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.
Keywords: GPR41/FFA3; GPR43/FFA2; acetate; butyrate; glucose-stimulated insulin secretion (GSIS); histone deacetylase (HDAC); microbiota; propionate.