Abstract
BackgroundFree fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic β-cell survival. Short-term exposure to FFAs, such as palmitate, increases insulin secretion. On the contrary, long-term exposure to saturated FFAs results in decreased insulin secretion, as well as triggering oxidative stress and endoplasmic reticulum (ER) stress, culminating in cell death. The effects of FFAs can be mediated either via their intracellular oxidation and consequent effects on cellular metabolism or via activation of the membrane receptor GPR40. Both pathways are likely to be activated upon both short- and long-term exposure to FFAs. However, the precise role of GPR40 in β-cell physiology, especially upon chronic exposure to FFAs, remains unclear.MethodsWe used the GPR40 agonist (GW9508) and antagonist (GW1100) to investigate the impact of chronically modulating GPR40 activity on BRIN-BD11 pancreatic β-cells physiology and function.ResultsWe observed that chronic activation of GPR40 did not lead to increased apoptosis, and both proliferation and glucose-induced calcium entry were unchanged compared to control conditions. We also observed no increase in H2O2 or superoxide levels and no increase in the ER stress markers p-eIF2α, CHOP and BIP. As expected, palmitate led to increased H2O2 levels, decreased cell viability and proliferation, as well as decreased metabolism and calcium entry. These changes were not counteracted by the co-treatment of palmitate-exposed cells with the GPR40 antagonist GW1100.ConclusionsChronic activation of GPR40 using GW9508 does not negatively impact upon BRIN-BD11 pancreatic β-cells physiology and function. The GPR40 antagonist GW1100 does not protect against the deleterious effects of chronic palmitate exposure. We conclude that GPR40 is probably not involved in mediating the toxicity associated with chronic palmitate exposure.
Highlights
Free fatty acids (FFAs) play a central role in cellular physiology as they are both components of biological membranes and an important cellular energy source
We investigated whether chronic treatment of our sensor-expressing BRIN-BD11 cells, with the GPR40 agonist GW9508, leads to H 2O2 changes
There is a high degree of interest in the development of novel drugs aimed at improving pancreatic β-cell function and survival, decelerating disease progression and enhancing patient well-being
Summary
Free fatty acids (FFAs) play a central role in cellular physiology as they are both components of biological membranes and an important cellular energy source. In pancreatic β-cells, FFAs can acutely enhance glucose-stimulated insulin secretion (GSIS) either by modulation of intracellular metabolism or via activation of specific G protein-coupled receptors (GPCRs) [1,2,3,4]. GPR40 activation activates PKD1, which acts on actin filaments to increase insulin secretion Both activation of PKC and the β-oxidation may lead to the production of reactive oxygen species (ROS) in the cytosol by the NADPH oxidase 2 (NOX2) complexes and by the electron transport chain in the mitochondrial matrix, respectively. We observed that chronic GPR40 stimulation does not lead to changes in pancreatic β-cell viability, Ca2+ homeostasis, UPR induction or H2O2 levels. We observed no protective effect of GRP40 inhibition in chronic palmitate exposure
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