Abstract
Synthetic glucagon-like peptide-1 (GLP-1) analogues are effective anti-obesity and anti-diabetes drugs. The beneficial actions of GLP-1 go far beyond insulin secretion and appetite, and include cardiovascular benefits and possibly also beneficial effects in neurodegenerative diseases. Considerable reserves of GLP-1 are stored in intestinal endocrine cells that potentially might be mobilized by pharmacological means to improve the body’s metabolic state. In recognition of this, the interest in understanding basic L-cell physiology and the mechanisms controlling GLP-1 secretion, has increased considerably. With a view to home in on what an L-cell is, we here present an overview of available data on L-cell development, L-cell peptide expression profiles, peptide production and secretory patterns of L-cells from different parts of the gut. We conclude that L-cells differ markedly depending on their anatomical location, and that the traditional definition of L-cells as a homogeneous population of cells that only produce GLP-1, GLP-2, glicentin and oxyntomodulin is no longer tenable. We suggest to sub-classify L-cells based on their differential peptide contents as well as their differential expression of nutrient sensors, which ultimately determine the secretory responses to different stimuli. A second purpose of this review is to describe and discuss the most frequently used experimental models for functional L-cell studies, highlighting their benefits and limitations. We conclude that no experimental model is perfect and that a comprehensive understanding must be built on results from a combination of models.
Highlights
Synthetic glucagon-like peptide-1 (GLP-1) analogues are effective anti-obesity and antidiabetes drugs
GLP-1 receptor (GLP-1R) targeting strategies are based on the use of either dipeptidyl peptidase-4 (DPP-4) inhibitors to prolong the half-life of the endogenous GLP-1, or on GLP-1 receptor agonists (GLP-1RAs) that are DPP-4 resistant per se and/or become DPP-4 resistant when bound to a larger protein such as albumin [1, 13, 14]
The original definition of an L-cell was based on electron microscopical appearance and immunohistochemical stainings, characterizing L-cells as open-type enteroendocrine cells with large dense core granules and containing GLP-1 and/or the other proglucagon-derived peptides
Summary
Studies in humans are the only way to provide definitive experimental answers on human physiology. The experiments that confirmed the existence of the incretin effect were based on studies carried out in humans [148, 149]. Studies in humans have contributed indisputably to the general understanding of L-cell physiology, and have been instrumental in deciphering the stimuli that causes GLP-1 secretion in humans [2, 3], and the extent to which each macronutrient evokes GLP-1 secretion [139]. Studies involving procedures more invasive than the simple ingestion
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