Effects Of Glucagon-like Peptide-1 Research Articles

Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor.

Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP‐1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP‐1 and receptor agonists, and the GLP‐1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP‐1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP‐1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP‐1 receptor‐dependent versus independent effects secondary of GLP‐1 metabolites. We conclude that the favourable cardiovascular profile of GLP‐1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non‐diabetic populations.LINKED ARTICLESThis article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc

Efficient Restoration of Beta Cell Dedifferentiation by Calorie Restriction With High Fat/Low Carbohydrate Diet in Obese Diabetes Model and the Possible Role of GLP-1

In type 2 diabetes, pancreatic beta cells are gradually ‘exhausted’ and fall into beta cell dysfunction, which proceeds more severe insulin dependence. Among the proposed mechanisms of beta cell dysfunction such as endoplasmic reticulum stress and oxidative stress, the beta cell heterogeneity has attracted the researcher’s interest recently. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetic mice model, and nowadays it is considered as one form of the beta cell heterogeneity and is observed broadly among diabetic animal models and human patients. Previously we showed that food restriction had the best effect to restore beta cell gene expression in obese diabetic model mice, among the known diabetic treatments which we tested. In the current study, we aimed to unveil the molecular basis in the improvement of beta cell dedifferentiation during the calorie restriction. First, we utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet, to determine whether fat restriction or sugar restriction reduces the beta cell dedifferentiation in obese mice. When calorie intake was restricted evenly, both HF diet and HC diet decreased the body weight and hyperglycemia in db/db mice equally. Albeit the same metabolic profile, db/db group fed with HC diet had more enlarged islets and more dedifferentiated beta cell features than db/dbs fed with HF diet, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. It is speculated that the insulin resistance in liver might impact on the beta cell dedifferentiation. Next, we analyzed the effect of glucagon-like peptide 1 (GLP-1) on beta cell dedifferentiation, since GLP-1 is secreted more from intestine by protein and fat intake, rather than by sugar intake. Also, increasing number of reports have suggested the improving effect of GLP-1 on beta cell dysfunction and fatty liver. Indeed, GLP-1 administration altered the reduced beta cell/alpha cell ratio in db/db mice, which indicated the restoration of beta cell heterogeneity. We are now investigating if GLP-1 administration reimburse the beta cell dedifferentiation in db/db mice fed with HC diet, to illuminate the role of incretins in beta cell dedifferentiation induced by unbalanced nutrition during diet. Also, we will present the RNA sequencing data of the liver in db/db mice fed with HF and HC diet, to elucidate the key molecules and genes which connect the beta cell function and metabolic state in liver.

GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer’s disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway

The glucagon-like peptide-1 (GLP-1) was shown to have neuroprotective effects in Alzheimer’s disease (AD). However, the underlying mechanism remains elusive. Astrocytic mitochondrial abnormalities have been revealed to constitute important pathologies. In the present study, we investigated the role of astrocytic mitochondria in the neuroprotective effect of GLP-1 in AD. To this end, 6-month-old 5 × FAD mice were subcutaneously treated with liraglutide, a GLP-1 analogue (25 nmol/kg/qd) for 8 weeks. Liraglutide ameliorated mitochondrial dysfunction and prevented neuronal loss with activation of the cyclic adenosine 3′,5′-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway in the brain of 5 × FAD mice. Next, we exposed astrocytes to β-amyloid (Aβ) in vitro and treated them with GLP-1. By activating the cAMP/PKA pathway, GLP-1 increased the phosphorylation of DRP-1 at the s637 site and mitigated mitochondrial fragmentation in Aβ-treated astrocytes. GLP-1 further improved the Aβ-induced energy failure, mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (MMP) collapse, and cell toxicity in astrocytes. Moreover, GLP-1 also promoted the neuronal supportive ability of Aβ-treated astrocytes via the cAMP/PKA pathway. This study revealed a new mechanism behind the neuroprotective effect of GLP-1 in AD.

Emerging Role of Caveolin-1 in GLP-1 Action.

