GLP-1 and Underlying Beneficial Actions in Alzheimer's Disease, Hypertension, and NASH

Abstract

GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer's disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.

Keywords: Alzheimer’s disease; DPP-4; GLP-1; blood pressure; non-alcoholic steatohepatitis; signaling pathway.

Figure 1

Diagram showing the relationship between translation and post-processing of glucagon precursors and its physiological processing pattern in the tissue. Coded by the preproglucagon gene, proglucagon is catalyzed by PCSK1/3 in the gut and brain and further processed to glicentin-related pancreatic polypeptide (GRPP) and oxyntomodulin (OXM), GLP-1, intervening peptide-2 (IP-2), and GLP-2. In the α-cells of the pancreatic islet, PCSK2 predominates and processes proglucagon to glucagon, GRPP, intervening peptide 1 (lP1), and a proglucagon fragment.

Figure 2

Model diagram of potential mechanisms of neuroprotective and anti-inflammatory effects of GLP-1. GLP-1 analogues like native GLP-1 have a longer half-life. Their effects are mediated through binding to GLP-1R, which could inhibit pathways such as the NF-κB pathway and MAPKs pathway. LPS, combined with TLR-4, activates the NF-κB pathway and triggers an inflammatory response while GLP-1 could inhibit the response to protect the synaptic plasticity. Besides, GLP-1 binds to GLP-1R to the active AMPK pathway involved in neuroprotection.

Figure 3

Illustration of the complex pathologic processes of NASH. T2DM and obesity increase the risk of NASH. IR in the adipose tissue and liver is a key driver, which leads to the imbalance of metabolism. Mitochondrial damage leads to less cellular energy production and adipose tissue hypertrophy, resulting in Mφ changing from the anti-inflammatory M2 Mφ state into the pro-inflammatory M1 Mφ. The process of all these changes will lead to enhance secretion of TNF-α, IL-6 and lipid accumulation in the hepatocyte, which eventually develop into fibrosis and cirrhosis.