MPI for Heart and Lung Research


Project leaders: Dr. Sarah Tonack, Dr. David Romanin, Dr. Remy Bonnavion

Figure G-protein-mediated signaling

Mechanisms of acetate-induced inhibition of glucose-stimulated insulin secretion (Tang et al., 2015). Glucose taken up by β-cells after metabolization results in the inhibition of potassium channels leading to depolarization which in turn opens voltage-dependent calcium channels. The subsequent increase in intracellular calcium is the main trigger for the exocytosis for insulin-containing vesicles from pancreatic β-cells. Part of the glucose taken up by β-cells is metabolized to acetate which in an auto-and paracrine fashion inhibits glucose-stimulated insulin secretion by activation of Gi-coupled FFA2 and FFA3 receptors on β-cells. The Gi-mediated inhibition of cAMP formation counteracts the activity of various incretins which activate Gs-coupled receptors and thereby negatively modulates glucose-stimulated insulin secretion. This mechanism may, under physiological conditions, avoid overshooting glucose-stimulated insulin secretion; under pathological conditions, there is evidence that this mechanism is overactivated at early stages to type-2-diabetes. For details see Tang et al., 2015.

This research area focuses on the regulation of adipocyte turnover and adipocyte function via G-protein-coupled receptors as well as via inflammatory signaling pathways mediated by Tak-1. Another focus is on the regulation of insulin secretion via GPCRs (Sassmann et al, 2016; Tang et al, 2015; Sassmann et al, 2010).

Literature

Sassmann-Schweda A, Singh P, Tang C, Wietelmann A, Wettschureck N, Offermanns S (2016). Increased apoptosis and browning of TAK1-deficient adipocytes protects agains obesity. JCI Insight 1, e81175

Tang C, Ahmed K, Gille A, Lu S, Gröne HJ, Tunaru S, Offermanns S (2015). Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat. Med. 21, 173-177

Offermanns S. (2014) Free Fatty Acid (FFA) and Hydroxy Carboxylic Acid (HCA) Receptors. Annu. Rev. Pharmacol. Toxicol. 54, 407-434

Blad CC, Tang C, Offermanns S (2012). G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat. Rev. Drug. Discov. 11, 601-619

Sassmann A, Gier B, Gröne HJ, Drews G, Offermanns S, Wettschureck N (2010). The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion J. Clin. Invest. 120, 2184-2193