Glucagon-like Peptide-1 Signaling Pathway Research Articles

#411 Magnesium deficiency abrogates the activation of Insulin-like growth factor-1 signaling pathway in the kidney induced by DPP4 inhibitor

Abstract Background and Aims Dipeptidyl peptidase-4 (DPP-4) inhibitor could attenuate cisplatin nephrotoxicity dependent on the glucagon-like peptide-1 (GLP-1) signaling pathway [1]. We had previously reported that the use of a DPP-4 inhibitor might also attenuate cisplatin nephrotoxicity in diabetic cancer patients [2], and its renoprotective effect was lost under magnesium (Mg) deficiency [3]. However, it remains to be investigated how the GLP-1 signaling pathway changes after the treatment of a DPP-4 inhibitor under Mg deficiency. The purpose of this study was to examine the changes in the downstream pathway of the GLP-1 signaling pathway after the treatment of DPP-4 inhibitor under Mg deficiency. Method Sprague Dawley rats received a Mg-deficient diet for 7 days to induce Mg deficiency (low Mg group). Control diet was given to the normal Mg group. Oral administration of a DPP-4 inhibitor was injected 1 day before sacrifice. The changes in serum active GLP-1, insulin, insulin-like growth factor (IGF-1), and the expression of their receptor in the kidney were examined. In addition, the phosphorylation of insulin/IGF-1 receptors in the kidney were investigated. Results Serum active GLP-1 increased equally in both groups with DPP-4 inhibitor administration. Renal GLP-1 receptor expression was not observed in the renal tubules. Serum IGF-1 did not change with DPP-4 inhibitor administration in the normal Mg group but increased in the low Mg group. In normal Mg group, renal IGF-1 receptor expression tended to increase with DPP-4 inhibitor administration, and its phosphorylation increased significantly. In contrast, the expression and phosphorylation of the IGF-1 receptor did not change with DPP-4 inhibitor administration in the low Mg group. The increase in serum insulin with the DPP-4 inhibitor was enhanced in the low Mg group, compared to the normal Mg group. The expression and phosphorylation of the insulin receptor did not change with DPP-4 inhibitor administration in both groups. Conclusion DPP-4 inhibitor activated the renal IGF-1 signaling pathway, but this effect disappeared under Mg deficiency. Further investigation is needed to determine whether the renal protective effect of DPP-4 inhibitor is dependent on the IGF-1 signaling pathway.

Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer's disease.

Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.

High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling

An increased vulnerability has been detected after ischemia/reperfusion injury in cardiomyocytes in diabetic patients. Glucagon-like peptide-1 (GLP-1) has been proven to have a notable cardioprotective effect in cardiomyocytes. However, in diabetic patients, the cardioprotective effects of GLP-1 are compromised, which is called GLP-1 resistance. β-arrestin is one of the two main downstream effectors of GLP-1 and β-arrestin signaling pathway exerts cardioprotective effects upon activation of GLP-1R. Our hypothesis is that the increased vulnerability of cardiomyocytes in diabetic patients is partly due to disruption of the β-arrestin signaling pathway. To test this, we analyzed cardiomyocyte viability and survival in high glucose and normal glucose condition after hypoxia/reoxygenation injury in vitro, additional GLP-1 was used to determine whether β-arrestin signaling pathway was involved. We also investigated the role of mitochondrial dysfunction in GLP-1 resistance. Our results showed that cardioprotective effects of GLP-1 were reduced in high glucose cultured H9C2 cells compared to normal glucose cultured H9C2, verifying the existence of GLP-1 resistance in high glucose cultured H9C2 cells. Further study suggested that β-arrestin plays a key role in GLP-1 resistance: β-arrestin expression is notably downregulated in high glucose condition and cardioprotective effects of GLP-1 can be diminished by downregulation of β-arrestin in normal glucose condition while upregulation of β-arrestin can restore cardioprotective effects of GLP-1 in high glucose condition. Then we explore how β-arrestin affects the cardioprotective effects of GLP-1 and found that β-arrestin exerts cardioprotective effects by improving mitochondria quality control via the PI3K/Akt signaling pathway. Thus, our study found out a new mechanism of GLP-1 resistance of cardiomyocytes in high glucose conditions that impaired β-arrestin expression, caused mitochondria dysfunction and eventually cell death. Our study provided a new perspective in treating myocardial ischemia/reperfusion injury in diabetic patients.

