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The notion that IGF-I stimulates islet cell growth has been challenged recently by IGF-I and receptor gene targeting. In order to test the effect of a general, more profound increase in circulating IGF-I, we have characterized MT-1GF mice which overexpress the IGF-I gene under the metallothionein I promoter. In previous reports, a 1.5-fold elevated serum IGF-I level caused accelerated somatic growth and pancreatic enlargement. Here it was demonstrated that the transgene expression, although widespread, was highly concentrated in the pancreatic islets. Yet, islet cell percentage and morphology were unaffected. However, IGF-I overexpression resulted in significant hypoglycemia, hypoinsulinemia, improved glucose tolerance and normal insulin sensitivity. Pyruvate tolerance test indicated suppressed hepatic gluconeogenesis. Due to a partial prevention of β-cell death against onset of diabetes and/or the insulin-like effect of IGF-I overexpression, MT-IGF mice were significantly resistant to streptozotocin-induced diabetes, with diminished hyperglycemia, weight loss and death. Thus, although IGF-I does not promote islet cell growth, its overexpression is clearly anti-diabetic. Figure 1. Normal insulin sensitivity, Increased glucose clearance and decreased gluconeogenesis in MT-IGF mice. Mice of 2.5-month-old, mixed male and female, were used. A, Insulin tolerance test. Wild-type and MT-IGF mice in random fed state were injected with insulin (0.75 IU/kg ip). Blood glucose levels were measured at 0, 20, 40 and 60 min. Percentage values relative to time 0 were expressed as means ± SE. (N = 4) B, Glucose tolerance tests. Mice were fasted for 24 h and injected with glucose (1.0 g/kg ip). (N = 4∼6) C, Pyruvate tolerance tests. Mice were fasted for 24 h and injected with pyruvate (2.0 g/kg ip). (N = 4∼5) D, Glutamine tolerance tests. Mice were fasted for 24 h and injected with L-glutamine (1.5 g/kg ip). (N = 7∼12) *P<0.05, **P<0.01, ***P<0.001 vs. wild-typo littermates. [ABSTRACT FROM AUTHOR]