and multiple cardiovascular risk factors, including hypertension. However, the mechanism of blood pressure ( BP )–lowering effects of these agents has not been e...
Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type 2 diabetes mellitus (T2DM) treatment with demonstrated weight loss benefits in clinical trials. However, the extent to which real-world patients with T2DM achieve clinically meaningful weight loss (≥5%) has not been well characterized. Analysis of real-world data suggests...
Background
Many studies have confirmed that ileal transposition can improve type 2 diabetes mellitus (T2DM), accompanied by increased glucagon-like peptide-1 (GLP-1). We performed the experiment on diabetic rats to evaluate the effects and mechanisms of ileal transposition on the glycemic metabolism.
Methods
Twenty Goto-Kakizaki (GK) rats were ran...
Citations
... The involvement of this particular pathway is of paramount importance in the regulation of cell metabolism, protein synthesis, and autophagy. Additionally, it exhibits intricate interactions with vital signaling molecules like GSK-3 (Glycogen Synthase Kinase-3), FOXO (Forkhead Box O), and PTEN (Phosphatase and Tensin Homolog), thereby exerting significant effects on a wide array of cellular processes, such as cell differentiation, migration, and apoptosis (27,28). The activation of the MAPK cascade involving cJNK, p38, and ERK1/2 can have context-dependent effects on proliferation and apoptosis. ...
Obesity, a complex and multifactorial disease influenced by genetic, environmental, and psychological factors, has reached epidemic proportions globally, posing a significant health challenge. In addition to its established association with cardiovascular disease and type II diabetes, obesity has been implicated as a risk factor for various cancers. However, the precise biological mechanisms linking obesity and cancer remain largely understood. Adipose tissue, an active endocrine organ, produces numerous hormones and bioactive molecules known as adipokines, which play a crucial role in metabolism, immune responses, and systemic inflammation. Notably, adiponectin (APN), the principal adipocyte secretory protein, exhibits reduced expression levels in obesity. In this scoping review, we explore and discuss the role of APN in influencing cancer in common malignancies, including lung, breast, colorectal, prostate, gastric, and endometrial cancers. Our review aims to emphasize the critical significance of investigating this field, as it holds great potential for the development of innovative treatment strategies that specifically target obesity-related malignancies. Furthermore, the implementation of more rigorous and comprehensive prevention and treatment policies for obesity is imperative in order to effectively mitigate the risk of associated diseases, such as cancer.
... This event was associated with a decrease in leptin along with an increase in adiponectin. A study by Mu et al. revealed that the latter is a direct effect of an increase in Sirt1/Foxo-1 signaling downstream GLP-1 receptor in adipose tissues, irrespective of a high-fat diet [176]. Interestingly, a similar increase in the phosphorylation of β-catenin and TCF7L2 was noticed upon in vitro treatment of stromal vascular fraction of mice epididymal fat tissues with liraglutide. ...
Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.
... indicated that DAF-16 played a pivotal role in alleviating Aβ (1-42) toxicity when Exendin-4 exerted its neuroprotective effects. It has been reported that Exendin-4 upregulated FoxO 1 expression both in vitro and in vivo (Wang et al., 2017), or regulated the phosphorylation of FoxO 1 in cardiomyocytes (Eid et al., 2021). So our results about the important roles of DAF-16 in mediating the function of exendin-4 are consistent with previous studies. ...
Epidemiological analyses indicate that type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD). They share common pathophysiological mechanisms. Thus, it has been increasingly suggested that several anti-T2DM drugs may have therapeutic potential in AD. Exendin-4, as a glucagon-like peptide-1 (GLP-1) receptor agonist, is an approved drug used to treat T2DM. In this research, the neuroprotective effect of Exendin-4 was investigated for the first time using transgenic Caenorhabditis elegans. Our results demonstrated that Exendin-4 attenuated the amyloid-β (1-42) (Aβ1-42) toxicity via multiple mechanisms, such as depressing its expression on protein and mRNA and reducing Aβ (1-42) accumulation. Exendin-4 at 0.5 mg/ml had been shown to extend life by 34.39% in CL4176 and delay the onset of paralysis in CL4176 and CL2006 which were increased by 8.18 and 8.02%, respectively. With the treatment of Exendin-4, the nuclear translocation of DAF-16 in the transgenic nematode TJ356 was enhanced. Superoxide dismutase-3 (SOD-3), as a downstream target gene regulated by DAF-16, was upregulated on mRNA level and activity. The reactive oxygen species (ROS) level was decreased. In contrast, we observed that the ability of Exendin-4 to regulate SOD was decreased in CL4176 worms with the DAF-16 gene silenced. The activity of SOD and the mRNA level of sod-3 were downregulated by 30.45 and 43.13%, respectively. Taken together, Exendin-4 attenuated Aβ (1-42) toxicity in the C. elegans model of AD via decreasing the expression and the accumulation of Aβ (1-42). Exendin-4 exhibited the ability of antioxidant stress through DAF-16. With continuous research, Exendin-4 would become a potential therapeutic strategy for treating AD.
