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Diabetes is considered a new pandemic of the modern world, and the number of sufferers is steadily increasing. Sustained hyperglycemia promotes the production of free radicals and leads to persistent, low-grade inflammation. Oxidative stress causes mitochondrial destruction, which along with activation of the hexosamine pathway, nuclear factor-κB (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), c-jun NH2 terminal kinase/stress-activated protein kinase (JNK/SAPK) or toll-like receptors (TLRs), leads to pancreatic β-cell dysfunction. However, there is also the protective mechanism that counteracts oxidative stress and inflammation in diabetes, mitophagy, which is a mitochondrial autophagy. An important part of the strategy to control diabetes is to lead a healthy lifestyle based on, among other things, regular physical activity, giving up smoking, eating a balanced diet containing ingredients with antioxidant potential, including vegetables and fruits, and using hypoglycemic pharmacotherapy. Tobacco smoke is a recognized modifiable risk factor for many diseases including diabetes, and it has been shown that the risk of the disease increases in proportion to the intensity of smoking. Physical activity as another component of therapy can effectively reduce glucose fluctuations, and high intensity interval exercise appears to have the most beneficial effect. A proper diet not only increases cellular sensitivity to insulin, but is also able to reduce inflammation and oxidative stress. Pharmacotherapy for diabetes can also affect oxidative stress and inflammation. Some oral drugs, such as metformin, pioglitazone, vildagliptin, liraglutide, and exenatide, cause a reduction in markers of oxidative stress and/or inflammation, while the new drug Imeglimin reverses pancreatic β-cell dysfunction. In studies of sitagliptin, vildagliptin and exenatide, beneficial effects on oxidative stress and inflammation were achieved by, among other things, reducing glycemic excursions. For insulin therapy, no corresponding correlation was observed. Insulin did not reduce oxidative stress parameters. There was no correlation between glucose variability and oxidative stress in patients on insulin therapy. The data used in this study were obtained by searching PubMed online databases, taking into account recent studies.

To avoid the biotoxicity and poor bioavailability of deferoxamine mesylate (DFO), an iron chelation for the treatment of Parkinson's disease (PD), a self-oriented DFO nanoparticle functionalized with Exendin-4 was developed, which can be targeted delivered into the lesion brain area to achieve synergistic effects against PD by iron chelation and inflammatory suppression. The self-oriented DFO nanoparticles (Ex-4@DFO NPs) were synthesized by double emulsion technique, and characterized in terms of the particle size, morphology and DFO encapsulation efficiency. The cellular internalization, biocompatibility and cytoprotection of NPs were assessed on BV-2 and SH-SY5Y cells. The brain targeting and therapeutic effect of NPs were investigated in MPTP-induced PD mice by near-infrared II fluorescence imaging and immunofluorescence staining, as well as mobility behavioral tests. Ex-4@DFO NPs with a particle size of about 100 nm, showed great biocompatibility and cytoprotection in vitro, which inhibited the decrease of mitochondrial membrane potential of SH-SY5Y cells and the release of inflammatory factors of BV-2 cells. In MPTP-induced PD mice, Ex-4@DFO NPs could penetrate the BBB into brain, and significantly mitigate the loss of dopaminergic neurons and inflammation in the substantia nigra, finally alleviate the mobility deficits. This self-oriented nanosystem not only improved the biocompatibility of DFO, but also enhanced therapeutic effects synergistically by ameliorating neuronal damage and neuroinflammation, showing a potential therapeutic strategy for PD.