Dysregulated Metabolism in the Pathophysiology of Non-Allergic Obese Asthma.

Asthma is an obstructive airway disease that is characterized by reversible airway obstruction and is classically associated with atopic, TH2 driven inflammation. Landmark studies in the second half of the twentieth century identified eosinophils as a key mediator of inflammation and steroids, both inhaled and systemic, as a cornerstone of therapy. However, more recently other phenotypes of asthma have emerged that do not respond as well to traditional therapies. In particular, obese patients who develop asthma as adults are less likely to have eosinophilic airway inflammation and do not respond to traditional therapies. Obese patients often have metabolic comorbidities such as impaired glucose tolerance and dyslipidemias, also known as metabolic syndrome (MetS). The unified pathophysiology of metabolic syndrome is not known, however, several signaling pathways, such as the neuropeptide glucagon-like peptide-1 (GLP-1) and nitric oxide (NO) signaling have been shown to be dysregulated in MetS. These pathways are targeted by commercially available medications. This review discusses the potential roles that dysregulation of the GLP-1 and NO signaling pathways, along with arginine metabolism, play in the development of asthma in obese patients. GLP-1 receptors are found in high density in the lung and are also detectable in bronchoalveolar lavage fluid. NO has long been associated with asthma. We hypothesize that these derangements in metabolic signaling pathways underpin the asthmatic phenotype seen in obese patients with non-eosinophilic airway inflammation and poor response to established therapies. While still an active area of research, novel interventions are needed for this subset of patient who respond poorly to available asthma therapies.

DPP-4 inhibitor improves learning and memory deficits and AD-like neurodegeneration by modulating the GLP-1 signaling

Glucagon-like peptide-1 (GLP-1) signaling in the brain plays an important role in the regulation of glucose metabolism, which is impaired in Alzheimer's disease (AD). Here, we detected the GLP-1 and GLP-1 receptor (GLP-1R) in AD human brain and APP/PS1/Tau transgenic (3xTg) mice brain, finding that they were both decreased in AD human and mice brain. Enhanced GLP-1 exerts its protective effects on AD, however, this is rapidly degraded into inactivated metabolites by dipeptidyl peptidase-4 (DPP-4), resulting in its extremely short half-time. DPP-4 inhibitors, thus, was applied to improve the level of GLP-1 and GLP-1R expression in the hippocampus and cortex of AD mice brains. It is also protected learning and memory and synaptic proteins, increased the O-Glycosylation and decreased abnormal phosphorylation of tau and neurofilaments (NFs), degraded intercellular β-amyloid (Aβ) accumulation and alleviated neurodegeneration related to GLP-1 signaling pathway.

Beneficial Effects of GLP-1 Agonist in a Male With Compulsive Food-Related Behavior Associated With Autism

Individuals with autism spectrum disorder (ASD) frequently display intensely repetitive, restricted thoughts, and behaviors. These behaviors have similarities to compulsions and/or obsessions in obsessive compulsive disorder (OCD) and are primarily treated with behaviourally-based interventions and serotonin uptake inhibitors (SSRIs). Due to the lack of treatment responses in many cases, however, new treatments are being sought. Here we report beneficial effects of treatment with liraglutide, a glucagon-like peptide-1 (GLP-1) analog, on severe obsessive food craving, binge eating, weight gain, and behavioral problems in an adolescent male with infantile autism and moderate intellectual impairment. Liraglutide treatment reduced weight and unwanted behavior seemingly by preventing food-related repetitive thoughts and compulsions. Our report provides clinical evidence that GLP-1 signaling pathway may represent a novel target for treating food-related behavioral problems and aggressive behavior in ASD.

