Anomer-Equilibrated Streptozotocin Solution for the Induction of Experimental Diabetes in Mice (Mus musculus)

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Streptozotocin (2-deoxy-2-[3-methyl-3-nitrosourea] 1-D-glucopyranose) occurs in 2 anomeric forms, α and β, which can be separated by HPLC. This drug is used for treating islet cell tumors of the pancreas and some neuroendocrine tumors 18 and has selective cytotoxicity for pancreatic β cells. It enters these cells by means of a glucose transporter (GLUT2) 17 and causes alkylation of DNA, resulting in rapid and irreversible necrosis. Streptozotocin is widely applied in medical research to gen-erate diabetes mellitus in many experimental animal species. 13 Most publications on diabetes induction by streptozotocin involve mice. A wide variety of dose schedules and routes of administration have been reported. The 2 most common protocols are intraperitoneal injection of a single high dose or multiple low doses. For diabetes induction through the single-high–dose regimen, reported doses vary from 100 mg/kg 5 to 220 mg/kg. 2 The low-dose protocol typically involves intraperitoneal administration of 5 consecutive daily doses of 40 mg/kg streptozotocin, 14 but the use of 4 (35 mg/kg) 9 and 6 6 daily administrations as well as of 2 separate courses of 5 injections of 40 mg/kg 3 have been reported also. An exceptionally aggressive regimen of 5 times 100 mg/kg induced diabetes in 90% of C3H mice, 19 but in that case streptozotocin was dissolved in PBS instead of acidic cit-rate buffer, which allegedly rapidly inactivates the drug. Even though induction through multiple low doses of streptozotocin is more laborious, many investigators adhere to this regimen based on the belief that it is more consistent in its yield of hy-perglycemic animals. With both regimens, investigators seem to select the hyperg-lycemic responders, commonly defined as showing persistent blood glucose levels of at least 16.6 mmol/L (300 mg/dL), although only a few publications specifically address subject selection. 6,8,19 Little information is provided on the percentage of nonresponders and reproducibility of the induction protocol in consecutive experiments. Mortality has been noted with both induction regimens, and all mortality reported to date appears to have been due to hyperglycemia. In addition, strain-, sex-, and age-associated differences in sensitivity to the streptozotocin induction regimens have been observed. 4,5,20 Most investigators specify 2,4,5,6,8,14,20 that streptozotocin solution (in citrate or acetate buffer, pH 4.5) was administered " immediately " but no later than 15 to 20 min after dissolving, as recommended by the National Institute of Diabetes and Digestive and Kidney Diseases Animal Models of Diabetic Complications Consortium. 1 The reason underlying this timing is an alleged instability of streptozotocin in these buffers, an assumption that has not been supported by solid data. On the contrary, as first reported in 1978, 11 the total amount of strepto-zotocin (as determined by HPLC) remains constant for several days at room temperature in acidic buffer solution. Due to mutarotation of the glucopyranose ring, approximate equimolar equilibrium between the 2 anomers is achieved 60 to 90 min after the powder goes into solution. 11,12,14 However, the α anomer is more toxic than is the β anomer, as manifested by a difference of approximately 5.5 mmol/L (100 mg/dL) in nonfasting plasma glucose levels at 48 h after administration. 14 This difference in blood glucose concentration was apparent in male Sprague–Dawley rats given 30 to 50 mg/kg

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