GLP-1a: Going beyond Traditional Use

Abstract

Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson's Disease and improve emotional well-being. In Alzheimer's disease, GLP-1 analogs can improve the brain's glucose metabolism by improving glucose transport across the blood-brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain's reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses.

Keywords: Alzheimer’s disease; Parkinson’s disease; depression; diabetes; glucagon-like peptide-1; non-alcoholic fatty liver disease; obesity; visceral insulin resistance adiposity syndrome.

Figure 1

Most important traditional organ targets for GLP-1 and its actions on each target. GLP-1: Glucagon-like peptide; ↓: decrease; ↑: increase; +: plus. The red color represents the indirect effects of GLP-1 on the determined organ, and the blue color represents direct effects. The red–blue mixtures represent the determining effects in direct and indirect related GLP-1 activity.

Figure 2

Flow chart showing the study selection.

Figure 3

Diabetes, obesity, and possible actions of GLP-1. GLP-1: glucagon-like peptide; NGLP-1: native GLP-1; LGLP-1: long-acting GLP-1 receptor agonist; SGLP-1: short-acting GLP-1 receptor agonist; ↓: decrease; ↑: increase; ⇒: equal; +: plus.

Figure 4

Substantia nigra in Parkinson’s disease and the healthy brain.

Figure 5

Main cellular pathways affected by GLP-1 in neurons. GLP-1R: GLP-1 receptor; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; MAPK: mitogen-associated protein kinase; CREB: cyclic adenosine monophosphate response element-binding protein; BAD: Bcl-2 antagonist of death; NFkB: nuclear factor-kappa B; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; GSK-3B: glycogen synthase kinase 3 beta; FOXO1/03: forkhead box protein O1; ↓: decrease; ↑: increase; ∅ = impairment; +: plus.

Figure 6

Physiopathology of NAFLD and the progression to NASH. ↓: decrease; ↑: increase; +: added to; ⇒: equal; TNF-α: tumor factor necrosis; CRP: C reactive protein; IL-8: interleukin 8; CXCL10: C–V–C motif chemokine ligand 10.

Figure 7

Anatomical and histological alterations in Alzheimer’s disease. ↓ = decrease.

Figure 8

Pathophysiology of Alzheimer’s disease focused on insulin resistance and the effects of GLP-1. Ad: Alzheimer’s disease; ↓: decrease; ↑: increase; Aβ: β-amyloid; ER: endoplasmic reticulum; HPP: hyperphosphorylation.

Figure 9

The actions of GLP-1 in key factors involved in the pathophysiology of depression. ↑ = increase; ↓ = decrease; GABA: gamma-amminobutyric acid; OS: oxidative stress; +: plus; Φ: impairment.

Figure 10

Considerations about the role of GLP-1 receptor agonists in the pathophysiology of chemical dependency. ↑: increase; ↓: decrease.