Glucagon-like peptide-1 (GLP-1) is a gut hormone mainly produced in the intestinal epithelial endocrine L cells, involved in maintaining glucose homeostasis. The use of GLP-1 analogous and dipeptidyl peptidase-IV (DPP-IV) inhibitors is well-established in Type 2 Diabetes. The efficacy of these therapies is related to the activation of GLP-1 receptor (GLP-1R), which is widely expressed in several tissues. Therefore, GLP-1 is of great clinical interest not only for its actions at the level of the beta cells, but also for the extra-pancreatic effects. Activation of GLP-1R results in intracellular signaling that is regulated by availability of downstream molecules and receptor internalization. It has been shown that GLP-1R co-localizes with caveolin-1, the main component of caveolae, small invagination of the plasma membrane, which are involved in controlling receptor activity by assembling signaling complexes and regulating receptor trafficking. The aim of this review is to outline the important role of caveolin-1 in mediating biological effects of GLP-1 and its analogous.

GLP-1 reduces the migration of hepatocellular carcinoma cells via suppression of the stress-activated protein kinase/c-Jun N-terminal kinase pathway

Incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are hormones secreted from small intestine accompanied with oral intake. We previously showed that transforming growth factor (TGF)-α stimulates the migration of hepatocellular carcinoma (HCC) cells via mitogen-activated protein (MAP) kinases, AKT and Rho-kinase. However, it remains to be elucidated whether incretins affect HCC cell functions. In the present study, therefore, we investigated whether incretins affect the migration of HCC cells using human HCC-derived HuH7 cells. GLP-1, but not GIP, reduced both TGF-α- and hepatocyte growth factor (HGF)-induced cell migration. IBMX, an inhibitor of cyclic nucleotide phosphodiesterase, enhanced the suppressive effect of GLP-1. GLP-1 attenuated the phosphorylation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) by TGF-α and HGF. Our results strongly suggest that GLP-1 suppresses TGF-α- and HGF-induced migration of HCC cells through inhibiting the SAPK/JNK signaling pathway, and that the inhibition by GLP-1 is due to cAMP production.

Glucagonostatic Potency of GLP-1 in Patients With Type 2 Diabetes, Patients With Type 1 Diabetes, and Healthy Control Subjects.

Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide-negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.

Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway.

Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis, can be prevalent in patients with type 2 diabetes mellitus (T2DM). However, no antidiabetic drug has been approved for the treatment of NAFLD in T2DM patients. Multiple daily injections of basal-bolus insulin are often the final therapeutic option for T2DM. We found that insulin treatment aggravated hepatic steatosis and oxidative stress in Zucker diabetic fatty (ZDF) rats. In addition to glycaemic control, we demonstrated the stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate insulin-aggravated hepatic fatty accumulation. The glucagon-like peptide-1 (GLP-1) agonists liraglutide and Ex-4 activated the expression of peroxisome proliferator-activated receptor alpha (PPARα) via a GLP-1 receptor-dependent 5′ AMP-activated protein kinase pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis by differentially regulating the expression of its target genes, including acetyl CoA carboxylase and carnitine palmitoyl transferase la both in vitro and in vivo. Moreover, GLP-1 could relieve liver injury by decreasing oxidative stress stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury by inhibiting GLP-1R expression. The findings indicate the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats. This knowledge, and the evidence for the underlying mechanism, provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM.

The effects of glucagon like peptide-1 (GLP-1) on cardiac remodeling: exploring the role of medication and physiological modulation after metabolic surgery.

Obesity and associated comorbidities reach epidemic proportions nowadays. Several treatment strategies exist, but bariatric surgery has the only longstanding effects. Since a few years, there is increasing interest in the effects of gastro-intestinal hormones, in particular Glucagon-Like Peptide-1 (GLP-1) on the remission of Type 2 Diabetes (T2DM) and its effects on cardiac cardiovascular morbidity, cardiac remodeling, and mortality. In the past years several high quality multicenter randomized controlled trials were developed to assess the effects of GLP-1 receptor agonist therapy on cardiovascular morbidity and mortality. Most of the trials were designed and powered as non-inferiority trials to demonstrate cardiovascular safety. Most of these trials show a reduction in cardiovascular morbidity in patients with T2DM. Some follow-up studies indicate potential beneficial effects of GLP-1 receptor agonists on cardiovascular function in patients with heart failure, however the results are contradictory, and we need long-term studies to make firm conclusions about the pleiotropic properties of incretin-based therapies. However, it seems that GLP-1 receptor agonists have different effects than the increased GLP-1 production after bariatric surgery on cardiovascular remodeling. One of the hypotheses is that the blood concentrations of GLP-1 receptor agonists are three times higher compared to GLP-1 increase after bariatric and metabolic surgery. The purpose of this narrative review is to summarize the effects of GLP-1 on cardiovascular morbidity, mortality and remodeling due to medication but also due to bariatric and metabolic surgery. The second objective is to explain the possible differences in effects of GLP-1 agonists and bariatric and metabolic surgery.

