by Vanita R. Aroda, MD

In the April 2021 issue of Endocrine Reviews, Brent McLean from the laboratory of Daniel Drucker, and co-authors, provide an extensive state-of-the-art update on GLP-1 (glucagon-like peptide-1) action – from sites of synthesis to receptor activation. Glucagon-like peptide was originally described more than 30 years ago as an insulin-stimulating glucoregulatory hormone, formed post-translationally from proglucagon.¹ Consistent with the incretin concept, GLP-1 was described as a hormone secreted in response to oral nutrients in the gut, enabling glucose-dependent insulin secretion from pancreatic beta cells.^1,2 This review highlights the emerging concepts with regards to sites of synthesis of GLP-1 and sites of action. Several early, and debatable, notions have been refined through advances in technology and the ability to better detect, isolate, and characterize GLP-1 and its receptor – though the authors highlight the challenges of understanding GLP-1 biology due to low levels of expression and issues in technical validation. Nonetheless, there have been clear advances in our knowledge of GLP-1 sites of synthesis and action.

First, though the L cell network of the gut is still considered the predominant contributor to circulating GLP-1, other sources of GLP-1 are now invoked, including pancreatic-derived GLP-1 and brain-derived GLP-1. In support of a paracrine model, the authors describe early preclinical data that suggest the alpha cell is capable of producing GLP-1 in response to injury, and that this pancreatic-derived GLP-1 may contribute to glucose homeostasis. Additionally, glucagon produced within the islet is able to stimulate insulin secretion through the GLP-1 receptor, further implicating local paracrine interactions between alpha and beta cells in the pancreas to help regulate glucose-stimulated insulin secretion.³

Brain-derived GLP-1 is also discussed, with proglucagon mRNA transcripts reported in the brainstem and glucagon-like peptides and the GLP-1 receptor reported to be widely distributed throughout the central nervous system. GLP-1-producing neurons in the brainstem, termed preproglucagon (PPG) neurons, produce GLP-1 – conceptualizing GLP-1 as a neurotransmitter ready for synaptic release from the axon terminal. Interestingly, inactivation of gut GLP-1 production does not impact control of food intake or body weight, implicating a potential role for local brainstem-derived GLP-1 in appetite regulation and body weight rather than gut-derived GLP-1.⁴ However, the authors share that the appetite-suppressing effects of GLP-1 receptor agonists are due to interactions with GLP-1 receptors on cells in the circumventricular organs outside the blood brain barrier, rather than activation of these PPG neurons, though this is an area ripe for further study.³   

Finally, the GLP-1 receptor is expressed in multiple organs throughout the body, possibly contributing to yet undiscovered effects and therapeutic potential. And, even though multiple organs express the GLP-1 receptor, it is also postulated that many of the benefits of GLP-1 receptor agonism may result from indirect mechanisms in organs and cell types with variable GLP-1 receptor expression. For example, although clinical studies have demonstrated the multiple cardiometabolic benefits of GLP-1 receptor agonists, many benefits – such as reduction in myocardial infarction, decrease in hepatic lipid accumulation, and decrease in albuminuria – are not explained by direct GLP-1 receptor mechanisms.³ Such advances in understanding sites of synthesis and action of GLP-1 – and both direct and indirect effects of GLP-1, as captured by McLean and colleagues – will continue to expand the potential for mechanistic and therapeutic discovery.

 

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References

1. Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest 2017;127:4217–27.
2. Holst JJ. From the incretin concept and the discovery of GLP-1 to today’s diabetes therapy. Front Endocrinol (Lausanne) 2019;10:260.
3. McLean BA, Wong CK, Campbell JE, et al. Revisiting the complexity of GLP-1 action from sites of synthesis to receptor activation. Endocrine Rev 2021;42:101–32.
4. Song Y, Koehler JA, Baggio LJ, et al. Gut-proglucagon-derived peptides are essential for regulating glucose homeostasis in mice. Cell Metab 2019;30:976–86.e3.