Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting GLP-1R have entered clinical treatment. However, novel functional molecules with reduced side effects and enhanced therapeutic efficacy are still in high demand. In this review, we summarize the basis of GLP-1R cellular signaling, and how it is involved in the treatment of T2DM. We review the functional molecules of incretin therapy in various stages of clinical trials. We also outline the current strategies and emerging techniques that are furthering the development of novel therapeutic drugs for T2DM and other metabolic diseases.
Diabetes is considered the fastest-growing global health problem, affecting about 10% of adults around the world. The diabetic population will reach 783 million globally in 2045 according to an estimate from the International Diabetes Federation. All types of diabetes share the common clinical manifestation of hyperglycemia and several characteristic symptoms, including thirst, polyuria, constant hunger, fatigue, weight loss, and blurred vision. As the disease progresses, complications such as retinopathy, nephropathy, and neuropathy may occur, and the risk of cardiovascular diseases, obesity, and nonalcoholic fatty liver disease will increase, which significantly affects the quality of life.
T2DM accounts for more than 90% of diabetes cases, although this percentage might be higher since approximately one-third of people living with T2DM are undiagnosed. Adopting a healthy lifestyle and taking metformin are the cornerstone for T2DM management. A combination of sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, and insulin injections can be added when the single antidiabetic medication is insufficient. However, these drugs can cause side effects such as hypoglycemia, weight gain, and cardiovascular risk.
Pancreatic β-cell dysfunction and resultant insulin deficiency are the key features of T2DM, however, most medications do not target β-cell and become less effective as diabetes progress. Fortunately, a couple of gut-derived natural peptides termed incretins that can stimulate insulin secretion have inspired novel T2DM treatments. Incretins were first discovered upon observing that oral glucose administration leads to greater insulinotropic effects than intravenous administration. Since then, researchers began to investigate gut-derived insulin secretagogues; and incretin-based therapies currently have become the preferred first injection therapy for T2DM treatment, due to their strong glycemic control effect and remarkable safety profile. Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Although both GLP-1 and GIP could promote insulin secretion in a healthy state, the therapeutic potential of GIP alone is controversial. In contrast, the GLP-1 receptor (GLP-1R) is thought to be one of the most important potential drug targets for glucose-dependent T2DM treatment, lowering hypoglycemia risk compared to insulin and sulfonylureas.
GLP-1, as the endogenous agonist of GLP-1R, is a promising natural antidiabetic product due to its anorexigenic, insulinotropic, and weight-reducing effects. However, in vivo GLP-1 can be cleaved by dipeptidyl peptidase 4 (DPP-4) immediately after secretion at the second amino acid (alanine) from its N-terminal. This will lead to an instant degradation of GLP-1 and a short circulation time in the human body. Although GLP-1 has many potential advantages, its short circulation time of about 2 min limits its application in treatment since such frequent administration is incompatible with patient compliance and thereby reducing drug effectiveness.
DPP-4 inhibitors and GLP-1 analogs with prolonged circulation time have already been applied in incretin therapy and have performed well. However, GLP-1R agonists are favored because they have superior body weight control and cardiovascular outcomes. In this review, we discuss the current GLP-1R signaling and ligand development strategies, trends in incretin therapy, and perspectives on T2DM treatment.
G protein-coupled receptors (GPCRs) are widely distributed in various tissues and play key roles in a diversity of physiological activities. As the largest receptor family, GPCRs are important drug targets for a broad range of indications. GPCRs share a conserved seven-transmembrane helix bundle with three extracellular loops (ECLs) and three intracellular loops (ICLs). The ECLs form an extracellular surface that interacts with orthosteric ligands. While the ICLs, to large extent, determine downstream receptor signaling. GLP-1R, together with four other glucagon receptors (GCGR, GLP-2R, GIPR, and GHRHR), belongs to the secretin (class B1) GPCR family, whose endogenous ligands are peptide hormones. Class B1 GPCRs have a large and structurally conserved extracellular domain (ECD) of 120–160 residues at the N-terminal, forming a three-layered α-β-β-α fold that is stabilized by three interlayer disulfide bonds.
The endogenous ligands of GLP-1R are GLP-1 (7-36) and GLP-1 (7-37), products from the post-translational processing of proglucagon. Proglucagon also produces several other peptide hormones for receptors in the glucagon receptor family, such as glucagon, oxyntomodulin (OXM), and GLP-2. On binding with endogenous peptides, the glucagon receptor family shares a similar recognition mode, which is described as a “two-domain” binding mode. The C-terminal α helix of peptide ligand initiates peptide recognition by binding to the ECD, then the peptide N-terminal can activate the receptor and trigger its downstream signaling cascade by binding to the transmembrane domain (TMD) ligand-binding pocket. Recently released cryo-EM structures of GLP-1R in complex with a peptide ligand revealed that peptides form a single helix in binding post, which is a unique feature shared in class B1 GPCRs.
Researchers have been pursuing functional studies of GLP-1R for many years to illuminate the mechanism of GLP-1R signaling. GLP-1R downstream signaling pathways network can be activated through coupling with the intracellular transducers. The diverse protein-binding forms will lead to complex downstream pathways.
Currently, it is believed that GLP-1R predominantly signals through the Gα s/cAMP pathway; however, there is evidence that GLP-1R couples with Gα q and other G proteins. After activation, GLP-1R undergoes phosphorylation at the C-terminal, which further recruits β-arrestin, leading to internalization and desensitization of the receptor. The Gα s/cAMP pathway directly leads to the glucose-induced secretion of insulin granules. After activation by full agonists such as GLP-1, GLP-1R couples with Gα s, activates adenylate cyclase (AC), and causes the accumulation of cAMP. With increasing cAMP levels, protein kinase A (PKA) and the exchange protein directly activated by cAMP-2 (Epac-2) are also activated. PKA and Epac-2 trigger the closure of K ATP and K V channels, which depolarizes the cell membrane, opens voltage-dependent calcium channels (VDCC), and causes Ca 2+ influx. In addition to the classical function of cAMP, the cAMP/CREB pathway could also induce the expression of insulin receptor substrate 2 (IRS2) and promote β-cell survival, demonstrating the protective effects of GLP-1 analogs on β-cells.
In addition to the Gα s/cAMP pathway, GLP-1R is also able to couple with other G protein subtypes including Gα i, Gα q, Gα o, and Gα 11.
