Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane

Abstract

New Findings r 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. r What is the main finding and its importance?In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II 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 type II 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 type II 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 type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-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 type II 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

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium‐glucose co‐transporter‐2, in people with type 2 diabetes mellitus

“…As treatment continues, serum glucose concentration decreases (in a dose‐dependent fashion). Notably, serum glucose concentration remained higher than the corresponding renal threshold for glucose, with no accompanying change in UGE …”

“…Notably, serum glucose concentration remained higher than the corresponding renal threshold for glucose, with no accompanying change in UGE. 24,25 The extent of SGLT2 inhibition produced by rongliflozin in participants with T2DM and in healthy participants (inhibition of glucose reabsorption: 20.7%-26.1% vs. 16.2%-31.4%, respectively) was comparable on day 1; however, greater inhibition of glucose reabsorption was observed in participants with T2DM on day 12 (29%-47%). This finding is similar to results reported for dapagliflozin, which were attributed to a decrease in mean serum glucose.…”

Renal glucose transporters ‘sweeten’ the pot

“…In this issue of Experimental Physiology, Chichger and co-workers aim to address these questions using several different diabetic rat models with varying degrees of hyperglycaemia, hyperinsulinaemia and insulin resistance (Chichger et al 2016). In the streptozotocin-induced type 1 diabetic rat model, in which the pancreatic β-cells are destroyed, protein expression of GLUT2 and its regulator protein kinase C-β1 (PKC-β1) in proximal tubule BBM are significantly increased; however, the protein expression levels of SGLT1 and SGLT2 are not different between the severely diabetic and control rats.…”

“…Depending on whether SGLTs are upregulated in the proximal tubule, the clinical use of SGLT inhibitors may have variable effects in lowering blood sugar levels. It is clear from the study by Chichger et al (2016) that renal glucose transporter expression is regulated in complex ways, depending on the type and severity of metabolic dysfunction. Some questions remain; these include the following.…”

“…Whether this also occurs in the kidney is not known. Thus, in the study by Chichger et al (2016), the authors also perform a short-term (2 h) I.V. infusion of artificial sweetener (saccharin) to assess whether this treatment alters glucose transporter expression in the proximal tubule.…”