Evidence of metabolic memory-induced neurodegeneration and the therapeutic effects of glucagon-like peptide-1 receptor agonists via Forkhead box class O.

07:00 EST 19th November 2018 | BioPortfolio

Summary of "Evidence of metabolic memory-induced neurodegeneration and the therapeutic effects of glucagon-like peptide-1 receptor agonists via Forkhead box class O."

Metabolic memory, which refers to diabetic stresses that persist after glucose normalization, is considered a major factor in addition to hyperglycaemia for diabetes complications, including dementia. We previously reported that glucagon-like peptide-1 receptor agonist (GLP-1RA) alleviated neuronal injury in diabetes-related dementia models. However, our understanding of the effects and mechanisms of GLP-1RA on metabolic memory-induced neurodegeneration are limited. The present study mainly focuses on the mechanisms of action of GLP-1RA on metabolic memory-induced neurotoxicity in vivo and in vitro. Thus, in this study, aiming at mimicking metabolic memory phenomena, in vivo and in vitro models were exposed to high glucose first and then normal glucose. We also used advanced glycation end products, which are key metabolic memory-related factors, to induce neuronal injury in vitro. Based on the models, here, we report that GLP-1RA alleviated neurodegeneration in db/db mice with normalized blood glucose levels controlled with metformin and neuronal damage induced by high glucose treatment followed by withdrawal. GLP-1RA ameliorated metabolic memory-induced Aβ and tau pathologies in vivo and in vitro. Furthermore, the data suggested that GLP-1RA can protect neurons against metabolic memory via Forkhead box class O (FoxO) pathways, and silent information regulator 2 homolog 1-dependent deacetylation and protein kinase B-dependent phosphorylation of FoxO1 were involved in the mechanisms underlying protective effects. This study provides evidence of the beneficial effects of GLP-1RA on neuronal cell metabolic memory, as well as GLP-1 analogues and metformin combination therapy efficiency on cognitive impairment.


Journal Details

This article was published in the following journal.

Name: Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X


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Medical and Biotech [MESH] Definitions

Cell surface receptors that bind glucagon with high affinity and trigger intracellular changes which influence the behavior of cells. Activation of glucagon receptors causes a variety of effects; the best understood is the initiation of a complex enzymatic cascade in the liver which ultimately increases the availability of glucose to body organs.

Disorders that result from the intended use of PHARMACEUTICAL PREPARATIONS. Included in this heading are a broad variety of chemically-induced adverse conditions due to toxicity, DRUG INTERACTIONS, and metabolic effects of pharmaceuticals.

Peptides derived from proglucagon which is also the precursor of pancreatic GLUCAGON. Despite expression of proglucagon in multiple tissues, the major production site of glucagon-like peptides (GLPs) is the INTESTINAL L CELLS. GLPs include glucagon-like peptide 1, glucagon-like peptide 2, and the various truncated forms.

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