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      GLP-1’s role in neuroprotection: a systematic review

      1 , 2 , 1 , 1 , 1 , 2 , 1 , 2
      Brain Injury
      Informa UK Limited

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          Abstract

          Glucagon-like peptide 1 (GLP-1) is a target for treatment of diabetes; however, its function in the brain is not well studied. In this systematic review, we aimed to analyze the neuroprotective role of GLP-1 and its defined mechanisms. Methods: We searched 'Web of Science' and 'Pubmed' to identify relevant studies using GLP-1 as the keyword. Two hundred and eighty-nine clinical and preclinical studies have been included. Data have been presented by grouping neurodegenerative, neurovascular and specific cell culture models. Results: Recent literature shows that GLP-1 and its agonists, DPP-4 inhibitors and combined GLP-1/GIP molecules are effective in partially or fully reversing the effects of neurotoxic compounds, neurovascular complications of diabetes, neuropathological changes related with Alzheimer's disease, Parkinson's disease or vascular occlusion. Possible mechanisms that provide neuroprotection are enhancing the viability of the neurons and restoring neurite outgrowth by increased neurotrophic factors, increasing subventricular zone progenitor cells, decreasing apoptosis, decreasing the level of pro-inflammatory factors, and strengthening blood-brain barrier. Conclusion: Based on the preclinical studies, GLP-1 modifying agents are promising targets for neuroprotection. On the other hand, the number of clinical studies that investigate GLP-1 as a treatment is low and further clinical trials are needed for a benchside to bedside translation of recent findings.

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          Most cited references246

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          The biology of incretin hormones.

          Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.
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            An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

            Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
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              Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study.

              Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects of continuous administration of this peptide hormone in a 6-week pilot study. 20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent beta-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A(1c), and fructosamine. The primary endpoints were haemoglobin A(1c) concentration, 8-h profile of glucose concentration in plasma, and beta-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol. One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in fructosamine concentration (p=0.0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4.3 mmol/L and 5.5 mmol/L (p<0.0001). Haemoglobin A(1c) decreased by 1.3% (p=0.003) and fructosamine fell to normal values (p=0.0002). Fasting and 8 h mean concentrations of free fatty acids decreased by 30% and 23% (p=0.0005 and 0.01, respectively). Gastric emptying was inhibited, bodyweight decreased by 1.9 kg, and appetite was reduced. Both insulin sensitivity and beta-cell function improved (p=0.003 and p=0.003, respectively). No important side-effects were seen. GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term effects of GLP-1 is needed.
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                Author and article information

                Journal
                Brain Injury
                Brain Injury
                Informa UK Limited
                0269-9052
                1362-301X
                December 17 2018
                May 12 2019
                April 02 2019
                May 12 2019
                : 33
                : 6
                : 734-819
                Affiliations
                [1 ] School of Medicine, Koç University, Istanbul, Turkey
                [2 ] Research Center for Translational Medicine, Koç University, Istanbul, Turkey
                Article
                10.1080/02699052.2019.1587000
                30938196
                e1c5acf9-f8d0-43c6-af9b-06a66f7ecd79
                © 2019
                History

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