Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose
Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong
Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong
View: Text | PDF
Research Article Cardiology Cell biology

Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose

Abstract

Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes–induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.

Authors

Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong

×

Figure 4

Bin1 deletion in cardiomyocytes impairs GLUT4 translocation and glucose utilization, weakening systemic glucose response to insulin in mice.

Options: View larger image (or click on image) Download as PowerPoint
Bin1 deletion in cardiomyocytes impairs GLUT4 translocation and glucose...
(A) Representative GLUT4 confocal images in isolated cardiomyocytes from WT and Bin1 HT mice with or without prior AAV9-cBIN1 rescue. Cardiomyocytes were treated with 0 or 10 nM insulin for 20 minutes before collection. The images of the boxed areas with the corresponding fluorescence intensity profiles are included in the bottom panels. Scale bar: 10 μm. (B) Quantification of GLUT4 peak power density at t-tubules (n = 30–47 cells from 3 hearts per group). (C) 2DG uptake following insulin (0 and 10 nM) stimulation in cardiomyocytes isolated from each group (n = 10–12 repeats from 3 animals per group). (D) 13C enrichment of extracellular lactate and intracellular glycolysis and TCA cycle intermediates from cardiomyocytes isolated from each group (n = 3–5). Schematic for metabolic pathway of 13C6-glucose is included. Pyr., pyruvate; Lac., lactate; Glc, glucose; F6P, fructose-6-phophate; F1,6BP, fructose-1,6-biphosphate; DHAP, dihydroxyacetone phosphate; 3PG, 3-phosphoglyceric acid; PEP, phosphoenolpyruvate; Cit., citrate; α-KG, alpha-ketoglutarate; Succ., succinate; Fum., fumarate; Mal, malate. (E) Percent of peak blood glucose during iGTT in each group (n = 4). (F) Percent of baseline blood glucose during iITT in each group (n = 4). Data are presented as mean ± SEM. Two-way ANOVA followed by Tukey’s (3 treatment groups, B–F) or Bonferroni’s (2 insulin doses, B and C) test is used. *, **, *** indicates P < 0.05, 0.01, 0.001, respectively, for comparison versus WT + PBS (B–F); †, ††, ††† indicates P < 0.05, 0.01, 0.001, respectively, for comparison between Bin1 HT + PBS and Bin1 HT + cBIN1 (B–F); and #, ### indicates P < 0.05, 0.001, respectively, for comparison of 10 nM versus 0 nM insulin within each group (B and C).