Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Abstract

It has been estimated that approximately 8.4% of the world population currently live with diabetes mellitus and type 2 diabetes is the most common form. Type 2 diabetes increases the risk of complications such as heart attacks, blindness, amputations and kidney failure. Glucagon like Peptide-1 (GLP-1) is an effective insulinotropic agent and therefore its effects on insulin secretion have been greatly examined for more than two decades. It is a polypeptide hormone secreted by the intestinal L-cells into the blood in response to food uptake. GLP-1 has a very short half-life in vivo due to the rapid proteolytic degradation by Dipeptidyl Peptidase IV (DPP-IV). Therefore DPP-IV resistant GLP-1 analogues, Exenatide and Liraglutide, have been developed and are currently being used in the treatment of type 2 diabetes. GLP-1 agonist functions by binding to its receptor, GLP1R, on the cell surface.The GLP-1R belongs to the class B peptide receptor family based on its structure and function. The binding of GLP-1 to its receptor results in activation of Gαs coupled adenylyl cyclase and the production of cyclic Adenosine Monophosphate (cAMP), which enhances glucose-induced insulin secretion. Continuous GLP-1R activation also causes insulin secretion and pancreatic islet β-cell proliferation and neogenesis. The GLP-1R is internalised following its activation, which regulates the biological responsiveness of the receptor. Structurally the GLP-1R contains a large N-terminal extracellular domain (TM1-TM7) joined by three intracellular loops (ICL1, ICL2, ICL3) and three extracellular loops (ECL1, ECL2, ECL3), and an intracellular C-terminal domain. These domains play critical roles in GLP-1R trafficking to the cell surface, and also in agonist dependent activation and internalisation of the receptor. This review is focused on type 2 diabetes, its treatment with GLP-1, GLP-1R structure and function, and the physiological affects resulting from GLP-1R activation.

Distinct regions in the C-Terminus required for GLP-1R cell surface expression, activity and internalisation

“…Glucagon like peptide-1 (GLP-1) mediates insulin secretion by acting on the GLP-1 receptor (GLP-1R), making the receptor an important target and of high therapeutic potential in the treatment of type 2 diabetes (Gallwitz, 2010;Thompson and Kanamarlapudi, 2013). GLP-1 in vivo half-life is very short (~1.5 min) due to its rapid proteolytic degradation by dipeptidyl peptidase-IV (DPP-IV) and therefore long acting GLP-1 analogues such as liraglutide, which have resistance to DPP-IV proteolysis, are developed for the treatment (Meier, 2012).…”

“…GLP-1 in vivo half-life is very short (~1.5 min) due to its rapid proteolytic degradation by dipeptidyl peptidase-IV (DPP-IV) and therefore long acting GLP-1 analogues such as liraglutide, which have resistance to DPP-IV proteolysis, are developed for the treatment (Meier, 2012). The GLP-1R, which is a member of the family B G-protein coupled receptors (GPCRs), functions at the cell surface by coupling to Ga s and Ga q pathways and causing extracellular signal-regulated kinase (ERK) phosphorylation (Thompson and Kanamarlapudi, 2013;Montrose-Rafizadeh et al, 1999). Agonistinduced GLP-1R internalisation plays an important role in glucose induced insulin secretion (Kuna et al, 2013).…”

“…The extracellular N-terminal domain in many GPCRs is important for their biosynthetic trafficking and maturation (Thompson and Kanamarlapudi, 2013;Dong et al, 2007). Like other family B GPCRs, the GLP-1R contains an N-terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for the newly synthesised receptor cell surface expression (Huang et al, 2010;Chen et al, 2010;Whitaker et al, 2012).…”

“…Furthermore, the C-terminal region is required for some GPCRs trafficking from the endoplasmic reticulum (ER) to the plasma membrane (Dong et al, 2007). The C-terminal domain of GPCRs is also known to interact with several intracellular proteins involved in the internalisation of the receptor to intracellular signalling pathways (Thompson and Kanamarlapudi, 2013;Dong et al, 2007).…”

“…Some GPCRs possess a helix-8 located just downstream of transmembrane (TM) 7 that associates with a number of intracellular proteins (Kuramasu et al, 2006). Additionally, many GPCRs possess a PDZ binding site at the very end of the C-terminal domain, which interacts with the PDZ domain of proteins required for biosynthetic trafficking of the receptor (Thompson and Kanamarlapudi, 2013;Ango et al, 2001).…”