The effects of a GLP-1 analog liraglutide on reward value and the learned inhibition of appetitive behavior in male and female rats.

Liraglutide, a relatively long-lasting analogue of glucagon-like peptide-1 (GLP-1), has received recent attention as a treatment for obesity. It has been proposed that activation of GLP-1 receptors in mesolimbic reward pathways contributes to this outcome by reducing hedonic value of food. However, other findings suggest that activation of GLP-1 signaling pathways may suppress appetitive behavior by enhancing a hippocampal-dependent form of learned inhibition. The present experiment compares these two alternatives. Rats first solved a hippocampal-dependent discrimination problem in which a target stimulus signaled the delivery of sucrose, except when it was preceded by an inhibitory cue that signaled nonreward. The effects of 12 daily intraperitoneal (i.p.) injections of liraglutide on responding to the target cue was then compared with and without the inhibitory stimulus. Relative to saline, liraglutide suppressed responding to the target cue only on trials when the inhibitory stimulus was also present (p<.05). This outcome was independent of sex and maintenance diet (Western diet or standard chow). The failure of liraglutide to suppress responding in the absence of the inhibitory cue argues against the notion that this GLP-1 agonist reduced the value of food reward and favors the idea that it enhanced a hippocampal-dependent form of behavioral inhibition.

A new mechanism of central sensitization underlying pain--the role of incretin hormones signaling

Background Central sensitization is a main mechanism underlying pain. Incretin is confined to mediate insulinmimetic effects, but recent study indicates that incretin may affect the central sensitization of pain. Objective This article reviews the studies about the effects of incretin on central sensitization of spinal cord in pain. Content This review summarized physiological characters and receptor localization of incretin. Glucagon like peptide-1 (GLP-1) and its receptor, glucose-dependent insulinotropic polypeptide (GIP) and its receptor influence the neuronal plasticity and the central sensitization of pain. The cross-talk between GLP-1 and GIP signaling pathway is a potential mechanism of the central sensitization underlying pain. Trend Central sensitization underlying pain can be induced by incretin signaling system and their cross-talk is an important and novel concept. Key words: Glucose-dependent insulinotropic polypeptide; Glucagon like peptide-1; Pain; Neural plasticity

Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function.

Studies in animal models of type 2 diabetes have shown that glucagon-like peptide 1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown. In this study, we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5 mmol/L palmitate and 25 mmol/L glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilization and release of cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Cotreatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. Small interfering RNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4. Collectively, our data highlight lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy/lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signaling pathway as a potential focus.

Dipeptidyl Peptidase IV Inhibitor Protects Against Tacrolimus-Induced Pancreatic and Renal Injury.

