Activation of the cAMP-dependent protein kinase (PKA) in β-cells provides sustained benefits to glucose control — ASN Events

Activation of the cAMP-dependent protein kinase (PKA) in β-cells provides sustained benefits to glucose control (#166)

Barton Wicksteed 1 , Kelly A Kaihara , Lorna M Dickson 1
  1. University of Chicago, Chicago, IL, United States

The cyclic AMP-dependent protein kinase, PKA, has been proposed to regulate many aspects of β-cell biology, including insulin secretion, insulin synthesis, β-cell survival and β-cell proliferation. We have established β-caPKA mice, a model of tamoxifen-inducible PKA activity that is targeted specifically to the islet β-cells. We have shown that enhanced insulin secretion in β-caPKA mice tightens glucose control and that this not dependent upon increased β-cell mass. Enhanced insulin secretion and improved glucose control was maintained to 52 weeks of age but β-cell mass at 52 weeks of age did not differ between β-caPKA mice and littermate controls, indicating again that activation of PKA in the islet β-cells does not promote β-cell proliferation. To determine whether PKA activity is protective for β-cells, PKA activity was induced in β-caPKA mice, then streptozotocin was administered to induced β-cell destruction. Increasing PKA activity in β-cells protected them from streptozotocin-induced death and the β-caPKA mice maintained glucose control, in contrast to littermate controls. PKA activity also protected INS-1 cells from cytokine induced apoptosis in vitro. To test whether enhanced β-cell function following PKA induction can compensate for reduced β-cell mass, streptozotocin was administered prior to tamoxifen-mediated PKA induction. Tracking of plasma glucose in ad libitum fed mice showed tighter control in mice with enhanced PKA activity in the islet β-cells, indicating that enhanced secretory function can compensate for hyperglycemia resulting from depleted β-cell mass. These data show that β-cells can sustain enhanced secretion to tighten glucose control, that PKA activity is protective for β-cells and that secretory function can compensate for reduced β-cell mass. Overall, the data highlight the capacity to enhance β-cell function to restore glucose control.

@ADSADEA