... It was also observed that exendin-4 can increase the production and secretion of adiponectin in a culture medium of 3T3-L1 adipocytes and in high-fat diet-fed mice, which was seen as an increased level of adiponectin mRNA [103]. The protein kinase A (PKA) and Sirt1/Foxo-1 signaling pathways are involved in the effect of exendin-4 on adiponectin secretion in adipocytes [103,104]. Adiponectin has anti-inflammatory and insulin-sensitizing properties [40]. ...
Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.
... This is evidenced by the finding that the key GLP-1 degradation enzyme, DPP-4, is also inhibited by PGG in a dose-dependent manner, as shown in the Supplementary data ( Figure S2). Restoration of GLP-1 levels would have several downstream effects, including the stimulation of insulin secretion (in a glucose-dependent manner), preservation of beta-cell function, expression and release of insulin-sensitizing adipokines, (e.g., adiponectin), and improved appetite control [32][33][34]. Therefore, restoration of gut health and an increase in incretin hormone levels due to PGG treatment may also play a role in maintaining glucose homeostasis in DIO mice. ...
Phytochemicals that interrupt adipocyte lifecycle can provide anti-obesity effects. 1,2,3,4,6-penta-O-galloyl-d-glucose (PGG) is a tannin with two isomers that occurs widely in plants and exhibits various pharmacological activities. The aim of the investigation is to comprehensively examine effects of PGG isomer(s) on adipocyte lifecycle and diet-induced obesity. Human mesenchymal stem cells (hMSC), 3T3-L1 fibroblasts, and H4IIE hepatoma cells were used to determine the effects of PGG isomers on cell viability and adipogenesis. Mice with diet-induced obesity were generated from male C57/BL6 mice fed with a 45% high fat diet. Oral administration of β-PGG (0.1 and 5 mg/kg) lasted for 14 weeks. Viability was reduced by repeated PGG treatment in hMSC, preadipocytes, and cells under differentiation. PGG mainly induces apoptosis, and this effect is independent of its insulin mimetic action. In vivo, administration of β-PGG attenuated shortening of the colon, hyperlipidaemia, fat cells and islet hypertrophy in DIO mice. Hepatic steatosis and related gene expression were improved along with glucose intolerance. Increased serum adiponectin, leptin, and glucagon-like peptide-1 levels were also observed. In conclusion, repeated PGG treatment interrupts the adipocyte lifecycle. PGG administration reduces adiposity and fatty liver development in DIO mice, and therefore, PGG could aid in clinical management of obesity.
... A complex of FOXO1 and C/enhancer-binding protein a forms on the promoter of the adiponectin gene to drive its transcription; deacetylation of FOXO1 by Sirt1 is required for formation of this nuclear complex. [56][57][58] ENHANCED SIRT1 ACTIVITY MAY EXPLAIN SOME BENEFITS OF COQ10 SUPPLEMENTATION The implications of cellular CoQ10 deficiency can thus extend far beyond ATP deficit and increased mitochondrial ROS generation. The clinical consequence will hinge on the specific types of cells in which CoQ10 is deficient. ...
For reasons that remain unclear, endogenous synthesis and tissue levels of coenzyme Q10 (CoQ10) tend to decline with increasing age in at least some tissues. When CoQ10 levels are sufficiently low, this compromises the efficiency of the mitochondrial electron transport chain, such that production of superoxide by site 2 increases and the rate of adenosine triphosphate production declines. Moreover, CoQ10 deficiency can be expected to decrease activities of Sirt1 and Sirt3 deacetylases, believed to be key determinants of health span. Reduction of the cytoplasmic and mitochondrial NAD ⁺ /NADH ratio consequent to CoQ10 deficit can be expected to decrease the activity of these deacetylases by lessening availability of their obligate substrate NAD ⁺ . The increased oxidant production induced by CoQ10 deficiency can decrease the stability of Sirt1 protein by complementary mechanisms. And CoQ10 deficiency has also been found to lower mRNA expression of Sirt1. An analysis of the roles of Sirt1/Sirt3 in modulation of cellular function helps to rationalise clinical benefits of CoQ10 supplementation reported in heart failure, hypertension, non-alcoholic fatty liver disease, metabolic syndrome and periodontal disease. Hence, correction of CoQ10 deficiency joins a growing list of measures that have potential for amplifying health protective Sirt1/Sirt3 activities.