Background: Dipeptidyl peptidase IV (DPP IV) inhibitors had a protective effect in various disease models. This study was performed to evaluate whether sitagliptin, a DPP IV inhibitor, is effective against tacrolimus-induced pancreatic and renal injury. Method: Tacrolimus (TAC, 1.5mg/kg/day, s.c.) with or without sitagliptin (10, 20 mg/kg/day, gavage) were administered to rats for 4 weeks. We evaluated the effect of sitagliptin on DPP IV activity and GLP-1 level in tacrolimus-treated rats, and assessed the protective effect of sitagliptin in an experimental model of chronic tacrolimus-induced nephropathy and pancreatic injury. Oxidative stress and oxidative resistance were evaluated by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG) and heme oxygenase-1 (HO-1). The protective mechanism of sitagliptin was also tested based on the glucagon like peptide-1 (GLP-1)/ (forkhead box O) FoxO pathway. Results: Tacrolimus treatment for 4 weeks caused a 2-fold increase in plasma DPP4 activity and a 5-fold decrease in serum active GLP-1 levels; however, concomitant treatment with sitagliptin reversed these effects. Sitagliptin treatment attenuated tacrolimus-induced pancreatic islet and renal dysfunction, with improvement of islet size and renal tubulointerstitial fibrosis. Tacrolimus treatment increased oxidative stress marker, 8-OHdG and decreased oxidative resistance gene (reduced HO-1), and its underlying pathways (FoxO1 activation and FoxO3 deactivation), whereas sitagliptin treatment reversed these changes. Treatment of primary rat islet and HK-2 cells with GLP-1 also decreased the oxidative injury caused by tacrolimus. Consequently, sitagliptin upregulated antioxidant enzymes e.g. manganese superoxide dismutase, and downregulated proapoptotic proteins e.g. B-cell lymphoma 2-interacting mediator of cell death and apoptotic cell death assessed by the number of TDT-mediated dUTP-biotin nick end labeling-positive cells. Conclusion:DPP IV inhibition by sitagliptin attenuated TAC-induced pancreatic islet and renal dysfunction and enhanced the GLP-1 signaling pathway, which may be associated with a decrease in oxidative injury and apoptotic cell death. These beneficial effects of the DPP IV inhibitor may be helpful in delaying the onset of TAC-induced diabetes and nephropathy in renal transplant patients.

Distribution of glucagon-like peptide 1-immunopositive neurons in human caudal medulla

In rodents, glucagon-like peptide-1 (GLP-1)-positive neurons within the caudal medulla respond to a broad array of interoceptive signals that suppress food intake and drive the hypothalamic-pituitary-adrenal stress axis. The collective results of experiments utilizing cFos to identify activated neurons in rats and mice indicate that GLP-1 neurons are consistently activated by stimuli that present actual or anticipated threats to bodily homeostasis. The distribution of GLP-1-positive neurons in the human brain is unreported. The present study identified GLP-1-positive neurons and mapped their distribution within the caudal medulla in two adult human subjects (one female, one male). The goal of the study was to obtain structural evidence with which to challenge the general hypothesis that functions ascribed to GLP-1 neurons in rodent species may reflect parallel functions that exist in humans. In both human subjects, GLP-1-immunopositive neurons were located within the dorsal medullary region containing the caudal (visceral) nucleus of the solitary tract and in the nearby medullary reticular formation, similar to the distribution of GLP-1 neurons in rats, mice, and Old World monkeys. Quantitative analysis indicates the presence of approximately 6.5-9.3K GLP-1-positive neurons bilaterally within the human caudal medulla. It will be important in future studies to map the distribution of GLP-1-positive fibers and terminals within higher regions of the human brain, to improve our understanding of how central GLP-1 signaling pathways might influence stress responsiveness, energy balance, and other physiological and behavioral functions.

Role of the Glucagon-like Peptide-1 Receptor Agonist in Maintaining Pluripotency in Human Embryonic Stem Cells

Previous studies have demonstrated that glucagon-like peptide-1 (GLP-1) stimulates β-cell formation and insulin secretion. Currently, there has been no report in understanding the effect of GLP-1 / its agonist exendin-4 in differentiation of human embryonic stem cells (hESCs) to definitive endodermal (DE). We hypothesized that exendin-4 signaling in hESCs via GLP-1 receptor (GLP-1R) may have potential role in DE differentiation. The effect of Ex-4 on pluripotent hESCs and the combined effect of Ex-4 and activin A-treated hESC-derived DE were examined. Analysis by quantitative real-time PCR (qPCR) demonstrates that Ex-4 alone was not sufficient to enhance DE formation in hESCs. On the other hand, a combinatorial treatment with activin A and Ex-4 resulted in significant decrease in expression levels of DE markers. The miRNA expression profiles between activin A-treated hESCs and activin A/Ex-4-treated hESCs after 5 days of treatment demonstrated similar expression levels of endoderm and pancreas-associated miRNAs. However, it was shown that the levels of pluripotency-associated miRNAs, miR-302a* and miR302c*, were upregulated in the presence of Ex-4. Furthermore, it was observed that exposure to bFGF and Ex-4 in apoptosis-inducing medium resulted in downregulation of CASP3 and p53. Taken together, these data revealed the possibility of Ex-4 in maintaining pluripotency and inhibiting apoptosis. The knowledge of GLP-1 signaling pathways could be useful for understanding the mechanism of GLP-1R-ligand interactions and their relevance to hESC development.

