Abstract
The incretin system is an emerging new field that might provide valuable contributions to the research of both the pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the roles of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain, as well as on the levels of these incretins, insulin, and glucose via inhibition of the central incretin receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer’s disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease closely connected to the brain’s insulin resistant state and dysregulated glucose metabolism [1]
A growing body of research shows that diabetes mellitus type 2 (T2DM) is a risk factor for AD and that drugs that can effectively treat T2DM may elicit neuroprotective effects [1], like drugs acting on the incretin system [2,3,4]
Central inhibition of the GIP receptor (GIPR) had a stronger impact than GLP-1 receptor (GLP-1R) inhibition on plasma levels of the measured hormones (Figure 2A,B)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease closely connected to the brain’s insulin resistant state and dysregulated glucose metabolism [1]. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the most important incretins for glucose regulation secreted by the gut upon food intake. As far as we know, their primary goal is to stimulate insulin secretion from pancreatic β cells [5,6]. Upon their secretion, these incretins are degraded by dipeptidyl peptidase 4 (DPP-4), which has a higher affinity towards GLP-1 than GIP. The most widely known physiological role of incretins upon their secretion is stimulation of insulin secretion by binding to the GIP receptor (GIPR) or the GLP-1 receptor (GLP-1R) on the pancreatic β cell [7]. GLP-1 slows down gastric emptying and inhibits glucose-dependent glucagon secretion. GIP promotes energy storage via direct actions on adipose tissue and stimulates bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis [8]
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