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

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R-HSA-381676
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Homo sapiens
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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
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
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
17900700 G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes

Winzell, MS, Ahren, B

Pharmacol Ther 2007
9914469 Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion

Lang, J

Eur J Biochem 1999
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
11078440 Triggering and amplifying pathways of regulation of insulin secretion by glucose

Henquin, JC

Diabetes 2000
17306374 Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle, ME, Egan, JM

Pharmacol Ther 2007
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