Glucose Transporter Biology

Pancreatic beta cell insulin secretion:
GLUT9 or Slc2a9 is a novel facilitative glucose transporter that is expressed as two isoforms differing only in their amino terminus, Slc2a9a and Slc2a9b. Prior studies have shown that Slc2a9 is a high affinity glucose transporter (Km 0.61mM) and fructose transporter (Km 0.42mM). Recent genomewide association scans identified association of genetic variants of Slc2a9 with serum urate level. In a recent study we demonstrate Slc2a9 splice variants function as high affinity urate transporters in Xenopus laevis oocytes and in kidney cells. Also, we showed Slc2a9 mediated urate transport can be facilitated by glucose and to a lesser extent fructose. Furthermore, we demonstrated that urate is transported into the mouse insulinoma cell line, MIN6, which endogenously expresses Slc2a9; and that this transport can be diminished by Slc2a9 targeted siRNA. Finally, we have established that Slc2a9 targeted siRNA decreases insulin secretion and ATP concentrations in beta cells expressing normal amounts of GLUT2 or Slc2a2. The combination of all these findings has led us to hypothesize that Slc2a9 has a critical role in glucose induced insulin secretion and that the mechanism may include uric acid transport. The objective for this study is to determine the function of GLUT9 in the beta cell. The rationale for this study is that if GLUT9 is serving as a glucose sensor in the beta cell and if uric acid is coupled to this process, then new therapeutic strategies targeted at improving GLUT9 expression and uric acid transport may be useful in improving insulin secretion in diabetic patients.

Enterocytic glucose transporters GLUTS and GLUT9:

GLUTS: The glucose transporter (GLUT) family of membane-spanning hexose transporters family members are subjects of intensive investigation for their potential as modifiable targets in treating or preventing obesity, metabolic syndrome and type II diabetes mellitus. Mounting evidence suggests that the ubiquitously expressed class Ill glucose transporter, GLUTS, has important metabolic homeostatic functions in males. We therefore tested the hypothesis that GLUTS is required for the deleterious metabolic effects of chronic high-fructose dietary exposure. Here, we demonstrate resistance to high fructose diet-induced weight gain and hypertriglyceridemia concomitant with enhanced oxygen consumption and thermogenesis in GLUTS-deficient male mice. Significantly lower systolic blood pressure at baseline and after high-fructose diet feeding was also observed by tail·cuff plethysmography in GLUTSKO mice versus wild-type controls. Resistance to fructose-induced metabolic dysregulation occurred in the context of enhanced hepatic PPARy protein abundance, while adenoviral hepatic GLUTS overexpression suppressed PPARy expression. Taken together, these findings suggest that GLUTS blockade prevents fructose-induced metabolic dysregulation,potentially by enhancing hepatic fatty acid metabolism through PPARy and its downstream targets. We thus establish GLUTS as a promising target in the prevention of diet-induced obesity, metabolic syndrome and type II diabetes mellitus.

GLUT9: Hyperuricemia – the state of elevated serum urate concentrations resulting predominantly from impaired urate clearance – is an independent risk factor for the metabolic syndrome and cardiovascular disease mortality. Although intestinal urate clearance accounts for 30-40% of daily urate excretion, the enterocyte transporters mediating intestinal urate clearance are poorly characterized. Here, we seek to elucidate the enterocyte transporters involved mediating serum urate clearance to identify modifiable targets in the treatment and prevention of hyperuricemia. GLUT9a is a high­ capacity basolateral renal epithelial urate transporter that we recently identified in the murine enterocyte basolateral membrane. GLUT9a is thus a promising candidate to mediate basolateral urate uptake from the blood into the enterocyte prior to intestinal excretion. Therefore, one objective of the lab is to test the hypothesis that enterocyte GLUT9a regulates intestinal uric acid handling and global urate homeostasis. If this approach is successful, we will demonstrate for the first time that GLUT9a plays a critical role in enterocyte uric acid regulation in vitro and in vivo, and that this transporter is a key regulator of urate homeostasis. These results will further establish the feasibility of using GLUT9 as a modifiable target for the treatment and prevention of hyperuricemia, cardiovascular disease and the metabolic syndrome.