Glucagon-like Peptide-1 Agonist Liraglutide Research Articles

Glucagon-like peptide agonists for weight management in antipsychotic-induced weight gain: A systematic review and meta-analysis.

Managing body weight in patients with antipsychotic-induced weight gain (AIWG) is challenging. Besides lifestyle interventions, pharmacological interventions may contribute to weight loss. This systematic review and meta-analysis evaluated the effect on weight loss and adverse effects of glucagon-like peptide-1 (GLP-1) agonists in patients with AIWG. Following PRISMA guidelines, we performed a meta-analysis of blinded and open-label randomised controlled trials (RCTs), non-randomised controlled trials and cohort studies that evaluated treatment with GLP-1 in patients with AIWG, regardless of psychiatric diagnosis. PubMed, Embase, PsycINFO and Cochrane Library databases were searched. Primary outcome measures were changes in body weight and BMI. Secondary outcomes were changes in adverse effects and severity of psychopathology due to GLP-1 agonists. Only data for exenatide and liraglutide could be included, that is, five RCTs and one cohort study. For exenatide the mean weight loss was -2.48 kg (95% Confidence Interval (CI) -5.12 to +0.64; p = 0.07), for liraglutide the mean weight loss was -4.70 kg (95% CI -4.85 to -4.56; p < 0.001). The mean change in BMI was -0.82 (95% CI -1.56 to -0.09; p = 0.03) in the exenatide groups and -1.52 (95% CI -1.83 to -1.22; p < 0.001) in the liraglutide groups. Exenatide and liraglutide did not adversely affect psychopathology. The most common adverse events were nausea, vomiting, and diarrhoea. The GLP-1 agonists exenatide and liraglutide are promising drugs for inducing weight loss in patients with AIWG. The adverse effects are acceptable, and the addition of GLP-1 does not increase the severity of psychopathology. However, more research is needed.

Circulating levels of proglucagon-derived peptides are differentially regulated by the glucagon-like peptide-1 agonist liraglutide and the centrally acting naltrexone/bupropion and can predict future weight loss and metabolic improvements: A 6-month long interventional study.

To investigate the changes of circulating levels of all proglucagon-derived peptides (PGDPs) in individuals with overweight or obesity receiving liraglutide (3 mg) or naltrexone/bupropion (32/360 mg), and to explore the association between induced changes in postprandial PGDP levels and body composition, as well as metabolic variables, after 3 and 6 months on treatment. Seventeen patients with obesity or with overweight and co-morbidities, but without diabetes, were assigned to receive once-daily oral naltrexone/bupropion 32/360 mg (n = 8) or once-daily subcutaneous liraglutide 3 mg (n = 9). Participants were assessed before treatment initiation and after 3 and 6 months on treatment. At the baseline and 3-month visits, participants underwent a 3-hour mixed meal tolerance test to measure fasting and postprandial levels of PGDPs, C-peptide, hunger and satiety. Clinical and biochemical indices of metabolic function, magnetic resonance-assessed liver steatosis and ultrasound-assessed liver stiffness were measured at each visit. Both medications improved body weight and composition, carbohydrate and lipid metabolism, and liver fat and function. Naltrexone/bupropion produced a weight-independent increase in the levels of proglucagon (P < .001) and decreases in glucagon-like peptide-2 (GLP-2), glucagon and the major proglucagon fragment (P ≤ .01), whereas liraglutide markedly upregulated total glucagon-like peptide-1 (GLP-1) levels in a weight-independent manner (P = .04), and similarly downregulated the major proglucagon fragment, GLP-2 and glucagon (P < .01). PGDP levels at the 3-month visit were positively and independently correlated with improvements in fat mass, glycaemia, lipaemia and liver function, and negatively with reductions in fat-free mass, at both the 3- and 6-month visits. PGDP levels in response to liraglutide and naltrexone/bupropion are associated with improvements in metabolism. Our study provides support for the administration of the downregulated members of the PGDP family as replacement therapy (e.g. glucagon), in addition to the medications currently in use that induced their downregulation (e.g. GLP-1), and future studies should explore whether the addition of other PGDPs (e.g. GLP-2) could offer additional benefits.

