Strain Differences in the Diabetogenic Activity of Streptozotocin in Mice
Biological and Pharmaceutical Bulletin
Diabetes mellitus is classified into two types, insulin-dependent (IDDM, type 1) and non-insulin-dependent diabetes mellitus (NIDDM, type 2). NIDDM is a disease characterized by peripheral insulin resistance and impaired insulin secretion. NIDDM patients are divided into 2 categories, obese type with hyperinsulinemia and non-obese type with hypoinsulinemia. Streptozotocin (STZ; N-nitroso derivative of glucosamine) is a broad-spectrum antibiotic extracted from Streptomyces acromogenes. 1) It is
... pancreatic b-cell toxin that induces rapid and irreversible necrosis of b-cells 2) and is widely used in making experimental animal models of IDDM. 3-6) Junod et al. 5) reported that the i.v. injection of 25 to 100 mg/kg STZ to rats was able to produce a dose-dependent hyperglycemia. Recently, we succeeded in producing a new mouse model of slowly progressive NIDDM by only a single i.p. injection of a subdiabetogenic dose (100 mg/kg) of STZ to 8-week-old male ICR mice. 7,8) However, there is yet no experimental evidence about whether or not the slowly progressive NIDDM is produced in mice of other strains, except for ICR, by a single i.p. injection of a subdiabetogenic dose of STZ. Therefore, in the present study, we examined the dose-dependent diabetogenic action of STZ in 8-week-old male ddY, BALB/c, and C57BL/6 mice and compared it with that in 8-week-old male ICR mice. We found that slowly progressive NIDDM was produced in ddY mice as well as ICR mice by a single i.p. injection of a subdiabetogenic dose (125 mg/kg) of STZ. In order to clarify the characteristics of the progressive diabetes in ddY mice, we also followed-up the changes in islet morphology (the number of aand b-cells) and serum glucose and insulin responses to oral glucose load after STZ administration. We have already reported that slowly progressive non-insulin-dependent diabetes mellitus (NIDDM) is produced by a single i.p. injection of a subdiabetogenic dose (100 mg/kg) of streptozotocin (STZ) to 8-week-old male ICR mice. The aim of the present study was to clarify whether or not the progressive NIDDM is induced in ddY, BALB/c, C57BL/6 and ICR mice by the administration of STZ. Eight-week-old male mice of the 4 different strains were administered a single i.p. injection of STZ at various doses (ICR, ddY and BALB/c: 100-200 mg/kg; C57BL/6: 75-150 mg/kg). Among the ddY, BALB/c and C57BL/6 mice, a time course-related rise in non-fasting serum glucose levels throughout the observation period of 1-12 weeks after STZ administration was only induced in the 125 mg/kg STZ ddY and 100 mg/kg STZ ICR mice. In contrast with serum glucose levels, the area of islets and the percentage of the relative number of insulin-immunoreactive cells (b b-cells) to glucagon-immunoreactive cells (a a-cells) in the 100 mg/kg STZ ICR and 125 mg/kg STZ ddY mice continued to decrease gradually over time. In addition, in low dose STZ mice of both strains, the insulin response to glucose stimulation was extremely impaired over time, although non-fasting serum insulin levels were maintained near normal levels. The rate of the progression of diabetes was faster in the 125 mg STZ ddY mice than in the 100 mg/kg STZ ICR mice.