Glucagon-like peptide-1 (GLP-1) improved diabetic lung fibrosis via AMPK and microRNA-27a (miR-27a).

BackgroundExtracellular matrix proliferation is an issue which leads to lung tissue damage in diabetes mellitus. Glucagon-like peptide-1 (GLP-1) analogues can improve the proliferation of extracellular matrix in diabetic pulmonary disease. In this study, we investigated the effect of GLP-1 on pulmonary fibrosis through the AMPK/microRNA-27a (miR-27a) pathway.MethodsHuman embryonic lung fibroblast (MRC-5) cells were cultured with a high-glucose medium, and were treated with miR-27a inhibitor, GLP-1 analogues, and AMPK inhibitor. Cell Counting Kit-8 (CCK-8) detected the proliferation of MRC-5 cells. The fibrosis-related genes were analyzed, including Col-IV, fibronectin, NF-κB p65, α-SMA, and TGF-β1. Bioinformatics and dual-luciferase reporter assays were used to identify the targets for miR-27a.ResultsCompared with the control group, the expression of miR-27a in the hyperglycemic group was significantly up-regulated (P<0.01) and the expression of peroxisome proliferator-activated receptor γ (PPARγ) significantly down-regulated (P<0.01). The expression of Col-IV, fibronectin, NF-κB p65, α-SMA and TGF-β1 increased significantly (P<0.01). The expression level of apoptosis factor caspase-3 decreased significantly (P<0.01). MiR-27a inhibitor could reverse the expression of these proteins. The effect of GLP-1 on miR-27a was time- and concentration-dependent. After pretreating MRC-5 cells via GLP-1, with or without compound C (AMPK inhibitor), the expression of miR-27a in the GLP-1 treated group was significantly lower than that in Vehicle group. The expression of miR-27a was increased after inhibition of the AMPK pathway. A predictive TargetScan algorithm showed that the PPARγ gene was a potential target of miR-27a. MiR-27a was also shown to target 3'-UTR of PPARγ.ConclusionsMiR-27a plays an important regulatory role in diabetic pulmonary fibrosis. GLP-1 could down-regulate the expression level of miR-27a by activating AMPK. Furthermore, the target gene PPARγ was up-regulated, consequently improving extracellular matrix proliferation in MRC-5 cells.

FXR-mediated epigenetic regulation of GLP-1R expression contributes to enhanced incretin effect in diabetes after RYGB.

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

Fasting Plasma GLP-1 Is Associated With Overweight/Obesity and Cardiometabolic Risk Factors in Children and Adolescents.

ContextThe importance of fasting glucagon-like peptide-1 (GLP-1) in altered metabolic outcomes has been questioned.ObjectiveThis work aimed to assess whether fasting GLP-1 differs in children and adolescents with overweight/obesity compared to a population-based reference, and whether concentrations predict cardiometabolic risk (CMR) factors.MethodsAnalyses were based on The Danish Childhood Obesity Data- and Biobank, a cross-sectional study including children and adolescents, aged 6 to 19 years, from an obesity clinic group (n = 1978) and from a population-based group (n = 2334). Fasting concentrations of plasma total GLP-1 and quantitative CMR factors were assessed. The effects of GLP-1 as a predictor of CMR risk outcomes were examined by multiple linear and logistic regression modeling.ResultsThe obesity clinic group had higher fasting GLP-1 concentrations (median 3.3 pmol/L; interquartile range, 2.3-4.3 pmol/L) than the population-based group (2.8 pmol/L; interquartile range, 2.1-3.8 pmol/L; P < 2.2E-16). Body mass index SD score (SDS), waist circumference, and total body fat percentage were significant predictors of fasting GLP-1 concentrations in boys and girls. Fasting GLP-1 concentrations were positively associated with homeostasis model assessment of insulin resistance, fasting values of insulin, high-sensitivity C-reactive protein, C-peptide, triglycerides, alanine transaminase (ALT), glycated hemoglobin A1c, and SDS of diastolic and systolic blood pressure. A 1-SD increase in fasting GLP-1 was associated with an increased risk of insulin resistance (odds ratio [OR] 1.59), dyslipidemia (OR 1.16), increased ALT (OR 1.14), hyperglycemia (OR 1.12) and hypertension (OR 1.12).ConclusionOverweight/obesity in children and adolescents is associated with increased fasting plasma total GLP-1 concentrations, which was predictive of higher CMR factors.

