Molecular target structures in alloxan-induced diabetes in mice.
Type 1 diabetes results from irreversible damage of insulin-producing beta-cells. In laboratory animals, diabetes can be induced with alloxan (ALX), a 2,4,5,6-tetraoxopyrimidine. ALX is a potent generator of reactive oxygen species (ROS), which can mediate beta-cell toxicity. However, the initial lesions on essential beta-cell structures are not known. In this study, we report that the glucose transporter 2 (GLUT2) and glucokinase (GK) are target molecules for ALX. Ex vivo, a gradual decrement of both GLUT2 and GK mRNA expression was found in islets isolated from ALX-treated C57BL/6 mice. This reduction was more pronounced for GLUT2 than for GK. The mRNA expression of beta-actin was also slightly affected with time after ALX exposure, the proinsulin mRNA, however, remained unaffected as well as the pancreatic total insulin content. Pretreatment with D-glucose (D-G) protected the mRNA expression of GLUT2 and GK against ALX toxicity and prevented diabetes. Yet, in these euglycemic mice, an impaired oral glucose tolerance persisted. Pretreatment with 5-thio-D-glucose (5-T-G) failed to prevent ALX diabetes, administration of zinc sulfate (Zn(2+))-enriched drinking water, however, reduced ALX-induced hyperglycemia. In conclusion, ALX exerted differential toxicity on beta-cell structures similar to in vitro results reported from this laboratory. Furthermore, the present results differ from those reported for the diabetogen streptozotocin (STZ). Injections of multiple low doses (MLD) of STZ reduced GLUT2 expression only, but failed to affect expression of GK and proinsulin as well as beta-actin as internal control. MLD-STZ diabetes was prevented by pretreatment with both D-G and 5-T-G and administration of Zn(2+)-enriched drinking water. Apparently, ALX and MLD-STZ exert diabetogenicity by different pathways requiring different interventional schedules for prevention.
German Diabetes Research Institute at the Heinrich-Heine-University of Duesseldorf, Auf'm Hennekamp 65, Germany.
Sabine Schulte
SS
im Walde
Claudia
C
Dohle
Patricia
P
Schott-Ohly
Helga
H
Gleichmann
D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015032:Zinc / Q000494:pharmacology
D000963:Antimetabolites; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D051273:Glucose Transporter Type 2; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000496:Alloxan; D003847:Deoxyglucose; D005941:Glucokinase; D015032:Zinc