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Glucose transporter 2 expression: prevention of streptozotocin-induced reduction in beta-cells with 5-thio-D-glucose
1Clinical Department, Diabetes-Research-Institute, Heinrich-Heine-University, Düsseldorf, Germany.
Abstract:
The effect of streptozotocin (STZ) on the glucose transporter 2 (GLUT2) expression in beta-cells was investigated in vitro and in vivo. By Western blot analysis, a gradually decreasing GLUT2 expression was found in islets prepared from C57BL/6 male mice that had received multiple low doses of STZ (MD-STZ) for induction of autoimmune diabetes. Reduction of GLUT2 expression correlated with the number of STZ injections administered and preceded development of hyperglycemia. When hyperglycemia had developed, GLUT2 expression was extremely reduced. In vitro, incubation of isolated islets with STZ resulted in a time- and dose-dependent reduction of beta-cell GLUT2 expression. In vivo, pretreatment of MD-STZ recipients with intraperitoneal injections with 5-thio-D-glucose (5-T-G) just before each of the STZ injections prevented MD-STZ-induced beta-cell GLUT2 reduction and hyperglycemia development. In vitro, preincubation of islet cultures with 5-T-G also prevented STZ-induced GLUT2 reduction. Unlike STZ, equimolar concentrations of methylnitrosourea (MNU), the aglycone moiety of STZ, failed to alter GLUT2 expression in vitro. In conclusion, our data demonstrate that STZ-induced beta-cell GLUT2 reduction was prevented by 5-T-G both in vitro and in vivo in the MD-STZ diabetes model. The noxious effect of STZ on GLUT2 expression is most likely facilitated through its glucose moiety, because MNU lacked to do so. Presumably, in autoimmune MD-STZ diabetes the GLUT2 glucose transporter might be a key target structure for STZ subtoxicity and diabetogenicity, which converge with subsequent immune reactions to beta-cell destruction.
Insights
Streptozotocin (STZ) reduces glucose transporter 2 (GLUT2) in beta-cells, leading to diabetes. Pretreatment with 5-thio-D-glucose (5-T-G) prevents this GLUT2 reduction and hyperglycemia development in a mouse model.
Area of Science:
- Endocrinology
- Cell Biology
- Diabetes Research
Background:
- Streptozotocin (STZ) is widely used to induce diabetes in animal models.
- The precise mechanism of STZ-induced beta-cell dysfunction, particularly its effect on glucose transporters, remains incompletely understood.
- Glucose transporter 2 (GLUT2) plays a crucial role in glucose sensing and insulin secretion by pancreatic beta-cells.
Purpose of the Study:
- To investigate the effect of STZ on GLUT2 expression in pancreatic beta-cells.
- To determine whether 5-thio-D-glucose (5-T-G) can protect against STZ-induced GLUT2 reduction and hyperglycemia.
- To elucidate the role of the glucose moiety of STZ in its diabetogenic effects.
Main Methods:
- Western blot analysis to assess GLUT2 expression in mouse islets and beta-cells.
- Induction of autoimmune diabetes using multiple low doses of STZ (MD-STZ) in C57BL/6 mice.
- In vitro incubation of isolated islets with STZ and 5-T-G.
- In vivo administration of 5-T-G as a pretreatment before STZ injections.
Main Results:
- STZ administration led to a progressive and dose-dependent decrease in GLUT2 expression in beta-cells, preceding hyperglycemia.
- In vitro incubation with STZ also reduced GLUT2 expression in a time- and dose-dependent manner.
- Pretreatment with 5-T-G effectively prevented STZ-induced GLUT2 reduction and the development of hyperglycemia, both in vivo and in vitro.
- Methylnitrosourea (MNU), the aglycone of STZ, did not affect GLUT2 expression, suggesting the glucose moiety is critical.
Conclusions:
- STZ significantly reduces GLUT2 expression in pancreatic beta-cells, contributing to its diabetogenic effects.
- 5-T-G demonstrates a protective role against STZ-induced beta-cell toxicity by preserving GLUT2 expression.
- The glucose moiety of STZ appears essential for its detrimental impact on GLUT2, highlighting GLUT2 as a potential key target in STZ-induced diabetes.