BackgroundPreclinical studies in rodents have demonstrated inhibitory effects of glucagon-like peptide-1 (GLP-1) receptor stimulation on alcohol consumption. The effects of GLP-1 receptor stimulation on alcohol intake in primates have not been investigated.MethodsWe performed placebo-controlled studies on the effects of the GLP-1 receptor agonists exenatide and liraglutide on alcohol consumption in alcohol-preferring male African vervet monkeys. Monkeys selected for voluntary alcohol drinking were observed for at least 10 days of baseline drinking and allocated to drug or vehicle (n = 11–12 per group) balanced with respect to alcohol intake. Monkeys had access to alcohol 4 h/day. In a first study, monkeys were treated with exenatide 0.04 mg/kg or vehicle once weekly for 5 weeks to obtain steady-state plasma levels. In a second study, monkeys were treated daily with liraglutide (increasing dosing, 10 to 50 μg/kg/day) or vehicle over 2 weeks. In both studies, access to alcohol was suspended during drug up-titration. Then, alcohol was again made available 4 h/day and treatment was continued for 2 weeks, during which alcohol intake was recorded. Observation of alcohol intake was continued for a week of drug washout.ResultsLiraglutide and to a lesser extent exenatide significantly reduced alcohol consumption without causing any signs of emesis and with no effect on water intake as compared to vehicle.ConclusionsThe present study demonstrates for the first time that GLP-1 receptor agonists can reduce voluntary alcohol drinking in non-human primates. The data substantiate the potential usefulness of GLP-1 receptor agonists in the treatment of alcohol use disorder.

Background Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. Methods In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. Results Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. Conclusion Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

The neuroinflammation is necessary for glial group initiation and clearance of damaged cell debris after nerve injury. However, the proinflammatory polarization of excessive microglia amplifies secondary injury via enhancing cross-talk with astrocytes and exacerbating neurological destruction after spinal cord injury (SCI). The glucagon-like peptide-1 receptor (GLP-1R) agonist has been previously shown to have a neuroprotective effect in neurodegeneration, whereas its potency in microglial inflammation after SCI is still unknown. The effect and mechanism of GLP-1R activation by exendin-4 (Ex-4) were investigated in cultured glial groups and in SCI mice. Alterations in the gene expression after GLP-1R activation in inflammatory microglia were measured using mRNA sequencing. The microglial polarization, neuroinflammatory level, and astrocyte reaction were detected by using western blotting, flow cytometry, and immunofluorescence. The recoveries of neurological histology and function were also observed using imaging and ethological examinations. GLP-1R activation attenuated microglia-induced neuroinflammation by reversing M1 subtypes to M2 subtypes and . In addition, activation of GLP-1R in microglia blocked production of reactive astrocytes. We also found less neuroinflammation, reactive astrocytes, corrected myelin integrity, ameliorated histology, and improved locomotor function in SCI mice treated with Ex-4. Mechanistically, we found that Ex-4 rescued the RNA expression of Arf and Rho GAP adapter protein 3 (ARAP3). Knockdown of ARAP3 in microglia reversed activation of RhoA and the pharmacological effect of Ex-4 on anti-inflammation . Ex-4 exhibited a previously unidentified role in reducing reactive astrocyte activation by mediation of the PI3K/ARAP3/RhoA signaling pathway, by neuroinflammation targeting microglia, and exerted a neuroprotective effect post-SCI, implying that activation of GLP-1R in microglia was a therapeutical option for treatment of neurological injury.

Glucagon-like peptide-1 receptor (GLP-1R) is an emerging critical target for the diagnosis and treatment of various diseases. Radiolabeled exendin-4 (Ex-4), a GLP-1R agonist, has been widely used as an imaging probe. However, its potential to induce hypoglycemia, especially in patients with insulinoma, limits its applicability. This study evaluated whether Ex-D3, a Glu3Asp substitution of Ex-4 with a higher internalization rate, could enhance the imaging efficacy of Ex-4 while reducing its hypoglycemic effects. We synthesized derivatives with an additional C-terminal Cys (Ex-D3-C40) for site-specific 125I labeling. Surface plasmon resonance analysis revealed that C-terminus modification did not significantly alter the binding affinity of Ex-D3-C40 to GLP-1R. In vivo studies in mice demonstrated that Ex-D3-C40 induced weaker hypoglycemic effects than Ex-4-C40. Biodistribution studies showed that 125I-labeled Ex-D3 ([125I]I-Ex-D3) achieved significantly higher pancreatic accumulation and higher pancreas-to-blood and pancreas-to-muscle ratios than [125I]I-Ex-4. Ex vivo autoradiography confirmed the binding specificity of [125I]I-Ex-D3 to GLP-1R-expressing pancreatic β-cells. These findings indicate that Ex-D3 is a promising parent peptide for the development of superior GLP-1R imaging probes with reduced hypoglycemic risk, highlighting the importance of considering pharmacological effects in designing molecular imaging probes.

