Complete protection from low-dose streptozotocin-induced diabetes in mice

Abstract

STREPTOZOTOCIN (SZ) is a broad-spectrum antibiotic with oncolytic, oncogenic and diabetogenic properties1–4. To produce diabetes in experimental animals, SZ is administered as a single bolus, injected either intravenously (i.v.) or intraperitoneally (i.p.). Within 72 h, selective destruction of pancreatic beta cells and hyperglycaemia occur3,5. Subdiabetogenic doses of SZ cause only mild degranulation of the β-cells without hyperglycaemia during the first 72 h, unlike multiple (five) subdiabetogenic (i.v. or i.p.) doses of SZ to Charles River Laboratory (CD-1) mice, which produce marked glucose elevations within 5–6 days of the last injection of SZ, associated with morphological evidence of insulitis6,7. To dissociate direct β-cell toxicity of SZ from the delayed appearance of the insulitis and hyperglycaemia, we used antilymphocyte serum and 3-O-methyl-D-glucose (3-OMG), a nonmetabolised glucose analogue, which prevents the occurrence of hyperglycaemia for at least 72 h, when administered to mice or rats prior to a single diabetogenic dose of SZ8,9. Antilymphocyte serum (ALS), while not altering the multiple subdiabetogenic SZ-induced hyperglycaemia, does protect against the lymphocytic infiltration of the pancreatic islets, without changing the delayed hyperglycaemic response observed following the combination of 3-OMG and SZ injections10. We report here that injections of ALS (for 5 weeks), in combination with a regimen of 3-OMG and SZ, prevented the development of hyperglycaemia for the entire 14 weeks of the experiment, and that mice demonstrated essentially normal intraperitoneal glucose tolerance tests and pancreatic histology during the 3rd and 4th months following SZ.