GLP-1 agonist Liraglutide prevents MK‑801–induced schizophrenia‑like behaviors and BDNF, CREB, p-CREB, Trk-B expressions in the hippocampus and prefrontal cortex in Balb/c mice

Glucagon-like peptide 1 (GLP-1) agonists are among the agents that can be used to treat type 2 diabetes mellitus, and they have also been reported to have neuroprotective effects. This study examined the effects of GLP-1 agonist Liraglutide on CREB, BDNF, Trk-B expression and emotional/cognitive behaviors in an experimental schizophrenia-like behavior model induced by MK-801. MK-801 (0.25 mg/kg, 0.1 ml/kg body weight) and/or Liraglutide (300 mcg/kg) were injected intraperitoneally once a day for 7 weeks into 8–10 weeks old male Balb/c mice (n = 78). Mice were randomly divided into 5 groups: Saline+Saline, MK-801 +Saline, Liraglutide+Saline, MK-801 +Liraglutide co-treatment, and Liraglutide+MK-801 co-treatment. A Morris water maze test, an elevated plus maze test, and an open field test were performed after injection. Western blots were performed on mice' hippocampus and PFC for BDNF, Trk-B, CREB, and p-CREB expression. Our study found that MK-801 impaired emotional and cognitive functions in mice. MK-801 administration did not affect Liraglutide's positive effects on spatial learning and memory activity in the Liraglutide+MK-801 group. Liraglutide administration (Liraglutide+MK-801 group) improved the BDNF/Trk-B and p-CREB/CREB ratio in the hippocampus, and the p-CREB/CREB ratio in the PFC to the control group level. The negative effects of MK-801 on cognitive behavior were not reversed by Liraglutide in the MK-801 +Liraglutide group. In conclusion, Liraglutide does not affect NMDA receptor blockade-induced emotional and cognitive behaviors. However, it has a protective effect against cognitive impairment. Furthermore, it is possible that the GLP-1 receptors in the hippocampus and PFC are involved in the modulation of NMDA receptor activity through CREB activation/deactivation.

Positive effect of vitamin D supplementation on weight loss in obese patients treated with glucagon-like peptide 1 and lifestyle interventions

Background. Obesity, prediabetes and type 2 diabetes mellitus (T2DM) are global diseases affecting the population of Ukraine, with an annual increase in morbidity. Insulin resistance occurs in up to 90% of obese patients, contributing to the accumulation of white adipose tissue, and has a risk for the further development of prediabetes and T2DM. However, other factors also play a negative role in the development of obesity, particularly cholecalciferol (vitamin D) deficiency. Vitamin D is a steroid hormone the main function of which is to regulate calcium and phosphorus metabolism, but this molecule also exhibits various properties, including the effects on carbohydrate metabolism. The purpose of this study was to identify and evaluate the role of vitaminD elevation in patients receiving glucagon-like peptide-1 agonists (GLP-1a) in combination with lifestyle interventions for the treatment of obesity and to compare its effectiveness with that in patients treating with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Materials and methods. A prospective study included 155 obese patients, and follow-up data were available for 49 of them. The study group consisted of 30 patients receiving combination therapy with GLP-1a liraglutide at a dose of 1.2 to 3.0 mg per day. The control group included 19 patients receiving combination therapy with metformin in daily doses of 500 to 2,000 mg, and SGLT2i in daily doses of 10 to 12.5 mg. Treatment of vitamin D deficiency was performed with cholecalciferol at a dose of 4,000 IU/day. Results. In study group GLP-1a, 25 (83.3%) patients had vitamin D insufficiency, which is statistically similar to control group (p&gt;0.05)— 17 (89.5%) cases. All patients with vitamin D insufficiency received 4,000 IU of cholecalciferol daily during the follow-up period. In study group GLP-1a, the mean body mass before the treatment was 104.6 kg, after treatment— 96.36 kg (p=0.000007), the mean weight lost was 7.8% (range is 1–23.71%) of the initial level. Mean body mass index (BMI) before treatment was 37.1 kg/m2, after treatment— 34.11 kg/m2 (p=0.000006). In the control group, the mean weight before the treatment was 99.4 kg, after treatment— 91.74 kg (p=0.000196), the mean weight lost was 7.73% (range is 0–16.9%) of the initial level. BMI before treatment averaged 35.6 kg/m2, after treatment— 34.11 kg/m2 (p=0.000196). The analysis of carbohydrate metabolism parameters showed a significantly lower blood glucose level— 5.75 mmol/l in the study group GLP-1a compared to 8.42 mmol/l in the control group (p=0.00024). It should be noted that a similar clinical picture was also observed after treatment, despite the compensation of T2DM in all patients: a significantly lower blood glucose level— 5.03 mmol/l in the study group GLP-1a compared to 5.99 mmol/l in controls (p=0.002453). However, significantly higher levels of insulin were detected in the study group GLP-1a before treatment— 27.02 mU/L compared to 18.59mU/L in control patients (p=0.003286). After treatment, a similar situation was observed in terms of significantly higher levels of insulin: 19.41 mU/l in patients of the study group GLP-1a compared to 14.42mU/l in controls (p=0.0024). Corresponding changes were also observed for the HOMA index. Conclusions. Our results suggest high effectiveness of increasing the level of vitamin D in case of its insufficiency as a part of measures for the treatment of obese patients with liraglutide, metformin or SGLT2i.