... [70][71][72] Furthermore, whilst GLP-1R agonists seem to exert direct anti-inflammatory actions on adipocytes resulting in adipose tissue remodelling in mice and promoting adiponectin upregulation in cultured adipocytes, it is still not known whether GLP-1 analogues exert vasoregulatory actions through modifying this cross-talk between PVAT and the vascular wall. [73][74][75] Thus, whilst further work is conducted into understanding the effects of insulin-sensitising agents on PVAT biology, the ability to non-invasively identify pro-atherogenic changes in PVAT is of critical importance in order to proactively identify patients at high-risk of atherosclerosis. ...
... This type of diet significantly decreased serum adiponectin as well as adiponectin mRNA and protein expression in adipose tissue, and the use of exendin-4 was able to prevent the decreased expression of adiponectin mRNA and protein (although a normal serum adiponectin concentration was not recovered). Changes in SIRT1 and Foxo1 expression were parallel with the changes observed for adiponectin: SIRT1 and Foxo1 were suppressed on a high-fat diet, and this effect was prevented by treatment with exendin-4 [109]. ...
The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.
... 270 A recent study found that exenatide increased adiponectin secretion from adipose tissue in both in vivo and in vitro studies. 271 Adiponectin is a peripheral tissue insulin sensitizer, and its levels are known to decrease in obese and T2D patients. 272 This study demonstrated that modulating GLP-1R activity has the potential to improve both insulin secretion and action in T2D and that GLP-1 analogues may also be able to induce weight loss by augmenting adiponectin secretion, as well as inducing satiety. ...
Type 2 diabetes (T2D), which has currently become a global pandemic, is a metabolic disease largely characterised by impaired insulin secretion and action. Significant progress has been made in understanding T2D aetiology and pathogenesis, which is discussed in this review. Extrapancreatic pathology is also summarised, which demonstrates the highly multifactorial nature of T2D. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics with a much longer half-life have been developed, which are currently an effective treatment option for T2D by enhancing insulin secretion in patients. Interestingly, there is continual emerging evidence that these therapies alleviate some of the post-diagnosis complications of T2D. Additionally, these therapies have been shown to induce weight loss in patients, suggesting they could be an alternative to bariatric surgery, a procedure associated with numerous complications. Current GLP-1-based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites to test their therapeutic potential. Recent studies have also demonstrated the potential of bi- and tri-agonists, which target multiple hormonal receptors including GLP-1R, to more effectively treat T2D. Improved understanding of T2D aetiology/pathogenesis, coupled with the further elucidation of both GLP-1 activity/targets and GLP-1R mechanisms of activation via different agonists, will likely provide better insight into the therapeutic potential of GLP-1-based therapies to treat T2D.
... Furthermore, adiponectin plays a crucial role in improving insulin sensitivity in adipose tissues, the liver and muscles, and exerts antidiabetic functions (67,68). GLP-1 agonist exendin-4 induces adiponectin expression (69). However, suppression of Foxo-1 impairs the effect of exendin-4 on the adiponectin expression in 3T3-L1 adipocytes (69). ...
... GLP-1 agonist exendin-4 induces adiponectin expression (69). However, suppression of Foxo-1 impairs the effect of exendin-4 on the adiponectin expression in 3T3-L1 adipocytes (69). Overexpression of mutant FoxO1 in brown adipose tissues increases the number of brown adipocytes and the expression of the uncoupling protein 1 (UCP1) gene in T37i cells (18). ...
Type 2 diabetes mellitus (T2DM) is a major chronic disease that is characterized by pancreatic β-cell dysfunction and insulin resistance. Autophagy is a highly conserved intracellular recycling pathway and is involved in regulating intracellular homeostasis. Transcription factor Forkhead box O1 (FoxO1) also regulates fundamental cellular processes, including cell differentiation, metabolism and apoptosis, and proliferation to cellular stress. Increasing evidence suggest that autophagy and FoxO1 are involved in the pathogenesis of T2DM, including β-cell viability, apoptosis, insulin secretion and peripheral insulin resistance. Recent studies have demonstrated that FoxO1 improves insulin resistance by regulating target tissue autophagy. The present review summarizes current literature on the role of autophagy and FoxO1 in T2DM. The participation of FoxO1 in the development and occurrence of T2DM via autophagy is also discussed.
