Diabetes and Glucose Alone Regulate Cardiac ABAT Levels
Authors: Pepin Mark E , Wende Adam R 
Published: November 2023

Diabetes is the 7th most common cause of death in the US, affecting 10% of the US population. As Diabetes Mellitus has become a growing area of concern in developing nations, so too are the consequences of this insidious disease. Roughly 65% of diabetic patients die from cardiovascular‐related complications, and the risk of heart failure in Diabetic patients is independent of hypertension, smoking, or coronary artery disease. Remarkably little is understood regarding the mechanism of heart failure in this population. Here, we explore the diabetic heart as a biological system with multifaceted levels of dysregulation, all contributing to the mechanism of diabetic cardiomyopathy. Specifically, the aim is to understand if diabetic heart failure is a maladaptation originating from epigenetic changes mediated at least in part by metabolic dysfunction. To better understand the effects of the metabolic disturbances seen in the diabetic heart, we first sought to understand how glucose alone affects the metabolic and contractile states of the heart. This was accomplished using two mouse models: a streptozotocin‐induced diabetic (STZ) mouse model and an inducible cardiomyocyte‐specific GLUT4 overexpressing (mG4H) mouse model. The mG4H model was designed to selectively enhance glucose delivery, in order to understand the role of glucose in the development of diabetic cardiomyopathy, independent of other systemic changes. In order to identify regulated genes and pathways in an unbiased fashion, differential gene expression analysis was performed according to both degree of fold change and p‐value. These genes were then sorted in order of robustness. From this preliminary analysis, several genes related to GABA signaling showed a high degree of differential expression in both STZ and mG4H models; qPCR and protein quantitation validated these findings. The most prominent in this pathway was γ‐aminobutyrate aminotransferase (Abat), which exhibited a 60% decrease in RNA levels and an 80% decrease of protein levels in both mG4H and STZ. Abat is a mitochondrial enzyme known to reintroduce γ‐aminobutyrate (GABA), a well‐characterized inhibitory neurotransmitter, back into the TCA Cycle within the so‐called GABA shunt. In 1990, Baekkeskov et al. identified that the autoimmune target of Type 1 Diabetes was the GABA‐synthesizing glutamic acid decarboxylase (GAD). It is now recognized that, in pancreatic islets, GABA operates in a PI3‐K/Akt dependent mechanism to regenerate beta cells and restore glycemic control in STZ‐induced diabetic mice. However, GABA signaling has not been explored in the heart, an organ of great concern in diabetes. Therefore, promoter characterization was warranted to determine the mechanism of glycemic regulation, as well as the functional effects of Abat as they pertain to the cardiac dysfunction. Together these data provide the first evidence that GABA signaling is both present in cardiomyocytes and directly responsive to the glycemic changes seen in Diabetes Mellitus.

Support or Funding Information

NIH R00 HL111322 to A.R.W.

NIH U24 DK076169 Diabetic Complications Consortium (DiaComp) to A.R.W.