Abstract
BackgroundType 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain.MethodsHere we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA.ResultsWe show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon.ConclusionThe findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders.
Highlights
Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies
glucagon-like peptide-1 (GLP-1)-positive cells are detected in cerebral cortex of mice and significantly reduced in an obese insulin-resistant mouse model To achieve the aim of this study, we investigated whether GLP-1-positive cells could be detected in parts of the brain outside of the nucleus of the solitary tract, where proglucagon mRNA expression has been previously observed
Proglucagon mRNA expression is detected in cerebral cortex and hippocampus of mice and significantly reduced in an obese insulin-resistant mouse model, while strongly correlated to the mRNA expression of the proinflammatory tumor necrosis factor-α (TNFα) To further confirm our finding of GLP-1-positive cells in an area outside of the nucleus of the solitary tract, where proglucagon mRNA expression has been previously observed, we investigated if proglucagon gene expression could be detected
Summary
Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients are characterized by hyperglycemia, but typically have increased circulating levels of free fatty acids that may accumulate in the central nervous system (CNS) [4] Incretin hormones, such as glucagon-like peptide-1 (GLP-1), are derived from proglucagon, which is produced by enteroendocrine L-cells, and augment mealstimulated insulin secretion in a glucose-dependent manner [5]. We aimed to investigate whether there are non-neuronal sources of GLP-1 secretion in the brain, and, if so, how secretion of GLP-1 can be stimulated and how it is affected by obesity and insulin-resistant conditions. Such knowledge may shed light on the pathogenesis of neurodegeneration in T2D patients. This information may lead to novel ways of stimulating neuroprotection in conditions linked to neurodegeneration, such as T2D, by modulating the secretion of one of the brain’s own neuroprotective peptides
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