Abstract 3561: Short-Term, Cardiac Specific Overexpression of GLUT4 Does not Rescue Metabolic and Contractile Dysfunction in the Diabetic Heart
Despite hyperglycemia, myocardial glucose utilization is decreased in diabetes. A critical point of metabolic control in cardiac muscle is glucose uptake via the insulin-regulated glucose transporter, GLUT4. This study examined if induction of GLUT4 expression in streptozotocin (STZ)-induced, type 1 diabetic mice would rescue cardiac dysfunction associated with diabetes. We generated mice with doxycycline (DOX)-inducible cardiac-specific overexpression of mycGLUT4 (mG4H). Mice were treated with vehicle or low-dose STZ for 5d and blood glucose monitored for 2wks at which time all STZ-mice had blood glucose > 350 mg/dL. Diabetic mice were randomized to standard or DOX chow for 2wks. DOX-treatment increased GLUT4 expression by 5-fold and STZ-treatment had no effect on transgene induction. By 4-weeks, all STZ-treated animals had blood glucose > 500 mg/dL. Glycogen levels were increased 2.6-fold in mG4H hearts versus controls (n = 5, P < 0.001), and were not further changed with hyperglycemia in both controls and transgenics. Liver glycogen was similar between controls and mG4H and increased by 1.7-fold in both diabetic groups. To further assess glucose utilization, substrate utilization was determined in isolated working hearts (IWH). Glycolysis and glucose oxidation, were reduced by diabetes in control animals (glycolysis 1226±130 to 881±96 nmol•min-1•gdhw-1; n = 10, P = 0.06) and (glucose oxidation 199±17 to 155±18 nmol•min-1•gdhw-1; n = 10, P = 0.08). mG4H induction resulted in increased levels of glycolysis and glucose oxidation at baseline (P < 0.001, vs. controls). GLUT4 expression blocked the diabetes-induced reduction in glycolysis (1932±183 to 1698±153 nmol•min-1•gdhw-1; n = 7, P = 0.3) but accelerated the decline in glucose oxidation (294±27 to 118±16 nmol•min-1•gdhw-1; n = 7, P < 0.001). In IWH, cardiac power declined in both diabetic groups (P < 0.001). Basal cardiac output was increased in mG4H (10.5±0.5 vs. 8.2±0.3 mL•min-1 P < 0.001) but decreased to levels similar to control following STZ (7.6±0.4 vs. 7.4±0.3 mL•min-1). Thus a short-term increase in glucose uptake via GLUT4, while maintaining glycolysis, does not increase glucose oxidation or preserve diabetes-associated contractile dysfunction.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).