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Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function

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Abstract

GLP‐1 was described as an incretin over 30 years ago. GLP‐1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP‐1 activates GLP‐1 receptors (GLP‐1r) on the β‐cell to induce insulin secretion in a glucose‐dependent manner. GLP‐1 also inhibits α‐cell secretion of glucagon. As few, if any, GLP‐1r are expressed on α‐cells, indirect regulation, via β‐ or δ‐cell products has been thought to be the primary mechanism by which GLP‐1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP‐1r on α‐cells for direct regulation as well. Although the predominant source of circulating GLP‐1 is the intestine, the α‐cell becomes a source of GLP‐1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP‐1 is also be important in regulating nutrient‐induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg‐derived protein produced by the α‐cell, in stimulating insulin secretion by acting on GLP‐1r. Altogether, these data clearly demonstrate the important role of Gcg‐derived peptides in regulating insulin secretion. Because of GLP‐1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus. © 2020 American Physiological Society. Compr Physiol 10:577‐595, 2020.

Figure 1. Figure 1. The incretin effect: Glucose levels are lower while insulin levels are higher when the same dose of glucose is administered directly into the gut versus when administered intravenously (IV). This difference in insulin between the gut and venous infusion is the “incretin effect” which occurs in response to GLP‐1 and GIP secreted from the distal gut. Adapted, with permission, from McIntyre N, et al. 153.
Figure 2. Figure 2. Intestinal GLP‐1 secretion: Several factors have been linked to GLP‐1 secretion. The parasympathetic nervous system (PNS) stimulates GLP‐1 secretion via cholinergic muscarinic receptors (MR). Activation of α‐adrenergic (AR) receptors stimulates while activation of β‐adrenergic receptors inhibits GLP‐1 release. Various GPCRS including ones activated by bile acids and various fatty acids stimulate GLP‐1 through PKA signaling and increases in calcium‐induced exocytosis. Lastly, direct glucose sensing, predominantly via SGLT1 in humans, activates sodium (Na+), and calcium (Ca2+) voltage‐gated channels to lead to the release of GLP‐1.
Figure 3. Figure 3. Factors that impact α‐cell GLP‐1 production. Metabolic stress, systemic inflammation, exercise, hyperglycemia, obesity, and diabetes stimulate α‐cell GLP‐1 production. IL‐6 seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of β‐cell mass and function is a likely endpoint.
Figure 4. Figure 4. Recent work highlights a more complexity to the role of Gcg‐derived peptides in the incretin effect. While historical work suggests intestinal GLP‐1 is important in regulating glucose homeostasis, there may be a role for α‐cell derived GLP‐1 as well. In addition, in response to amino acids, glucagon is secreted and acts on local GLP‐1r to regulate insulin secretion.
Figure 5. Figure 5. Postprandial GLP‐1 increases several‐fold after bariatric surgery and has been implicated as a mechanism in both positive and negative impacts of bariatric surgery. On the positive side, GLP‐1 has been implicated in increasing postprandial insulin levels to restrain postprandial glucose homeostasis, improvements in insulin sensitivity lead to reductions in fasting insulin, improved hepatic insulin sensitivity, and overall improved β‐cell function. However, on the negative side, the increase in postprandial insulin is thought to contribute to post‐bariatric hypoglycemia which occurs in as much as 30% of surgery patients.


Figure 1. The incretin effect: Glucose levels are lower while insulin levels are higher when the same dose of glucose is administered directly into the gut versus when administered intravenously (IV). This difference in insulin between the gut and venous infusion is the “incretin effect” which occurs in response to GLP‐1 and GIP secreted from the distal gut. Adapted, with permission, from McIntyre N, et al. 153.


Figure 2. Intestinal GLP‐1 secretion: Several factors have been linked to GLP‐1 secretion. The parasympathetic nervous system (PNS) stimulates GLP‐1 secretion via cholinergic muscarinic receptors (MR). Activation of α‐adrenergic (AR) receptors stimulates while activation of β‐adrenergic receptors inhibits GLP‐1 release. Various GPCRS including ones activated by bile acids and various fatty acids stimulate GLP‐1 through PKA signaling and increases in calcium‐induced exocytosis. Lastly, direct glucose sensing, predominantly via SGLT1 in humans, activates sodium (Na+), and calcium (Ca2+) voltage‐gated channels to lead to the release of GLP‐1.


