Abstract
In the past 15 years, gut microbiota emerged as a crucial player in health and disease. Enormous progress was made in the analysis of its composition, even in the discovery of novel species. It is time to go beyond mere microbiota-disease associations and, instead, provide more causal analyses. A key mechanism of metabolic regulation by the gut microbiota is through the production of short-chain fatty acids (SCFAs). Acting as supplemental nutrients and specific ligands of two G-protein-coupled receptors (GPCRs), they target the intestines, brain, liver, and adipose tissue, and they regulate appetite, energy expenditure, adiposity, and glucose production. With accumulating but sometimes conflicting research results, key questions emerged. Do SCFAs regulate pancreatic islets directly? What is the effect of β-cell-specific receptor deletions? What are the mechanisms used by SCFAs to regulate β-cell proliferation, survival, and secretion? The receptors FFA2/3 are normally expressed on pancreatic β-cells. Deficiency in FFA2 may have caused glucose intolerance and β-cell deficiency in mice. However, this was contrasted by a double-receptor knockout. Even more controversial are the effects of SCFAs on insulin secretion; there might be no direct effect at all. Unable to draw clear conclusions, this review reveals some of the recent controversies.
Highlights
FFA2 agonist phenylacetamide (PA, compound 58) potentiated glucose- and arginine-stimulated insulin secretion in wild-type islets. Consistent with these findings, PA or acetate enhanced cell proliferation, insulin level, and Pdx1 and NeuroD gene expression in MIN6 cells, which was mediated via an association with Gαq/11. These results suggest that FFA2 is normally expressed in β-cells, and that its activity is essential for β-cell compensation in response to obesity in mass and insulin secretion through Gαq/11- and PLC-mediated IP3/Ca2+ pathways; it is a potential therapeutic target [36]
We can conclude that both sodium acetate and propionate protected cytokine- or palmitate-induced islet cell death; FFA2 deficiency caused β-cell death and reduced β-cell mass, while short-chain fatty acids (SCFAs) acted through FFA2-protected islet β-cells
Based on earlier and more recent observations made using in vivo, in vitro, and ex vivo approaches, we can safely propose that FFA2 agonists, especially when clearly acting through Gαq/11, would stimulate insulin secretion, while FFA3 agonists acting through Gαi/0 would only cause an inhibition
Summary
It is estimated that billions of microorganisms live in the human gut, including 1–2 kg of bacteria of ~40,000 different species. FFA2 agonist phenylacetamide (PA, compound 58) potentiated glucose- and arginine-stimulated insulin secretion in wild-type islets Consistent with these findings, PA or acetate enhanced cell proliferation, insulin level, and Pdx and NeuroD gene expression in MIN6 cells, which was mediated via an association with Gαq/11. Loss of both FFA2 and FFA3 receptors, improved insulin secretion and glucose tolerance under HFD, but had no effect on β-cell mass These subtle changes, or lack of, suggest instead that the normal expression of both receptors enabled a net negative influence on β-cell function. FFA2/3 double KO improved glucose tolerance and insulin secretion but caused no change in β-cell mass; single KOs had no effect (done mostly on chow diet), and acetate inhibited insulin secretion via FFA2/3 receptors and their interaction with Gαi. When the two receptors were ablated together, the positive outcome in insulin secretion and glucose tolerance may suggest that, normally, FFA3 has a negative but dominant effect over FFA2; the latter seems to be more pro-islets
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