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible. Blood–brain barrier dysfunction occurs in ageing and in neurodegenerative diseases. Here, the authors use scRNA-seq to identify transcriptomic changes in endothelial cell subtypes in the aged mouse brain, some of which may generalize to human and can be reversed by treatment with a GLP-1R agonist.

Introduction. Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM. Methods. In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n=19), dulaglutide group (n=19), insulin glargine group (n=10), and placebo (n=17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry. Results. Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11±0.24% vs. 7.40±0.16%, P=0.007), dulaglutide (8.77±0.37% vs. 7.06±0.28%, P<0.001), and insulin glargine (8.57±0.24% vs. 7.23±0.25%, P<0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P=0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P<0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P<0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P<0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P=0.001). Conclusions. Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.

Background Cognitive function can be affected in conditions with raised intracranial pressure (ICP) such as idiopathic intracranial hypertension (IIH). Drugs used off label to treat raised ICP also have cognitive side effects, underscoring the unmet need for effective therapeutics which reduce ICP without worsening cognition. The Glucagon Like Peptide-1 (GLP-1) receptor agonist, exenatide, has been shown to significantly reduce ICP in IIH, therefore this study aimed to determine the effects of exenatide on cognition in IIH. Methods This was an exploratory study of the IIH:Pressure trial (ISTCRN 12678718). Women with IIH and telemetric ICP monitors (n = 15) were treated with exenatide (n = 7) or placebo (n = 8) for 12 weeks. Cognitive function was tested using the National Institute of Health Toolbox Cognitive Battery at baseline and 12 weeks. Results Cognitive performance was impaired in fluid intelligence ((T-score of 50 = population mean), mean (SD) 37.20 (9.87)), attention (33.93 (7.15)) and executive function (38.07 (14.61)). After 12-weeks there was no evidence that exenatide compromised cognition (no differences between exenatide and placebo). Cognition improved in exenatide treated patients in fluid intelligence (baseline 38.4 (8.2), 12 weeks 52.9 (6.6), p  = 0.0005), processing speed (baseline 43.7 (9.4), 12 weeks 58.4 (10.4), p  = 0.0058) and episodic memory (baseline 49.4 (5.3), 12 weeks 62.1 (13.2), p  = 0.0315). Conclusions In patients with raised ICP due to IIH, exenatide, a drug emerging as an ICP lowering agent, does not adversely impact cognition. This is encouraging and has potential to be relevant when considering prescribing choices to lower ICP.

Depression is a frequent and serious comorbidity associated with diabetes which adversely affects prognosis and quality of life. Glucagon-like peptide-1 receptor (GLP-1R) agonists, widely used in the treatment of diabetes, are reported to exert neuroprotective effects in the central nervous system. Thus, we aim to evaluate whether GLP-1R agonist exendin-4 (EX-4) could alleviate depression-like behaviors in diabetic mice and to explore its underlying mechanism. The antidepressant effects of EX-4 were evaluated using behavioral tests in db/db mice. The effects of EX-4 on microglial pyroptosis and neuroinflammation were assessed in N9 microglial cells. EX-4 administration alleviated depression-like behaviors in diabetic db/db mice. GLP-1R activation by EX-4 significantly suppressed microglial pyroptosis and neuroinflammation by downregulation of gasdermin D (GSDMD) and interleukin (IL)-1β in diabetic mice and lipopolysaccharide (LPS)-primed N9 microglia. Mechanistically, GLP-1R activation improved mitochondrial function and promoted mitophagy by decreasing the accumulation of mitochondrial reactive oxygen species (mtROS) and intracellular ROS production. EX-4 exhibits antidepressant effects in depression associated with diabetes in diabetic mice, which may be mediated by inhibiting microglial pyroptisis via promoting mitophagy. It is supposed that GLP-1R agonists may be a promising therapy in depression associated with diabetes.