GLUT2 in Pancreatic Islets: Crucial Target Molecule in Diabetes Induced With Multiple Low Doses of Streptozotocin in Mice

Abstract

In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.

Transgenerational inheritance of susceptibility to diabetes-induced male subfertility

“…STZ is recognized by glucose transporter GLUT2, and mainly targeted to pancreatic β cells 36 . The half-life of STZ is extremely short between 5–15 min in vivo and therefore cannot function for a prolonged time.…”

Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes

“…The glucose analogue STZ is reported to be transported into β-cells by the glucose transporter 2 (GLUT2) for exerting its apoptotic effect (Wang and Gleichmann 1998). While we did not study the effect of genistein on GLUT2 protein expression in mouse islets, our recent studies found that genistein had no such an effect in cultured β-cells (Fu and Liu 2009), suggesting that improvement of islet β-cell mass and survival by genistein may not be due to modulation of GLUT2 expression, thereby preventing STZ influx in β-cells.…”

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“…A PPARα-agonist also induced GLUT2 expression in islets but the effect on glucokinase was not documented [109]. Improved glucose metabolism, however, has not been a consistent outcome of PPARγ induction [103].…”