Abstract:

Impaired insulin signaling is defined as a reduced response to insulin stimulation. In vertebrates, almost all cell types are responsive to insulin signaling. Impaired insulin signaling, also called as insulin resistance, is a central characteristic feature to develop the metabolic syndrome including diabetes, cardiovascular disease, cancer, and other life-threatening disorders. However, there is increasing evidence that insulin resistance itself may affect central nervous system (CNS) functions. Particularly, impaired insulin signaling in the brain has been linked to AD, the most common type of dementia. AD is more broadly defined to include the pathogenic mechanisms underlying amyloid β (Aβ)-induced neurotoxicity. Interestingly, increasing evidence suggests defective brain insulin signaling may play a key role in AD pathogenesis. Brain insulin resistance in AD was firstly proposed about two decades ago. In 1994, Hoyer et al. hypothesized that neuronal insulinin sensitivity may explain reduced brain metabolism in such neurodegenerative disorder. Although the detailed mechanism of the brain insulin resistance is uncertain, a serial studies reported significantly decreased neuronal insulin signaling in the neocortex and hippocampus of AD cases. GLP-1 is produced in the brain mediating many neuronal functions, including neuroprotection, improvement of learning and memory ability, and potentiation of insulin signaling. This indicates GLP-1 may display the potential to serve as therapeutic or preventive strategies against diabetes-related AD. As DPP-4 inhibitors can effectively increase GLP-1 levels, they may also exert protective effects against AD-related neurodegeneration.
It is known the proglucagon gene encodes GLP-1 peptides, which is located on the long arm of human chromosome 2 with the entire coding sequence within exon 4. In past years, GLP-1 peptide is thought to be mainly expressed in the pancreas α cells and intestine L-cells. However, mammalian GLP-1gene is now known to be actively transcribed in brain neurons. Such evolutionary correlations may provide important clues of insulin signaling in the brain neuronal functions. Accordantly, GLP-1 signaling is known to modulate many neuronal functions in the brain; therefore, GLP-1 signaling have demonstrated the potential to serve as therapeutic or preventive strategies against diabetes-related AD. Considering the important roles of the Aβ-induced oxidative stress in AD pathogenesis, our research unveils a potential neuroprotective mechanism by linagliptin through suppressing oxidative damage and preserving mitochondria function via restoration of neuronal insulin signaling.