Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs

Abstract

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

Phospholipid Derivatives of Cinnamic Acid Restore Insulin Sensitivity in Insulin Resistance in 3T3-L1 Adipocytes

“…This was previously studied in our research groups and was proved in terms of anticancer properties [ 30 ]. It was previously shown that the conjugation with phospholipids is an effective method for increasing the biological properties of numerous natural compounds [ 31 , 40 , 41 , 42 , 43 ].…”

Screening of Relevant Metabolism-Disrupting Chemicals on Pancreatic β-Cells: Evaluation of Murine and Human In Vitro Models

“…The reasons for the discrepancy may include different time treatments, cellular models, and species used. In addition, we have to consider that the biological characteristics of 2D-monolayered cell models are not identical to islets cells as, it is well known that cell-to-cell communication and spatial arrangement in the islets allow signal synchronization, leading to more effective insulin secretion [38]. In any case, although few epidemiological studies have been published, they all conclude that BPS is associated with an increased risk of type 2 diabetes [39,40].…”

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

“…In fact, the direct or indirect effect of LPC and G2A or GPR4 is controversial. In addition, the LPC derivative also targeted four other G protein-coupled receptors, namely GPR40, GPR55, GPR119, and GPR120 [ 126 , 127 ]. Studies have indicated that the stimulatory effect of isoprenoid derivatives of LPC on Ca 2+ signaling in MIN6 cells was GPR40-, GPR55-, GPR119-, and GPR120-dependent [ 127 ].…”

“…In addition, the LPC derivative also targeted four other G protein-coupled receptors, namely GPR40, GPR55, GPR119, and GPR120 [ 126 , 127 ]. Studies have indicated that the stimulatory effect of isoprenoid derivatives of LPC on Ca 2+ signaling in MIN6 cells was GPR40-, GPR55-, GPR119-, and GPR120-dependent [ 127 ]. GPR40/GPR55 has been implicated in inflammatory pain and neuropathic pain [ 128 , 129 ], but studies on LPC and these receptors in chronic pain are lacking.…”