GLP-1 agonist liraglutide improves ouabain-induced mania and depressive state via GSK-3β pathway

Bipolar disorder (BD) is a severe mental illness characterized by aberrant mood changes between hypomania and mania or mixed states and depression. Metabolic changes also accompany disease progression and cause significant morbidity. Symptomatic treatment options are available, but asymptomatic patients and poor drug responders are significant problems. Based on the most common pharmacological agent that is used in the treatment, lithium and its main mechanisms of action, oxidative stress, and glycogen synthase kinase-3β (GSK-3β) signaling are extensively investigated. However, knowledge about the effects of compounds that positively affect oxidative stress and GSK-3β signaling, such as glucagon-like peptide-1 (GLP-1) mimetics, liraglutide, is still missing. Therefore, in this study, we aimed to investigate the effects of liraglutide on the ouabain-induced bipolar disease model in rats. After intracerebroventricular single dose ouabain administration, animals were treated with 100, 200, and 400 µg/kg liraglutide (s.c.) and valproic acid (200 mg/kg, i.p.) for 10 d. The locomotion and depressive states of animals were assessed by an open field, forced swimming test, and sucrose preference tests. Serum total antioxidant (TAS) and oxidant states (TOS) and glutathione, malonyl dialdehyde (MDA) levels in the brain tissue were determined. GSK-3β phosphorylation was evaluated by western blotting. Our results demonstrated that liraglutide attenuated ouabain-induced hyperlocomotion and depressive state. Additionally, liraglutide prevented oxidative stress after ouabain administration. Decreased GSK-3β phosphorylation due to the ouabain insult was alleviated by liraglutide treatment. These findings indicate that the manic and depressive-like behaviors are ameliorated by liraglutide, which exerted antioxidant action, possibly improving GSK-3β phosphorylation.

Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement

The glucose intolerance of diabetes aggravates atherosclerosis indirectly through its effect on lipids and endothelial function. The cardiovascular (CV) impact of this metabolic disturbance is seen in the worsening of atherosclerotic vascular disease predominantly manifest as progression of coronary and cerebrovascular disease. The microvascular changes induced by prolonged glucose intolerance lead to ultrastructural changes in the glomerular basement membrane and renal mesangium which alters intrarenal haemodynamics, which may become evident initially as proteinuria and later lead to a decline in glomerular filtration rate. As the kidney plays a central role in blood pressure control, these changes have far-reaching CV consequences in patients with diabetes.Despite this, glucose lowering has been shown to have only a modest impact on CV outcomes in diabetes. The new antidiabetic medications have been studied in clinical trials designed to assure safety as grounded in the FDA guidance of 2008. Whilst a direct comparison of results from these trials is not possible in view of heterogeneity in trial design, the individual CV outcome measures have broadly re-defined their role in terms of equivalence (non-inferiority) and/or benefit (superiority). The composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke (major adverse cardiovascular events, MACE) may be perceived as surrogate markers for atherosclerotic cardiovascular disease (ASCVD). This has been universally accepted as the primary endpoint in these cardiovascular outcome trials (CVOTs) and has been helpful in understanding the possible CV impact these drugs may have on patients with diabetes.The dipeptidyl peptidase 4 (DPP-IV) inhibitors (sitagliptin, alogliptin, saxagliptin, linagliptin), two sodium-glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin and ertugliflozin) and two glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1 RA) drugs (lixisenatide and extended-release exenatide) have demonstrated non-inferiority on MACE outcomes with comparators – that is, they have assured CV safety when used in conjunction with other glucose-lowering treatment to improve glycaemic control. Four GLP-1 agonists (liraglutide, albiglutide, semaglutide and dula- glutide) and two SGLT2 inhibitors (empagliflozin and canagliflozin) have demonstrated CV benefit on MACE outcomes; such demonstration of superiority may be seen as evidence for benefit. The SGLT2 inhibitors canagliflozin, empagliflozin, dapagliflozin and ertugliflozin have all demonstrated a significant benefit in reducing the risk of hospitalisation due to heart failure (HHF) as a secondary/ exploratory outcome measure in their CVOTs. Further confirmation of benefit in heart failure independent of the presence of glucose intolerance has been demonstrated with dapagliflozin and empagliflozin in heart failure patients with or without diabetes. However, a comparable benefit in heart failure has not so far been seen in studies with the DPP-IV inhibitors or GLP-1 receptor agonists. Albiglutide is not available in the UK and may have little relevance to the practising clinician other than through the information it contributes about the possible mechanisms of action of GLP-1 RA medications.

Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue.

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116-734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals (P=0.02). The vasorelaxing response to canagliflozin was not modified (P=0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H2O2 scavenging (catalase); also, canagliflozin-induced relaxation was similar (P=0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na+/H+ exchanger 1 inhibitor BIX (P=0.67), but greater than that to the Na+/Ca++ exchanger inhibitor SEA 0400 (P=0.001), hinting a role of Na+/H+ exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide (P=0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

Glucagon-like peptide 1 reverses myocardial hypertrophy through cAMP/PKA/RhoA/ROCK2 signaling.

Myocardial hypertrophy is a major pathological and physiological process during heart failure. Glucagon-like peptide 1 (GLP-1) is a glucagon incretin hormone released from the gut endocrine L-cells that has protective effects on various cardiovascular diseases, including hypertension, atherosclerosis, and myocardial hypertrophy. However, the protective mechanisms of GLP-1 in myocardial hypertrophy remain unclear. Here, we showed that the GLP-1 agonist liraglutide and dipeptidyl peptidase 4 inhibitor alogliptin decreased heart weight and cardiac muscle cell volume in spontaneously hypertensive rats (SHR). In H9C2 cell hypertensive models induced by angiotensin II, GLP-1 treatment reduced myocardial cell volume, inhibited the expressions of atrial natriuretic peptide, brain/B-type natriuretic peptide, β-myosin heavy chain, RhoA, and ROCK2, and decreased MLC and MYPT1 phosphorylation. When H9C2 cells were treated with H89, a PKA inhibitor, the inhibitory effect of GLP-1 disappeared, while the inhibitory role was enhanced under the treatment of Y-27632, a ROCK2 inhibitor. These results suggested that GLP-1 might reverse myocardial hypertrophy through the PKA/RhoA/ROCK2 signaling pathway.

Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease.

