Exendin-4: A GLP-1R Agonist

Type 2 diabetes is a chronic metabolic disorder characterized by elevated blood sugar levels and impaired insulin function. Over the years, researchers and pharmaceutical companies have been striving to develop innovative therapies that effectively manage the condition and improve patients' quality of life. One such breakthrough in diabetes treatment is Exendin-4, a remarkable peptide with potent glucose-lowering effects. This remarkable peptide was originally isolated from the saliva of the Gila monster lizard (Heloderma suspectum). It has proven to be a potent agonist of the glucagon-like peptide-1 receptor (GLP-1R) and activates various signaling pathways involved in multiple biological activities, such as cell apoptosis, insulin secretion, and microglial cell inactivation.

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Figure 1. Exendin-4, a GLP-1R agonist plays a vibrant role in various biological activities such as apoptosis, Beta-cells proliferation, and glucose through different signaling pathways.
(Source: Rajabi, H. et al., 2022)

Clinical Efficacy of Exendin-4

• Effect of Exendin-4 on epitheliogenesis and cutaneous wounds
  Ex-4 has a significant impact on epithelial growth and skin wound healing. It reduces the accumulation of pro-oxidants and byproducts that lead to cutaneous and gastric wounds in diabetic individuals. Ex-4 administration decreases superoxide anions and serum IL-6 levels, promoting a decrease in inflammation and oxidative stress. It has angiogenesis potential, increasing tubulogenesis rate and enhancing protein levels associated with angiogenesis. Ex-4 also induces keratinocyte proliferation and diminishes the frequency of gastric ulcers by suppressing inflammation and oxidative stress, thus accelerating healing and confining ulcer progression.
• Effect of Exendin-4 on cancer
  Ex-4 has demonstrated anti-cancer properties, inhibiting the proliferation and metastasis of breast cancer cells and promoting apoptosis. It modulates key effectors involved in cancer progression, such as Caspase-9, Akt, and MMP-2. Ex-4 also attenuates ovarian cancer cell proliferation and confines tumor mass via the GLP-1R signaling pathway. In pancreas and prostate cancers, Ex-4 reduces tumor size, stimulates cytotoxic T cells, and modulates regulatory T cell function. Moreover, Ex-4 sensitizes cancer cells to radiation and shows promise in preventing cachexia and reducing insulin levels in tumor-bearing subjects.
• Effect of Exendin-4 on neurodegenerative disorders
  Ex-4 exhibits neuroprotective effects in the CNS by inhibiting apoptosis and passing through the blood-brain barrier to activate signaling pathways. It promotes SERCA expression, inhibits apoptosis, and decreases pro-apoptotic effectors while increasing Bcl-2 expression in spinal cord injury. In the context of degenerative diseases like Alzheimer's and Parkinson's, Ex-4 reduces tau protein aggregation by decreasing GSK-3β phosphorylation and increasing insulin signaling pathways. In an experimental model of Parkinson's disease, Ex-4 reduces degeneration of dopaminergic neurons and microglial MMP-3 secretion. Additionally, Ex-4 can inhibit endothelial injury through the PI3K/p-Akt/Bcl-xl/Bcl-2 axis, potentially impacting epithelial growth and skin wound healing.
• Effect of Exendin-4 on cardiovascular disease
  Ex-4 has an impact on cardiovascular disorders in diabetic patients. Ex-4 activates AMPK and the mTOR signaling pathway, reducing cardiac injury and remodeling. It promotes angiogenesis, neovascularization, and mitochondrial function while suppressing oxidative stress. Ex-4 inhibits vascular smooth muscle cell (VSMC) proliferation and migration induced by angiotensin-II, improving hypertension and atherosclerosis. It also regulates the proliferation of VSMCs by inhibiting NOR1 promoter activity. In pulmonary arterial hypertension, Ex-4 reduces pro-inflammatory cytokines, restores right ventricular function, and improves smooth muscle myosin heavy chain levels.
• Effect of Exendin-4 on hepatic tissue
  Ex-4 has a significant impact on hepatic tissue. In non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), Ex-4 improves hepatic lipid metabolism and reduces lipotoxicity, oxidative stress, and hepatic steatosis. It promotes hepatic lipid metabolism by activating GLP-1R signaling and PPAR-α, leading to decreased synthesis of apolipoprotein C and enhanced degradation of fatty acids. Additionally, Ex-4 reverses the dysfunction of Sirt-1 and controls ER homeostasis, contributing to improved hepatic function.

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Exendin-4-Related Antigens

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