Figure 3. Factors that impact α‐cell GLP‐1 production. Metabolic stress, systemic inflammation, exercise, hyperglycemia, obesity, and diabetes stimulate α‐cell GLP‐1 production. IL‐6 seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of β‐cell mass and function is a likely endpoint.


Figure 4. Recent work highlights a more complexity to the role of Gcg‐derived peptides in the incretin effect. While historical work suggests intestinal GLP‐1 is important in regulating glucose homeostasis, there may be a role for α‐cell derived GLP‐1 as well. In addition, in response to amino acids, glucagon is secreted and acts on local GLP‐1r to regulate insulin secretion.


Figure 5. Postprandial GLP‐1 increases several‐fold after bariatric surgery and has been implicated as a mechanism in both positive and negative impacts of bariatric surgery. On the positive side, GLP‐1 has been implicated in increasing postprandial insulin levels to restrain postprandial glucose homeostasis, improvements in insulin sensitivity lead to reductions in fasting insulin, improved hepatic insulin sensitivity, and overall improved β‐cell function. However, on the negative side, the increase in postprandial insulin is thought to contribute to post‐bariatric hypoglycemia which occurs in as much as 30% of surgery patients.
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Teaching Material

Ellen M. Davis and Darleen A. Sandoval. Glucagon-like Peptide-1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 10 : 2020, 577-595.

Didactic Synopsis

Major Teaching Points:

1. Glucagon-like peptide-1 (GLP-1) is an important postprandial stimulus of pancreatic insulin secretion and regulator of glucose homeostasis.

2. GLP-1 is coded by the preproglucagon gene which is expressed in the gut, brain, and ?-cells of the pancreas.

3. Due to tissue-specific post-translational processing, GLP-1 is predominantly made in the gut and brain but can also be made in the pancreatic ?-cells in response to nutrients and under times of stress.

4. Recent work suggests that ?-cell GLP-1 and glucagon, another preproglucagon-derived peptide, can stimulate insulin secretion through the GLP-1r.

5. GLP-1 has been implicated as a cause of the metabolic success of surgeries performed to correct obesity but research in genetic mouse models challenges this assumption.

6. GLP-1 has been targeted very successfully for treatment of both type 2 diabetes and obesity.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching Points. The incretin effect was originally a hypothesis used to explain why plasma insulin levels could be higher when the same dose of glucose was administered orally vs. when administered into the veins. The difference in insulin levels was thought to be due to a factor secreted by the gut. We now know that GLP-1 and GIP are both such factors that are secreted from the distal gut and also stimulate insulin secretion. Adapted from McIntyre N, et al. Lancet. 1964;41:20-21.

Figure 2. Teaching points. This figure illustrates some of the many cellular mechanisms that have been linked to GLP-1 secretion. Two branches of the nervous system that innervate the gut impact GLP-1 secretion. These are the parasympathetic nervous system (PNS) stimulates GLP-1 secretion via specific muscarinic receptors that bind to acetylcholine (MR). The sympathetic branch of the nervous system increases GLP-1 secretion via activation of specific ?-adrenergic (AR) receptors but can inhibit GLP-1 secretion via activation of β-adrenergic receptors. Nutrients and nutrient by-products act via GPCRs to increase a protein kinase A signaling pathway to induce GLP-1 secretion. Glucose absorption via two different transport mechanisms; one being GLUT2 and one being SGLT1 also lead to the release of GLP-1.

Figure 3. Teaching points. This figure illustrates some of the many factors that impact ?-cell GLP-1 production. Stress from excessive metabolites and/or inflammation resulting from infection, exercise, hyperglycemia, obesity, and diabetes all stimulate ?-cell GLP-1 production. Activation of a particular inflammatory cytokine (IL-6) seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of the number and function of β-cells is a likely endpoint.

Figure 4. Teaching points. This figure highlights an advancement to the incretin model where GLP-1 and another peptide, glucagon, that is encoded by the same Gcg gene acts on local GLP-1r to regulate insulin secretion in response to high levels of amino acids.

 

Figure 5. Teaching points. This figure highlights the potential positive and negative effects of the several-fold increase in postprandial GLP-1 that occurs in bariatric surgery patients. 


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How to Cite

Ellen M. Davis, Darleen A. Sandoval. Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 2020, 10: 577-595. doi: 10.1002/cphy.c190025