Reactome | Glucagon-like Peptide-1 (GLP1) regulates insulin secretion

Glucagon-like Peptide-1 (GLP1) regulates insulin secretion

Stable Identifier

R-HSA-381676

DOI

10.3180/R-HSA-381676.8

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, plasma membrane

ReviewStatus

5/5

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Glucagon-like Peptide-1 (GLP1) regulates insulin secretion

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Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits.
The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.
Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.
cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane.

Literature References

PubMed ID	Title	Journal	Year
17306374	Mechanisms of action of glucagon-like peptide 1 in the pancreas Doyle, ME, Egan, JM	Pharmacol Ther	2007
11078440	Triggering and amplifying pathways of regulation of insulin secretion by glucose Henquin, JC	Diabetes	2000
11815463	Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion Bratanova-Tochkova, TK, Cheng, H, Daniel, S, Gunawardana, S, Liu, YJ, Mulvaney-Musa, J, Schermerhorn, T, Straub, SG, Yajima, H, Sharp, GW	Diabetes	2002
9914469	Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion Lang, J	Eur J Biochem	1999
17900700	G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes Winzell, MS, Ahren, B	Pharmacol Ther	2007
12475787	The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion MacDonald, PE, El-Kholy, W, Riedel, MJ, Salapatek, AM, Light, PE, Wheeler, MB	Diabetes	2002
15569269	Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential Gromada, J, Brock, B, Schmitz, O, Rorsman, P	Basic Clin Pharmacol Toxicol	2004
8830891	Molecular mechanism underlying glucagon-like peptide 1 induced calcium mobilization from internal stores in insulin-secreting beta TC3 cells Gromada, J, Rorsman, P	Acta Physiol Scand	1996