Glucagon-like peptide 1 (GLP-1) and metabolic diseases

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, mainly secreted after meals, which enhances glucose-induced insulin secretion and induces satiety. It has been reported that GLP-1 levels after a mixed meal and after an oral glucose load are reduced in patients with Type 2 diabetes. The reduction of oral glucose-stimulated active GLP-1 levels in patients with Type 2 diabetes has also been observed during euglycemic iperinsulinemic clamp. The reduction of post-prandial circulating active GLP-1 in Type 2 diabetic subjects, as a consequence of chronic hyperglycemia, could contribute to the reduction of early post-prandial insulin secretion; in fact, the administration of GLP-1 receptor antagonists to healthy volunteers elicits both an impairment of meal-induced insulin secretion and an increase of post-prandial glycemia similar to that observed in Type 2 diabetes. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), an enzyme produced by endothelial cells in different districts and that circulates in plasma. It is still not clear whether the reduction of mealor oral-glucose stimulated GLP-1 levels in Type 2 diabetic patients is due to impairment of secretion, increase of degradation, or both. The major limitation of using GLP-1 to treat diabetic patients is the short half-life of the native compound. There are now several compounds in various stages of pre-clinical or clinical development for the treatment of Type 2 diabetes that utilize the GLP-1 signaling pathway; these include GLP-1 receptor agonists with extended half-lives, and inhibitors of DPP-IV that increase circulating levels of endogenous, intact and bioactive GLP-1.

Distinct Effects of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 on Insulin Secretion and Gut Motility

Glucose-induced insulin secretion from pancreatic beta-cells depends critically on ATP-sensitive K(+) channel (K(ATP) channel) activity, but it is not known whether K(ATP) channels are involved in the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP). In mice lacking K(ATP) channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2(-/-) mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that K(ATP) channels are essential in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2(-/-) mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1. Although both GIP and GLP-1 increase the intracellular cAMP concentration and potentiate insulin secretion, these results demonstrate that the GLP-1 and GIP signaling pathways involve the K(ATP) channel differently.

Exendin-4, a GLP-1 Receptor Agonist, Interacts with Proteins and Their Products of Digestion to Suppress Food Intake in Rats

This study investigated the hypotheses that dietary proteins suppress food intake partly through the glucagon-like peptide-1 (GLP-1) signaling pathway, and that this effect is mediated by products of protein digestion. The GLP-1 receptor agonist, Exendin-4 (Ex-4) (0.5 micro g/rat), was given intraperitoneally to male Wistar rats, and food intake was measured when Ex-4 was given alone or with preloads of intact whey and casein proteins, their hydrolysates and amino acid mixtures (0.5 g x 4 mL(-1) x rat(-1)). Both Ex-4 and the preloads suppressed food intake (P < 0.05), but the effect of Ex-4 on food intake was reduced when coadministered with the preloads (P < 0.05). Because the effect of Ex-4 was reduced by the protein hydrolysates and by the amino acid preloads, the results support a role for the end products of protein digestion and GLP-1 release in the suppression of food intake in response to protein ingestion. We concluded that the GLP-1 signaling pathway, activated by the release of products of protein digestion, is another mechanism accounting for the reduction of food intake after protein ingestion.