We compared the effects of weight loss induced with the glucagon-like peptide-1 agonist liraglutide, with that of lifestyle modification, followed by weight maintenance after discontinuing intervention, in obese adults with non-alcoholic fatty liver disease (NAFLD). Thirty obese (mean age 40.7±9.1years, BMI 33.2±3.6kg/m2 , 90% male) adults with NAFLD defined as liver fat fraction (LFF) > 5% on magnetic resonance imaging without other causes of hepatic steatosis were randomized to a supervised programme of energy restriction plus moderate-intensity exercise to induce ≥ 5% weight loss (DE group, n=15), or liraglutide 3mg daily (LI group, n=15) for 26weeks, followed by 26weeks with only advice to prevent weight regain. Diet and exercise and LI groups had significant (P<0.01) and similar reductions in weight (-3.5±3.3 vs -3.0±2.2kg), LFF (-8.1±13.2 vs -7.0±7.1%), serum alanine aminotransferase (-39±35 vs -26±33 U/L) and caspase-cleaved cytokeratin-18 (cCK-18) (-206±252 vs -130±158 U/L) at 26weeks. At 52weeks, the LI group significantly (P<0.05) regained weight (1.8±2.1kg), LFF (4.0±5.3%) and cCK-18 (72±126 U/L), whereas these were unchanged in the DE group. Liraglutide was effective for decreasing weight, hepatic steatosis and hepatocellular apoptosis in obese adults with NAFLD, but benefits were not sustained after discontinuation, in contrast with lifestyle modification. Continuing the exercise learned in the structured programme contributed to the maintenance of liver fat reduction.

Prevention of pentylenetetrazole-induced kindling and behavioral comorbidities in mice by levetiracetam combined with the GLP-1 agonist liraglutide: Involvement of brain antioxidant and BDNF upregulating properties

Kindling is a model for studying epileptogenesis and associated neuropsychiatric conditions. The antiepileptic drug levetiracetam (LEV) presents anti-kindling properties, but some severe neuropsychiatric events, especially depression, have been associated with its use in epileptic patients. The positive modulation of glucagon-like peptide-1 (GLP-1) receptors emerged as a potential target for the treatment of epilepsy and other neurological disorders. Here, we investigated behavioral and neurochemical effects of liraglutide (LIRA), a GLP-1 receptor agonist, alone or combined with LEV in mice subjected to PTZ-induced kindling. Male mice received PTZ on alternate days for 21 days. Before PTZ, the animals received LIRA, LEV (alone or in combination with LIRA) or saline. After seizures staging according to Racine’s scale, behavioral evaluations were performed to verify anxiety-, depressive-like and cognitive performance. Brain oxidative alterations and BDNF levels were also measured. LEV showed anti-kindling properties, but aggravated depressive-like behavior in PTZ-kindling. In control conditions, LEV induced a pro-depressant effect and impaired avoidance memory retention. LIRA delayed but did not prevent the full kindling development. LIRA prevented the depressive-like behavior induced by PTZ kindling and PTZ + LEV. LEV + LIRA protected against PTZ-induced anxiety-like alterations and impairments in locomotion and cognition. Furthermore, LEV + LIRA reduced nitrite levels and lipid peroxidation in the hippocampus and prefrontal cortex, while it increased reduced glutathione levels in all evaluated brain areas. LIRA or LEV + LIRA increased hippocampal BDNF levels. In conclusion, our results showed that LIRA can be a promising adjunctive therapy for epilepsy-related neuropsychiatric comorbidities and to improve the management of antiepileptic drug associated behavioral adverse effects.

Management of Diabetes Mellitus With Glucagonlike Peptide-1 Agonist Liraglutide in Renal Transplant Recipients: A Retrospective Study

BackgroundDiabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) in Taiwan. Despite the use of steroids and/or calcineurin inhibitors (CNIs) in renal transplantation (RTx), additional challenges occur when a patient displays persisting metabolic disease, carries on an unhealthy lifestyle, or experiences genetic effects. Although RTx recipients could get better glycemic control by oral anti-diabetic drugs (OADs) or several insulin agents, they still need more than two kinds of medication. Liraglutide, a GLP-1 receptor agonist, stimulates insulin secretion and inhibits glucagon secretion and hepatic glucose production in a glucose-dependent manner. In addition, it delays gastric emptying and suppresses appetite through the central pathways. Herein we report on the long-term benefits of liraglutide in the management of DM in RTx recipients. MethodsWe retrospectively retrieved 7 RTx patients in August 2015, who had been prescribed liraglutide due to their poor glycemic control; however, 2 of them discontinued their scheduled doses within 1 month. The mean follow-up period was 19.4 ± 7.6 (range 10.5–27.6) months. ResultsGlycemic control improved fasting blood sugar (FBS) from an initial 228.6 ± 39.1 mg/dL to a final FBS of 166.0 ± 26.6 mg/dL (P = .103), with a significant improvement in nadir glucose control (136.4 ± 5.8 mg/dL, P = .017) and with glycated hemoglobin (HbA1c) from an initial 10.0 ± 1.6% to a final 8.1 ± 0.8% (P = .043). The average body weight was from an initial of 78.0 ± 7.8 kg to a nadir of 75.1 ± 9.1 kg (P = .032). Graft renal function of the estimated glomerular filtration rate (eGFR) significantly improved from an initial 67.7 ± 18.7 to a nadir of eGFR 76.5 ± 18.7 mg/dL (P = .024). There was no significant change in urinary protein:creatinine ratio. ConclusionLiraglutide may be safe and effective for RTx recipients with poor diabetic glycemic control, although there have been incidences of intolerance in some patients, and potential concern regarding absorption of oral medications due to a delay of gastric emptying. Evidence of liraglutide in diabetic RTx recipients is limited, so additional prospective clinical studies should be undertaken in the future.

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: A pilot randomized trial.

We compared the effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m2 , mean weight 96.0 ± 16.3 kg) non-diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate-intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (-3.5 ± 3.3 vs -3.5 ± 2.1 kg, respectively, P = .72), LFF (-8.9 ± 13.4 vs -7.2% ± 7.1%, P = .70), serum alanine aminotransferase (-42 ± 46 vs -34 ± 27 U/L, P = .52) and aspartate aminotransferase (-23 ± 24 vs -18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight-loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.

LEADER and the new ‘cardiovascular’ glucose‐lowering agents

<scp>LEADER</scp> and the new ‘cardiovascular’ glucose‐lowering agents

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes.

Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagon-like peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR.

GLP-1 Agonists Inhibit ox-LDL Uptake in Macrophages by Activating Protein Kinase A

Oxidized low-density lipoprotein (ox-LDL) uptake by monocytes/macrophages plays a pivotal role in atherogenesis. This study was designed to examine the effect of glucagon-like peptide-1 (GLP-1) agonists on ox-LDL uptake in macrophages. Human primary monocytes/macrophages were incubated with native GLP-1 (nGLP-1) or GLP-1 agonist liraglutide to evaluate their effect on ox-LDL uptake and the expression of scavenger receptors (SRs), such as SR-A, CD36, and lectin-like ox-LDL SR-1, in this process. Our study showed a decrease in ox-LDL uptake and CD36 expression in macrophages treated with nGLP-1 or liraglutide. However, nGLP-1 and liraglutide did not affect the expression of other SRs SR-A and lectin-like ox-LDL SR-1. Simultaneously, there was an increase in the expression of activated protein kinase A (PKA). To examine the role of PKA in the effects of nGLP-1 or liraglutide, we treated macrophages with PK inhibitor (6-22) amide, a PKA inhibitor, followed by treatment with nGLP-1 or liraglutide. Inhibition of PKA activation markedly reversed the effect of nGLP-1 or liraglutide on ox-LDL uptake and enhanced the expression of CD36. Our results suggest that GLP-1 agonism inhibits ox-LDL uptake through PKA/CD36 pathway in macrophages. This study provides a novel insight in the mechanism of foam cell formation and the role by GLP-1 agonists therein.

Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

Antipsychotic-like effect of GLP-1 agonist liraglutide but not DPP-IV inhibitor sitagliptin in mouse model for psychosis

Recent studies indicate a high comorbidity between type-2 diabetes mellitus (T2DM) and neurological disorders. Many are associated with abnormalities in dopamine neurotransmission such as schizophrenia. Because most of the antipsychotic drugs aggravate pre-existing insulin resistance in type-2 diabetics, there is a need to search for alternative antipsychotics. Glucagon like peptide-1 (GLP-1) is a gut hormone primarily involved in glucose homeostasis. GLP-1 agonist (liraglutide) and dipeptidyl peptidase-IV (DPP-IV) inhibitor (sitagliptin) are the US-FDA approved medications for the management of T2DM. However, little is known about their role in dopamine mediated neurological disorders like schizophrenia. To address this, we used apomorphine-induced cage climbing behavior as a murine model for psychosis and examined for potential antipsychotic-like effect of liraglutide and sitagliptin. While acute liraglutide treatment (50μg/kg; i.p.) significantly attenuated apomorphine (3mg/kg, s.c.) induced cage climbing, sitagliptin (50mg/kg; i.p.) failed to elicit such effect. This is the first preclinical evidence for antipsychotic-like effect of GLP-1 receptor agonist. These results open an opportunity to explore GLP-1 analogs for their potential to modulate spectrum of dopamine-mediated neurological disorders.

The novel GLP‐1‐gastrin dual agonist, ZP3022, increases β‐cell mass and prevents diabetes in db/db mice

Diabetes is characterized by β-cell deficiency, and therefore restoration of β-cell function has been suggested as a potential therapy. We hypothesized that a novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist, ZP3022, improves glycaemic control via improvement of β-cell status in db/db mice. Diabetic mice were studied following short- or long-term treatment with either the GLP-1-gastrin dual agonist or the commercially available GLP-1 agonists (exendin-4 and liraglutide). The effects on glycaemic control were addressed by repeated glucose tolerance tests and/or measurements of HbA1c levels, and pancreatic islet and β-cell masses were determined by stereology. ZP3022 and the pure GLP-1 agonists improved glycaemic control after both short- and long-term treatment compared with vehicle. Interestingly, the effect was sustainable only in mice treated with ZP3022. Stereology data displayed a dose-dependent increase of β-cell mass (p < 0.05) following treatment with ZP3022, whereas no significant effect of liraglutide was observed (β-cell mass: vehicle 3.7 ± 0.2 mg; liraglutide (30 nmol/kg) 3.4 ± 0.5 mg; ZP3022 (30 nmol/kg) 4.3 ± 0.4 mg and ZP3022 (100 nmol/kg) 5.2 ± 0.4 mg). The novel GLP-1-gastrin dual agonist, ZP3022, improved glycaemic control in db/db mice, and pancreatic islet and β-cell mass increased significantly following treatment with ZP3022 compared with vehicle.

GLP-1 Agonists Exenatide and Liraglutide: A Review About Their Safety and Efficacy

Recently incretin-based therapies have been developed in the clinical practice, this class includes both the dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin), and the glucagon-like peptide- 1 (GLP-1) receptor agonists [exenatide, exenatide long acting release (LAR) and liraglutide]. In particular exenatide and liraglutide have structural similarity and bind to the GLP-1 receptor, displaying a similar broad range of activities relevant to improving glycemic control, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake; it also promotes β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models. We conducted a review analyzing clinical efficacy and safety of GLP-1 receptor agonists exenatide and liraglutide, both alone and in combination with other anti-diabetic drugs, including the most important studies about them in the latest ten years. We concluded that GLP-1 receptor agonists appear to be a good choice to decrease HbA1c levels and to lower postprandial blood glucose levels. They also suppress glucagon secretion and slow gastric motility. They also have positive effects on β-cell function and they gave a significant decrease of body weight. They are not associated with hypoglycemia, but cause a relatively high frequency of gastrointestinal disturbances, with some patients experiencing one or more episodes of nausea, vomiting, or diarrhea. However, after an evaluation of the advantages and the disadvantages, we concluded that, once metformin fails to reach an adequate glycemic control, GLP-1 receptor agonists can be a valid alternative, especially in obese type 2 diabetic patients. GLP-1 receptor agonists should be considered also in patients in therapy with metformin and another agent, such as a sulfonylurea, because of the minor risk of developing hypoglycemia and the positive effect on body weight.

Counselling patients for GLP-1 analogue therapy: Comparing GLP-1 analogue with insulin counselling

Counselling patients for GLP-1 analogue therapy: Comparing GLP-1 analogue with insulin counselling