Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation

Abstract

Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.

Failure of the brain glucagon-like peptide-1-mediated control of intestinal redox homeostasis in a rat model of sporadic Alzheimer’s disease

“…Incretin effects of GLP-1 have been discovered in the 1980s, and they have been successfully exploited for pharmacological glucoregulation by the 2000s [85]. Nevertheless, the physiology of the GLP-1 is still actively explored, and many of its exciting roles are yet to be fully understood [43,86]. It has been proposed that brain GLP-1Rs are involved in the regulation of peripheral glucose homeostasis, fuel partitioning, and monitoring energy levels to prepare the organism for the fasting that comes after a meal [43,59].…”

How glucagon-like peptide 1 receptor agonists work

“…The mechanisms behind the cardioprotective properties of GLP-1RAs are still unclear. Studies have demonstrated that GLP-1RAs exert a direct effect on the heart and blood vessels 6 and an indirect effect via improved glycaemia 24 , a reduction in blood pressure and postprandial rise in triglycerides 25 , a reduction in markers of oxidative stress and systemic inflammation 26,27 (Figure 3). The reduction in MACE observed with treatment with GLP-1RAs is mainly driven by a significant reduction in fatal or non-fatal stroke, but also a significant reduction in risks for CV death and fatal or non-fatal myocardial infarction 15 , suggesting that GLP-1RAs may exert their cardioprotective effects through anti-atherosclerotic mechanisms.…”

“…Brain-derived GLP-1 act as a neurotransmitter and can target multiple GLP-1Rs throughout the central nervous system, including effects on satiety 6 . In addition, GLP-1R activation in the brain have been linked to neuroprotective properties in experimental neurodegenerative disease models 6 . Deduced from both preclinical and human studies, GLP-1 has extra-pancreatic effects in the gut, kidney, nervous system, heart and immune system (Figure 1) 2 .…”

“…Multiple GLP-1R agonists (GLP-1RAs) utilizing the plasma glucose-lowering and body weight-lowering effects of GLP-1 have been developed, and today we have more than 15 years of clinical experience with GLP-1RAs for the treatment of T2D and 6 years of clinical experience with GLP-1RA-based treatment of obesity. Despite the long clinical experience with GLP-1RAs, the exact mechanisms by which GLP-1RAs exert their effects are still debated 6 retain their ability to delay gastric emptying leading to lower postprandial glucose excursions compared with the long-acting GLP-1RAs, which are associated with the development of tolerance (tachyphylaxis) to GLP-1's effect on gastric emptying 10 .…”

“…In normal physiology, GLP-1 modifies gastrointestinal function by decreasing motility of the stomach and intestine, thereby delaying gastric emptying and reducing postprandial plasma glucose excursions ( 5 ). Brain-derived GLP-1 acts as a neurotransmitter and can target multiple GLP-1Rs throughout the central nervous systemCNS, including effects on satiety ( 6 ). In addition, GLP-1R activation in the brain has been linked to neuroprotective properties in experimental neurodegenerative disease models ( 6 ).…”