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Altered glucose metabolism has long been suggested in diabetes pathogenesis causing secondary micro/macrovascular complication. Mostly these secondary complications arise in organs, such as renal, peripheral nervous system (PNS), and central nervous system (CNS) that exhibit insulin-independent glucose uptake. Often, this leads to increased glucose levels beyond normal to maintain tissue homeostasis or cellular metabolism. Pathophysiological complications associated with diabetes are mainly attributed to shunting of excess glucose via transporters through different metabolic pathways leading to hyperglycemic end-organ damage. Thus, any changes in glucose transporter function or expression dramatically affects brain glucose homeostasis and function. Moreover, diabetes itself is a risk factor for heart disease and stroke. Given that at least one third of stroke patients are hyperglycemic on admission, with most being diabetic, the diabetic stroke patient provides opportunity for unique pharmacologic interventions to improve neurological outcome. For these reasons, our studies aimed to decipher the effects of chronic hyperglycemia on glucose transporter function at the blood-brain barrier (BBB) and in the brain. For these studies we measured changes in glucose transporter function and expression at the BBB and in the brain of two week old Streptozotocin (STZ)-diabetic mice. We estimated changes in glucose transporter function at the BBB using in situ brain perfusion and in the brain using an acute brain slice uptake method. Glucose transporter function was evaluated from the unidirectional brain uptake of radio-labeled glucose substrates with/without inhibitors. The concentration dependence of BBB [3H) D-glucose transport in diabetic animals followed Michaelis-Menten kinetics with an apparent Km of 5.69 ± 1.79 mM and a Vmax of 0.022 ± 0.001 μmol/min/g compare to Km of 5.03 ± 1.26 mM and a Vmax of 0.022 ± 0.001 μmol/min/g in control non-diabetic animals. Brain [3H] D glucose unidirectional influx was significantly inhibited by phloretin (GLUT1-inhibitor) in both control and diabetic mice. Interestingly, we found -40% phlorizin (P<0.01) (SGL Tsinhibitor) sensitive [3H] D-glucose transport in diabetic mouse brain. However, we did not observe significant a-methyl-D-glucopyranoside (AMG) uptake, a specific sodium dependent glucose transporter (SGL T) substrate, in either control or diabetic animals. Therefore, the current observation of significant inhibition of glucose uptake by phlorizin with no luminal AMG uptake suggests that increased SGL T function at the BBB in diabetic animals may be due to function at the abluminal (brain) surface of the BBB. We confirmed the observed sodium dependent glucose transport function across the BBB by estimating glucose influx rate in Na•-free condition and in the presence of sodium transporter inhibitors, such as the Na/H-exchanger (NHE) and Na•,K•,2cr-cotranporter (NKCC), using dimethylamilioride (OMA) and bumetenide (BUM) respectively. Additionally, we also tested brain [3H]-myo-inositol unidirectional influx across BBB. We observed no significant reduction in myo-inositol (Ml) transport. Instead, Ml transport was significantly (P<0.001) inhibited by a competitive substrate, D-glucose (1 SmM). Taken together, these observations suggest a possible alternative role of sodium dependent myo-inositol transporter (SMIT) in transporting glucose across the BBB in diabetic mice, seemingly also inhibited by phlorizin. We also tested the function and expression of SGL T and SMIT in diabetic brain of mice. We measured increased mRNA expression and function of SGL T1 and SMIT2 (SGL T6) in diabetic brain. Consistent with these observations, neuronal protein expression of SGL T1 was increased with no change in GLUT1 protein expression of diabetic brain. Further, D-glucose and D-galactose, competitive substrate inhibitors of the SGL T specific substrate, AMG, inhibited uptake in acute brain slice preparations, demonstrating increased SGL T1 function in the diabetic brain. Similarly, increased Ml uptake induced by diabetes, was inhibited by 0-chiro-inositol (DCI), suggesting increased SMIT2 (SGL T6) function in the diabetic brain. In summary, current studies highlights the possible role of sodium dependent glucose transport across the BBB and increased function and expression of SGL T and SMIT2 in diabetic brain.



Sodium dependent glucose transporter, Glucose, Diabetic brain