Regulation of Glucagon-like Peptide-1 Secretion by the Exocytotic Protein Munc18-1

The incretin glucagon-like peptide-1 (GLP-1) is a rhythmically secreted insulin-secretion enhancing hormone produced in the intestinal L-cell. The increasing incidence of Type 2 Diabetes warrants the advent of new therapies that can increase endogenous GLP-1 secretion, which will manipulate regulatory L-cell secretory pathways such as exocytosis. Three exocytotic proteins have already been identified as regulators of GLP-1 secretion. I hypothesized that the accessory exocytotic protein, Munc18-1, is also an important regulator of GLP-1 secretion in the L-cell - specifically at the peak of its secretion. Munc18-1 expression in many, but not all L-cells was confirmed, and its recruitment to the cell membrane was observed under stimulation. The role of Munc18-1 in GLP-1 secretion was established by loss-of-function experiments in the Munc18-1 knockdown mGLUTag L-cell line, inducible L-cell Munc18-1 knockout mice and primary Munc18-1 knockout L-cells. Together, the results indicate that Munc18-1 is an essential regulator of peak GLP-1 secretion.M.Sc.2020-11-19 00:00:0