Insulin-like growth factor I (IGF-I) is normally produced from hepatocytes and various other cells and tissues, including the pancreas, and is known to stimulate islet cell replication in vitro, prevent Fas-mediated -cell destruction and delay the onset of diabetes in non-obese diabetic mice. Recently, however, the notion that IGF-I stimulates islet cell growth has been challenged by the results of IGF-I and receptor gene targeting. In order to test the effects of a general, more profound increase in circulating IGF-I on islet cell growth and glucose homeostasis, we have characterized MT-IGF mice which overexpress the IGF-I gene under the metallothionein I promoter. In early reports, a 1.5-fold elevated serum IGF-I level caused accelerated somatic growth and pancreatic enlargement. We demonstrated that the transgene expression, although widespread, was highly concentrated in the -cells of the pancreatic islets. Yet, islet cell percentage and pancreatic morphology were unaffected. IGF-I overexpression resulted in significant hypoglycemia, hypoinsulinemia, improved glucose tolerance but normal insulin secretion and sensitivity. Pyruvate tolerance test indicated significantly suppressed hepatic gluconeogenesis, which might explain the severe hypoglycemia after fasting. Finally, due to a partial prevention of -cell death against onset of diabetes and/or the insulin-like effects of IGF-I overexpression, MT-IGF mice were significantly resistant to streptozotocin-induced diabetes, with diminished hyperglycemia, weight loss and death. Although IGF-I does not promote islet cell growth, its overexpression is clearly anti-diabetic by improving islet cell survival and/or providing insulin-like effects.