Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic beta-cell physiology and function

Author(s)

Vilas-Boas, Eloisa Aparecida ; Karabacz, Noemie ; Marsiglio-Librais, Gabriela Nunes ; Rezende Valle, Maira Melo ; Nalbach, Lisa ; Ampofo, Emmanuel ; Morgan, Bruce ; Carpinelli, Angelo Rafael ; Roma, Leticia Prates

• Document type: Journal article
• Source: PHARMACOLOGICAL REPORTS; v. 72, n. 6, p. 13-pg., 2020-04-09.

Abstract

Background Free fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic beta-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 beta-cell physiology, especially upon chronic exposure to FFAs, remains unclear. Methods We used the GPR40 agonist (GW9508) and antagonist (GW1100) to investigate the impact of chronically modulating GPR40 activity on BRIN-BD11 pancreatic beta-cells physiology and function. Results We 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 H(2)O(2)or superoxide levels and no increase in the ER stress markers p-eIF2 alpha, CHOP and BIP. As expected, palmitate led to increased H(2)O(2)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. Conclusions Chronic activation of GPR40 using GW9508 does not negatively impact upon BRIN-BD11 pancreatic beta-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. (AU)

• FAPESP's process: 11/04511-4 - Acute and chronic effects of oleic and palmitic acids and the agonist GW9508 on insulin secretion and oxidative stress of the lineage BRIND-BD11
• Grantee: Eloisa Aparecida Vilas Boas
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 09/51893-0 - The role of NAD(P)H oxidase in the molecular mechanisms of pancreatic beta cell physiology
• Grantee: Angelo Rafael Carpinelli
• Support Opportunities: Research Projects - Thematic Grants