2089-P: Islet GLUT2 Plasticity Improves Glycemic Control in Insulin-Resistant KK Mice but Not T2DM KKAy Mice

Abstract

Beta cells secrete insulin in response to glucose entry by GLUT transporters. GLUT are reduced in beta cells from T2DM rodents. We hypothesized that glucose entry into islets would be reduced in T2DM mice. Islets were isolated from euglycemic mice (C57/Bl6, ICR), insulin-resistant but euglycemic mice (4 and 8 wk KK), prediabetic mice (4 wk KKAy), and T2DM mice (8 wk KKAy). Islets were exposed to the fluorescent glucose analogue 2-NBDG in presence or absence of high glucose or the GLUT inhibitor phloretin. Islet fluorescence was visualized using confocal microscopy and quantified from 3-D images using FIJI Image J. GLUT2 protein was determined in isolated islets by ELISA. Islet GLUT2 location was determined using IF sections with blinded observers assigning a score from 0 (cytosol) to 10 (cell membrane). *p<0.05. Using islets from euglycemic mice, 2-NBDG entry was competitively reduced 59% by high glucose and 30% by phloretin. Despite a 44% decrease in islet GLUT2 protein in prediabetic mice (KK, 4.0±0.5; KKAy, 2.3±0.3*), 2-NBDG entry into islets was similar (KK: 7.32±0.86; KKAy: 7.25±0.86). More GLUT2 transporters were located in the membrane of islets from KKAy (5.88±2.14*) as compared to KK (4.44±3.06) mice. Phloretin significantly decreased 2-NBDG entry in both KK (6.31±0.61*) and KKAy (6.52±0.69*) mice. By 8 wks of age, islet GLUT2 protein had decreased by 51% in KK mice (1.97±0.50*) with no change in KKAy mice (2.58±0.22), yet 2-NBDG entry was not altered (KK: 7.32±0.63; KKAy: 7.35±0.62). More GLUT2 was located in the membrane of 8 wk KK (7.08±1.68*) as compared to 4 wk KK mice. Membrane GLUT2 was unchanged in KKAy mice. Phloretin increased 2-NBDG entry into islets from both KK (8.05±0.48*) and KKAy (7.95±0.79*) mice. With age, HbA1c did not change in KK mice (4.53-4.97%) but increased in KKAy mice (5.27-6.57%). Plasticity in islet GLUT2 content, location and transport was evident in islets from KK mice but not KKAy mice. Plasticity may contribute to better glycemic control in aging KK mice. Disclosure K.J. LePard: None. K.L. Sondgeroth: None. Funding Midwestern University (to K.J.L.)