Exenatide promotes the autophagic function in the diabetic hippocampus: a review

Figures & data

Figure 1. Schematic illustration of the steps of autophagy. The phagophore assembly site (PAS) denotes the proposed site for autophagosome formation, to which most of the core autophagy-related proteins (ATG) are recruited. The elongation of the phagophore forms the autophagosome, which undergoes maturation by fusion with a lysosome. Finally, the autophagosome inner membrane and cargo are degraded, with the recycling of the resultant macromolecules. Many regulatory components control the steps of autophagy such as the vesicle membrane protein (VMP1) that can trigger autophagy by its overexpression and might function as a transmembrane protein, the UNC-51-like kinase (ULK) complex that contains various ATG proteins, the class III phosphatidylinositol 3-kinase (PtdIns3K) complex that is involved in autophagosome formation or clearance, the lipidated form of LC3 (LC3-II) that is attached to both faces of the phagophore, and TP53INP2 that can interact with LC3 as well as VMP1 [20].

Figure 2. The relation between ER stress, apoptosis & autophagy. Many diabetic factors including hyperglycemia and oxidative stress can lead to increased proinsulin misfolding and mTORC1 activation, with subsequently inhibited autophagy and ER stress, and ultimately β-cell death via apoptosis. The mTORC1 inhibitors such as rapamycin can activate autophagy, stopping the ER stress and β-cell apoptosis. Eventually, these events lead to decreased proinsulin and insulin biosynthesis. Protein kinase R (PKR)-like eukaryotic inhibition factor 2a kinase (PERK), inositol requiring enzyme 1alpha (IRE1α), activating transcription factor 6 (ATF6) [30].

Figure 3. A diagrammatic illustration of the neuronal cell loss that can result from autophagy suppression. The hyperglycemia in diabetic GK rats causes increased nitric oxide (NO) level in the hippocampus, so the autophagy-regulator protein (ATG4B) undergoes S-nitrosation (SNO). This results in compromising the enzyme activity of the precursors and deconjugating members of the Atg8-family, preventing the phagophore expansion and the formation of autophagosomes and autolysosomes [33].

Figure 4. A diagram demonstrating the mechanisms responsible for the effects of chronic continuous peripheral exenatide administration on type 2 diabetic rats. Exenatide may initiate an insulinotropic response, lower triglycerides and heart rates, increase brain weight by stimulation of neuroprotective mechanisms and rescue of brain vasculature, and protect brain cortices against apoptosis. The increased brain levels of GLP-1 can result from either crossing the blood-brain barrier or local production after stimulation of the vagal nerve. The increased brain levels of cGMP may protect against apoptosis. AMPK is a metabolic regulator, which prevents neuronal apoptosis and autophagic activation via the inactivation of mTOR. Exenatide can partially rescue the brain cortical AMPK levels, enhancing the autophagic pathway, which is associated with increased PI3K class III, LC3-II, Atg7, and glycosylated LAMP-1. The lower caspases activity is reinforced by higher Bcl2 levels, which is a well-known anti-apoptotic protein [7].

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