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 Show more
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. Show less
Gastrointestinal dyshomeostasis is investigated in the context of metabolic dysfunction, systemic, and neuroinflammation in Alzheimer's disease. Dysfunctional gastrointestinal redox homeostasis and th Show more
Gastrointestinal dyshomeostasis is investigated in the context of metabolic dysfunction, systemic, and neuroinflammation in Alzheimer's disease. Dysfunctional gastrointestinal redox homeostasis and the brain-gut incretin axis have been reported in the rat model of insulin-resistant brain state-driven neurodegeneration induced by intracerebroventricular streptozotocin (STZ-icv). We aimed to assess whether (i) the structural epithelial changes accompany duodenal oxidative stress; (ii) the brain glucose-dependent insulinotropic polypeptide receptor (GIP-R) regulates redox homeostasis of the duodenum; and (iii) the STZ-icv brain-gut axis is resistant to pharmacological inhibition of the brain GIP-R. GIP-R inhibitor [Pro3]-GIP (85 μg/kg) was administered intracerebroventricularly to the control and the STZ-icv rats 1 month after model induction. Thiobarbituric acid reactive substances (TBARSs) were measured in the plasma and duodenum, and the sections were analyzed morphometrically. Caspase-3 expression and activation were assessed by Western blot and multiplex fluorescent signal amplification. Intracerebroventricular [Pro3]-GIP decreased plasma TBARSs in the control and STZ-icv animals and increased duodenal TBARSs in the controls. In the controls, inhibition of brain GIP-R affected duodenal epithelial cells, but not villus structure, while all morphometric parameters were altered in the STZ-icv-treated animals. Morphometric changes in the STZ-icv animals were accompanied by reduced levels of caspase-3. Suppression of brain GIP-R inhibited duodenal caspase-3 activation. Brain GIP-R seems to be involved in the regulation of duodenal redox homeostasis and epithelial cell turnover. Resistance of the brain-gut GIP axis and morphological changes indicative of abnormal epithelial cell turnover accompany duodenal oxidative stress in the STZ-icv rats. Show less