Irisin and Incretin Hormones: Similarities, Differences, and Implications in Type 2 Diabetes and Obesity.

Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis–involving the gut, muscle, and endocrine pancreas that controls energy homeostasis.

Central serotonin participates in the anorexigenic effect of GLP-1 in rainbow trout (Oncorhynchus mykiss)

The incretin, glucagon-like peptide-1 (GLP-1) is a major player in the gut-brain axis regulation of energy balance and in fish it seems to exert a negative influence on food intake. In this study, we investigated the role of the brain serotonergic system in the effects promoted by a peripheral GLP-1 injection on food intake in rainbow trout (Oncorhynchus mykiss). For this, in a first experiment the incretin was intraperitoneally injected (100 ng/g body weight) alone or in combination with a 5HT2C receptor antagonist (SB 242084, 1 µg/g body weight) and food intake was measured 30, 90, and 180 min later. In a second experiment, we studied the effect of these treatments on mRNA abundance of hypothalamic neuropeptides that control food intake. In addition, the effect of GLP-1 on serotonin metabolism was assessed in hindbrain and hypothalamus. Our results show that GLP-1 induced a significant food intake inhibition, which agreed with the increased expression of anorexigenic neuropeptides pomc and cart in the hypothalamus. Furthermore, GLP-1 stimulated the synthesis of serotonin in the hypothalamus, which might be indicative of a higher use of the neurotransmitter. The effects of GLP-1 on food intake were partially reversed when a serotonin receptor antagonist, SB 242084, was previously administered to trout. This antagonist also reversed the stimulatory effect of the hormone in hypothalamic pomca1 mRNA abundance. We conclude that hypothalamic serotonergic pathways are essential for mediating the effects of GLP-1 on food intake in rainbow trout. In addition, the 5HT2C receptor subtype seems to have a prominent role in the inhibition of food intake induced by GLP-1 in this species.

Post-oral fat-induced satiation is mediated by endogenous CCK and GLP-1 in a fat self-administration mouse model

Triacylglycerol is the most abundant dietary lipid, and a strong stimulator of satiation. Absorption of triacylglycerol in the small intestine occurs in the form of free fatty acids and 2-monoacylglycerol, a process known to trigger not only the release of cholecystokinin (CCK) but also glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). It remains controversial, however, whether endogenously released GLP-1 and PYY are required for fat-induced satiation. Using a self-administration model where mice are trained to self-administer Intralipid 30% intragastrically, we show that blocking the CCK1 receptors with intraperitoneal devazepide diminishes the post-oral satiation effect of ingested fat. Similarly, s.c. administration of a GLP-1 receptor antagonist with a prolonged half-life (Jant4-C16) also reduced the post-oral satiation effect of ingested fat. Importantly, coadministration of the GLP-1 antagonist together with devazepide increased fat self-infusions to a level equal to the combined blockade of each individual peptide action alone, indicating an additive effect of endogenous CCK and GLP-1 in fat satiation signaling. Blocking the PYY Y2 receptor did not further enhance the fat intake in devazepide-treated mice. Consistent with the above, we show that voluntary post-oral ingestion of fat increases CCK and GLP-1 plasma levels and is correlated positively with CCK and GLP-1 plasma concentrations. Taken together, our results support the role of endogenous GLP-1 in the regulation of fat intake and suggest that both CCK and GLP-1 are required for the fat satiation signaling.

