Structural Insight on GPR119 Agonist as Potential Therapy for Type II Diabetes: A Comprehensive Review

Abstract

Diabetes Mellitus [DM] is a long-term metabolic condition that is characterized by excessive blood glucose. DM is the third most death-causing disease, leading to retinopathy, nephropathy, loss of vision, stroke, and cardiac arrest. Around 90% of the total cases of diabetic patients have Type II Diabetes Mellitus[T2DM]. Among various approaches for the treatment of T2DM. G protein-coupled receptors [GPCRs] 119 have been identified as a new pharmacological target. GPR119 is distributed preferentially in the pancreas β-cells and gastrointestinal tract [enteroendocrine cells] in humans. GPR119 receptor activation elevates the release of incretin hormones such as Glucagon-Like Peptide [GLP1] and Glucose Dependent Insulinotropic Polypeptide [GIP] from intestinal K and L cells. GPR119 receptor agonists stimulate intracellular cAMP production via Gαs coupling to adenylate cyclase. GPR119 has been linked to the control of insulin release by pancreatic β-cells, as well as the generation of GLP-1 by enteroendocrine cells in the gut, as per In vitro assays. The dual role of the GPR119 receptor agonist in the treatment of T2DM leads to the development of a novel prospective anti-diabetic drug and is thought to have decreased the probability of inducing hypoglycemia. GPR119 receptor agonists exert their effects in one of two ways: either by promoting glucose absorption by β-cells, or by inhibiting α-cells' ability to produce glucose. In this review, we summarized potential targets for the treatment of T2DM with special reference to GPR119 along with its pharmacological effects, several endogenous as well as exogenous agonists, and its pyrimidine nucleus containing synthetic ligands.

Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents

“…GPR119 is mainly coupled to the Gαs pathway and activated to increase intracellular cAMP levels, thereby promoting GSIS and incretin secretion [39] (Figure 2). At the same time, GPR119 activation also increases glucagon secretion, which may reduce the risk of medically induced hypoglycemia in patients with diabetes undergoing intensive insulin therapy [40]. Currently, no GPR119 agonists have entered clinical phase III trials, possibly owing to its poor efficacy, as the sequence of GPR119 in rodents differs from that in humans, making it difficult to translate in vivo models in mice or rats into human clinical trials [37].…”