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.
Highlights
The pancreas is a crucial organ in tight control of blood glucose levels. β-cells located within Langerhans’ islets secrete insulin, further stimulating glucose uptake into skeletal muscles and adipose tissue
1-cytronellic acid (CA)-LPC over the full range of analyzed concentrations. 1-geranic acid (GA)-LPC reduced the viability of MIN6 cells only at the highest concentration (500 μM)
MIN6 cells by about 50%, even at the lowest concentration used (5 μM) while in the case of 1-FARA-LPC, a similar effect was observed at a concentration of 10 μM (Figure 2A)
Summary
The pancreas is a crucial organ in tight control of blood glucose levels. β-cells located within Langerhans’ islets secrete insulin, further stimulating glucose uptake into skeletal muscles and adipose tissue. The pancreas is a crucial organ in tight control of blood glucose levels. Β-cells located within Langerhans’ islets secrete insulin, further stimulating glucose uptake into skeletal muscles and adipose tissue. Blood glucose homeostasis is under the control of glucagon-like peptide-1 (GLP-1). GLP-1, a peptide secreted from intestinal enteroendocrine L cells, is proposed to act as a factor in reducing appetite and food intake working on the central nervous system [2]. GLP-1 mimetics show glucose-lowering efficacies as well as notable weight-loss effects, treatment with exenatide and sitagliptin, GLP-1–derived medications, was supposed to increase cancer risk, especially pancreatic and thyroid carcinomas [3]. Cases of pancreatitis were described in connection with the use of exenatide, liraglutide, and other GLP-1 analogs
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