The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Local integrin activation in pancreatic beta cells targets insulin secretion to the vasculature (#159)

Peter Thorn 1 , Wan Jun Gan , Oanh Hoang Do , Louise Cottle , Elena Kosobrodova , Marcela Bilek
  1. University of Sydney, Sydney, NSW, Australia

We have previously shown that insulin secretion from beta cells within an islet is selectively targeted to the area where each beta cell makes contact with the vasculature1, 2. Focal adhesions are known to affect insulin secretion3 and one of the factors that might underlie a mechanism of targeting secretion is an integrin-extracellular matrix interaction. Here we test the hypothesis that extracellular matrix proteins, secreted by endothelial cells of the vasculature, induce integrin responses in the beta cells which through focal adhesions provide a cue for beta cell orientation and targeted insulin secretion.

Immunostaining in situ, within islets of Langerhans, show active focal adhesions are formed in b cells exclusively at the point where they contact the capillary basement membrane. In vitro, we demonstrate b cells respond to the basement membrane substrates, collagen IV, laminin 511 and fibronectin, with an increase in proliferation and insulin secretion. Using function blocking antibodies we show the enhanced secretion is dependent on b1 integrin activation. To determine any spatial consequences of local integrin activation we use 3D mapping of insulin granule fusion to show exocytosis is targeted to where the b cells contact the basement membrane. This targeting is not seen with cells cultured on poly-l-lysine and is disrupted either by blocking the b 1 integrin receptor or by inhibition of focal adhesion kinase. Micro-pattern printing of stripes of E-cadherin and fibronectin shows individual b cells grow across both stripes but selectively respond to the fibronectin stripe with focal adhesion activation, targeting of the exocytic machinery and regional targeting of insulin granule fusion.

We conclude that integrin activation occurs exclusively at the vascular face of pancreatic b cells and is a mechanism that targets insulin granule fusion to this region.

  1. [1] Gan, W. J., Zavortink, M., Ludick, C., Templin, R., Webb, R., Webb, R., Ma, W., Poronnik, P., Parton, R. G., Gaisano, H. Y., Shewan, A. M., and Thorn, P. (2017) J. Cell Sci. 130, 143-151.
  2. [2] Low, J. T., Zavortink, M., Mitchell, J. M., Gan, W. J., Do, O. H., Schwiening, C. J., Gaisano, H. Y., and Thorn, P. (2014) Diabetologia 57, 1655-1663.
  3. [3] Rondas, D., Tomas, A., and Halban, P. A. (2011) Diabetes 60, 1146-1157.