NONGENETIC MOUSE MODELS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS

The purpose of the study was to develop a mouse model of non-insulin-d ependent diabetes mellitus (NIDDM) that closely simulates the metaboli c abnormalities of the human disease and is also cost-effective compar ed with the genetic models currently available. For this purpose, insu lin resistance was induced in male C57BL/6J or Institute of Cancer Res earch (ICR) mice by feeding diets enriched in either fructose or fat, and hyperglycemia was induced by injecting these mice with a dose of s treptozotocin (STZ) that does not cause diabetes in chow-fed mice. In the case of C57BL/6J mice, insulin levels initially increased in respo nse to the fructose-and fat-enriched diets and then decreased to level s comparable to or still higher than those in chow-fed mice following STZ injection. Associated with the decrease in insulin levels followin g STZ, fat-fed and fructose-fed C57BL/6J mice became significantly hyp erglycemic, reaching values of 388 +/- 38 and 366 +/- 58 mg/dL, respec tively. In contrast, neither plasma glucose nor insulin concentrations changed in chow-fed mice injected with an identical amount of STZ, Es sentially identical findings were seen before and after STZ injection in fat-fed compared with chow-fed ICR mice. Although a direct comparis on was not made, sensitivity to the diabetogenic effects of STZ appear ed to be greater in fat-fed ICR compared with fat-fed C57BL/6J mice. F inally, plasma glucose decreased when mice with these experimental mod els of NIDDM were treated with either metformin or tolbutamide, Given these results, it seems reasonable to suggest that the combination of dietary-induced insulin resistance and relatively low-dose STZ results in mouse models that should be of use in studying the pathophysiology of NIDDM or in evaluating therapeutic compounds for the treatment of NIDDM. Copyright (C) 1998 by W.B. Saunders Company.