Exogenous GLP-1 stimulates TCA cycle and suppresses gluconeogenesis and ketogenesis in late-fasted northern elephant seals pups

The post-weaning fast of northern elephant seal pups is characterized by a lipid-dependent metabolism and associated with a decrease in plasma glucagon-like peptide-1 (GLP-1), insulin, and glucose and increased gluconeogenesis (GNG) and ketogenesis. We have also demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of GNG, ketogenesis, and glycolysis. To assess the effects of GLP-1 on metabolism using primary carbon metabolite profiles in late-fasted seal pups, we dose-dependently infused late-fasted seals with low (LDG; 10 pM/kg; n=3) or high (HDG; 100 pM/kg; n=4) GLP-1 immediately following a glucose bolus (0.5g/kg), using glucose without GLP-1 as control (n=5). Infusions were performed in similarly aged animals 6-8 weeks into their post-weaning fast. The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions, and network maps constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased key tricarboxylic acid (TCA) cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate (P<0.05) suggesting that elevated levels of GLP-1 promote glycolysis and suppress GNG and ketogenesis, which collectively increase glucose clearance. These GLP-1-mediated effects on cellular metabolism help to explain why plasma GLP-1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose during the late-fasting period.

A Functional Inhibitory Role of Habenular Glucagon-Like Peptide-1 (GLP-1) in Forebrain Reward Signaling

There is emerging evidence implicating glucagon-like peptide-1 (GLP-1) in reward, including palatable food reinforcement and alcohol-based reward circuitry. While recent findings suggest that mesolimbic structures, such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc), are critical anatomical sites mediating the role of GLP-1’s inhibitory actions, the present study focused on the potential novel impact of GLP-1 within the habenula, a region of the forebrain expressing GLP-1 receptors. Given that the habenula has also been implicated in the neural control of reward and reinforcement, we hypothesized that this brain region, like the VTA and NAc, might mediate the anhedonic effects of GLP-1. Rats were stereotaxically implanted with guide cannula targeting the habenula and trained on a progressive ratio 3 (PR3) schedule of reinforcement. Separate rats were trained on an alcohol two-bottle choice paradigm with intermittent access. The GLP-1 agonist exendin-4 (Ex-4) was administered directly into the habenula to determine the effects on operant responding for palatable food as well as alcohol intake. Our results indicated that Ex-4 reliably suppressed PR3 responding and that this effect was dose-dependent. A similar suppressive effect on alcohol consumption was observed. These findings provide initial and compelling evidence that the habenula may mediate the inhibitory action of GLP-1 on reward, including operant and drug reward. Our findings further suggest that GLP-1 receptor mechanisms outside of the midbrain and ventral striatum are critically involved in brain reward neurotransmission.

Effects of glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors on major adverse cardiovascular events in type 2 diabetes by race, ethnicity, and region

Background:The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists on major adverse cardiovascular events (MACE) in type 2 diabetic subgroups defined by race, ethnicity, and region are unestablished.Methods:We searched PubMed and Embase for related randomized controlled trials. We conducted random-effects meta-analysis, stratified by drug class, on MACE in various subgroups defined by 3 factors of interest (ie, race, ethnicity, and region) to estimate pooled hazard ratio (HR) and 95% confidence interval. Random-effects meta-regression was conducted to evaluate the differences between 2 drug classes.Results:We included 11 randomized controlled trials for pooled analysis. Compared with placebo, SGLT2is and GLP-1 RAs significantly reduced the risk of MACE (HR ranged from 0.76 to 0.93) in most diabetic subgroups defined by 3 factors of interest. The 2 drug classes did not significantly reduced this risk in the Black race group (HR 0.92, 95% confidence interval 0.70–1.20). The effect of the 2 drug classes on MACE was not significantly different in all diabetic subgroups of interest (P-value for subgroup differences ranged from .101 to .971).Conclusions:SGLT2is and glucagon-like peptide 1 receptor agonists can significantly reduce the risk of MACE in most type 2 diabetic subgroups defined by race, ethnicity, and region, whereas they fail to do it in Black individuals.

