Abstract
What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki typeII diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the typeII diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in typeII diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to typeII diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki typeII diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinaseC-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in typeII diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC-βI. However, the junk-food diet also increased SGLT1 and SGLT2 levels at the proximal tubule BBM. Glucose reabsorption across the proximal tubule BBM, via GLUT2, SGLT1 and SGLT2, is not solely dependent on glycaemic status, but is also influenced by diet-induced changes in glucose metabolism. We conclude that different metabolic disturbances result in complex adaptations in renal glucose transporter protein levels and function.
Highlights
Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal disease
The Vmax for SGLT-mediated glucose uptake was 66% greater in brush border membrane (BBM) prepared from kidneys from type II diabetic rats and Kt increased by 80%
The use of SGLT2 inhibitors is a new treatment modality for maintaining glycemic control in patients with type II diabetes, and it has been suggested that this approach may limit the long-term renal consequences of diabetic nephropathy, to date it has not been shown to provide unequivocal ‘renoprotection’ other than by improving blood sugar control
Summary
Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal disease. While there are conflicting reports of the impact of diabetes on SGLT-mediated transport (Marks et al, 2003; Albertoni Borghese et al, 2009), inhibitors of SGLT2 have been demonstrated to increase glycosuria and reduce hyperglycemia in type II diabetes (Han et al, 2008). The glucose transporters SGLT1 and GLUT2 play a role in glucose reabsorption across the proximal tubule brush-border (Marks et al, 2003; Hummel et al, 2011), and may represent additional targets for the control of hyperglycemia in diabetes. The role of glucose transporters at the proximal tubule BBM in diabetes requires further study
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