Liraglutide, a GLP-1 Analog, Stimulates both Exocytosis and Mobilization of Insulin Granules

Ma, Li; Labno, Christine; Kuznetsov, Andrey; Bindokas, Vytautas P.; Philipson, Louis H.
June 2007
Diabetes;Jun2007 Supplement 1, Vol. 56, pA436
Academic Journal
GLP-1 increases cAMP and stimulates insulin granule exocytosis but the effects on insulin granule dynamics are incompletely understood. We used total internal reflection fluorescence (TIRF) microscopy to image the exocytosis and transport of GFP-insulin granules near the plasma membrane in stable transfected glucose-responsive MIN6 insulinoma cells. We found that the long-acting GLP-1 analog liraglutide evoked insulin granule exocytosis in a biphasic manner. In the first five minutes after stimulation (first phase of release) fusion events were seen mostly from previously docked granules. In low (2 mM/L) glucose there were few exocytotic events (loss of granules < 2% of total visualized granules) unchanged with or without liraglutide. In 5 mM/L glucose, there was only a slight increase in insulin granule exocytosis with liraglutide compared with controls (4.0 ± 0.82% to 3.3 ± 0.87%, P > 0.05). However, in 8 mM/L glucose, there was almost a doubling in the disappearance of docked insulin granules with liraglutide than without it (8.6 ± 0.93% to 4.6 ± 1.3%, P < 0.01). To isolate the effect of liraglutide on internal granule trafficking to the plasma membrane, previously docked granules (PDG) were first photo-bleached using TIRF (TIRF-FRAP) and the appearance of newly docked granules (NDG) at the plasma membrane over the next 5-20 minutes was recorded. In the presence of liraglutide, there was an increase in the rate of appearance NDG, as expressed as percentage of total PDG (2.37 ± 0.496 per min. compared to 1.52 ± 0.301 per min. for controls, P < 0.01). These findings indicate that liraglutide increases insulin granule exocytosis from the pre-docked pool and leads to the mobilization of more insulin secretory granules from the large reservoir pool to then dock at the plasma membrane. Both of these processes are glucose dependent. This method of using TIRF and TIRF-FRAP approach can therefore evaluate both exocytosis of docked insulin granules as well as transport of insulin granules to the plasma membrane.


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