GLP-1 preserves β cell function via improvement on islet insulin signaling in high fat diet feeding mice

BackgroundNumerous studies have shown that Glucagon like peptide-1 (GLP-1) treatment can protect β cell function, but the exact mechanism remains unclear. We hypothesized that GLP-1 may protect β cell function via its action on insulin signaling pathway. MethodsMice were fed with high fat diet (HFD, 20 weeks) in the presence or absence of GLP-1 receptor agonist (exenatide) treatment. The islet structure was demonstrated by HE staining. Immunofluorescence antibodies targeting insulin and glucagon were used to illustrate α and β cell distribution. The insulin and glucagon abundance was measured by ELISA using pancreatic homogenates. The molecules involved in insulin signaling pathway (IRc, IRS1, IRS2, mTOR) in islet were examined with immunohistochemistry and immunoblotting. The effect of IRS1 silencing on mTOR and apoptosis were examined on NIT cells(β cell line)with immunoblotting and flow cytometry. ResultsHE and immunofluorescence staining demonstrated that the normal structure of islet was deformed in HFD mice but preserved by exenatide. Insulin and glucagon contents were increased in islet and blood stream of HFD mice (HFD vs. Control, p<0.05) but resumed by exenatide. Meanwhile the expressions of IRc, IRS-1, mTOR from insulin signaling pathway and β cell apoptosis in the pancreas were significantly reduced (p<0.05) by HFD but reversed by exenatide. ConclusionExenatide improved insulin signaling pathway that was suppressed by HFD in mice islet. Our results reveal a novel mechanism of the protective effects of GLP-1 on β cell function.

Functional interaction between Ghrelin and GLP-1 regulates feeding through the vagal afferent system

The gastrointestinal tract transmits feeding-regulatory signals to the brain via neuronal and hormonal pathways. Here we studied the interaction between the orexigenic gastric peptide, ghrelin, and the anorectic intestinal peptide, glucagon-like peptide 1 (GLP-1), in terms of feeding regulation via the vagal afferents. GLP-1 preadministration 30 min before ghrelin administration to rats and mice abolished ghrelin-induced food intake, while ghrelin preadministration abolished the anorectic effect of GLP-1. Ghrelin preadministration suppressed GLP-1-induced Fos expression in the nodose ganglia (NG). Electrophysiological assessment confirmed that the initially administered peptide abolished the vagal afferent electrical alteration induced by the subsequently administered peptide. Both the growth hormone secretagogue receptor (GHSR) and the GLP-1 receptor (GLP-1R) are co-localised in a major proportion of NG neurons that innervate the stomach. In these Ghsr+Glp1r+ neurons, ghrelin preadministration abolished the GLP-1-induced calcium response. Ghrelin generated a hyperpolarising current and GLP-1 generated a depolarising current in isolated NG neurons in a patch-clamp experiment. Ghrelin and GLP-1 potently influenced each other in terms of vagally mediated feeding regulation. This peptidergic interaction allows for fine control of the electrophysiological properties of NG neurons.

Albumin-binding domain extends half-life of glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is considered to be a promising peptide for the treatment of type 2 diabetes mellitus (T2DM). However, the extremely short half-life of GLP-1 limits its clinical application. Albumin-binding domain (ABD) with high affinity for human serum albumin (HSA) has been used widely for half-life extension of therapeutic peptides and proteins. In the present study, novel GLP-1 receptor agonists were designed by genetic fusion of GLP-1 to three kinds of ABDs with different affinities for HSA: GA3, ABD035 and ABDCon. The bioactivities and half-lives of ABD-fusion GLP-1 proteins with different types and lengths of linkers were investigated in vitro and in vivo. The results demonstrated that ABD-fusion GLP-1 proteins could bind to HSA with high affinity. The blood glucose-lowering effect of GLP-1 was significantly improved and sustained by fusion to ABD. Meanwhile, the fusion proteins significantly inhibited food intake, which was beneficial for T2DM and obesity treatment. The half-life of GLP-1 was substantially extended by virtue of ABD. The in vivo results also showed that a longer linker inserted between GLP-1 and ABD resulted in a higher blood glucose-lowering effect. The fusion proteins generated by fusion of GLP-1 to GA3, ABD035 and ABDCon exhibited similar bioactivities and pharmacokinetics in vivo. These findings demonstrate that ABD-fusion GLP-1 proteins retain the bioactivities of natural GLP-1 and can be further developed for T2DM treatment and weight loss. It also indicates that the ABD-fusion strategy can be generally applicable to any peptide or protein, to improve pharmacodynamic and pharmacokinetic properties.