Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

PKA-mediated potentiation of acute insulin release enhances insulin action and reverses glucose intolerance. (#101)

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

The magnitude of the acute insulin response to glucose (AIR), which is the insulin released 0-10 minutes following a glucose bolus, is a primary determinant of the efficacy of glucose clearance. We recently showed that the cyclic AMP-dependent protein kinase (PKA) potentiates the AIR through our use of β-caPKA mice, which carry a tamoxifen-inducible activated PKA catalytic subunit that is expressed specifically in the islet beta-cells. Here we used β-caPKA mice as a model of inducible enhancement of the AIR to determine whether therapeutic targeting of the AIR can improve pre-existing glucose intolerance. Initially we showed that PKA-mediated potentiation of the AIR improved insulin action at muscle by enhancing Akt phosphorylation and glucose uptake, leading to improved glucose tolerance. When glucose intolerance was pre-established, either by feeding a high fat diet to induce insulin resistance or through streptozotocin-mediated depletion of β-cell mass, induction potentiated AIR through PKA activation fully reversed the impaired glucose control. The potentiation of insulin release was not attributable to changes in β-cell mass, leading us to conclude that PKA activation is not proliferative for beta-cells, although it was protective from streptozotocin-mediated β-cell loss. Nor were lower glucose levels associated with chronic hyperglycemia. Instead, we conclude that the improved glucose control is attributable to an improved profile of insulin release. This enhanced profile of release is sustainable to 52 weeks, indicating that it does not cause β-cell exhaustion.