Glucose transport in the diabetic kidney (2015–2019)

Abstract:
More than 1 million Australians are diagnosed with diabetes, of which 30% have diabetic kidney disease. SGLT2 inhibitors are available as a glucose-lowering agent for type 2 diabetic patients in Australia. These therapies work by blocking the sodium-dependent glucose transporter 2 (SGLT2) in kidney proximal tubule cells which is responsible for the bulk of glucose reabsorption. This promotes urinary glucose loss, thereby lowering blood glucose concentrations. It is being considered whether these therapies offer the added benefit of preventing kidney disease given that they avert glucose from proximal tubule cells and may therefore prevent glucose-induced damage. However, I have novel data from human and mouse samples suggesting that another transporter, glucose transporter type 4 (GLUT4), is present within these tubule cells and increased in a high-insulin environment. SGLT2 inhibition in type 2 diabetic individuals may further increase the expression of GLUT4 as the kidney tries to compensate for the loss of glucose into the urine. Very little is known regarding the renal effects of manipulating this tightly controlled physiological system and it is likely that a number of other consequences are initiated. I have pilot data suggesting that SGLT2 inhibition does not protect against kidney disease in diabetic mice, despite being highly efficacious as a blood glucose-lowering agent. This proposal aims to investigate how glucose is handled by the diabetic kidney and whether SGLT2 blockade in diabetes can adversely modulate kidney function despite blood glucose lowering. Using cultured human cells and mouse models of diabetes, I will block SGLT2 and/or GLUT4 and examine its effects on glucose transport. I will assess changes in kidney structure and function, and cardiovascular risk factors. My findings will have implications for the utility of SGLT2 inhibitors in their protection against diabetic kidney disease.
Grant type:
NHMRC Early Career Fellowships
Researchers:
  • UQ Amplify Lecturer
    School of Biomedical Sciences
    Faculty of Medicine
Funded by:
National Health and Medical Research Council