GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

Abstract

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

Keywords: GLP-1 receptor agonists; cancer; cardiovascular; endocrine; neurological.

Figure 1

The effects of GLP-1RAs on multiple human organizations. GLP-1RAs exert a positive therapeutic effect on human brain, pancreas, heart, gastrointestinal tract (GI tract) and liver.

Figure 2

Spinal microglia GLP-1R/IL-10/β-endorphin analgesic pathway. IL-10 stimulates the GLP-1R activation-induced microglial expression of β-endorphin and neuropathic spinal cord anti-allergic response in an autocrine manner. The figure is modified from Ref .

Figure 3

The effect of GLP-1RAs on the cardiovascular system. GLP-1RAs have direct and indirect effects on the cardiovascular system. Endocrine factors can ameliorate the risk factors for cardiovascular diseases.

Figure 4

GLP-1RAs are involved in a variety of disease pathways. GLP-1RAs can activate several signaling pathways, such as the PI3K/AKT/mTOR, p-AMPKα/NOX2/JNK1/2, Wnt/β-catenin, Akt/GSK-3β/β-catenin, NF-κB/RANKL, and MKK4/JNK pathways thus exerting a therapeutic effect in different diseases.

Figure 5

The effect of diabetes on tumor cell microenvironment and intracellular signaling transduction. Diabetic patients can increase their levels of insulin and stimulate the PI3K/Akt/mTOR, Ras/Raf/MAPK, and Jak/Stat signaling pathways in different ways, thereby inhibiting cancer cell apoptosis and promoting the spread, migration, and invasion of cancer cells. Solid arrows indicate strong affinity for the receptor, and dashed arrows represent weak affinity for the receptor. The figure is modified from Ref .