Certain teleost fish have large anatomically discrete islet organs called Brockmann bodies (BBs). When transplanted into streptozotocin diabetic athymic nude mice, tilapia BBs provide long-term normoglycemia. This has afforded us the opportunity to examine tilapia islet in vivo function in a non-piscine environment and compare this with in vivo function in the donor species. As expected, fasting and non-fasting glycemic levels in long-term murine recipients of tilapia BBs were analogous to corresponding values in donor tilapia, but, surprisingly, tilapia BB grafts provided mammalian-like glucose tolerance profiles. Teleost fish, in general, are severely glucose intolerant. When glucose tolerance tests were performed in tilapia, the mean glucose disappearance rates were very low; however, diabetic nude mice bearing long-term tilapia BB grafts were extremely glucose responsive. This suggested a severe or absolute peripheral resistance to the glucostatic effects of insulin. Using Western blotting with polyclonal antibodies and then confirmed by Northern analysis, tilapia peripheral tissues appear to be devoid of GLUT-4, the insulin-sensitive glucose transporter responsible for the hypoglycemic effect of insulin in mammals, but not GLUT-1, the insulin independent glucose transporter. This may explain why tilapia, and possibly other teleost fish, are severely glucose intolerant after pharmacologic glucose-loading. Because tilapia do not tend to consume large quantities of glucose in the wild, it is not surprising that they have evolved without a mechanism to move glucose rapidly from the bloodstream into muscle and fat. Nevertheless, insulin still appears to play an important role in maintaining normoglycemia in tilapia; however, this is mostly likely a result of its effect on glucose uptake in the liver. We also present comparative data on tilapia beta cell function, quantification of islet cell numbers and types, islet products, insulin gene structure and expression, and beta cell sensitivity to the diabetogenic drug streptozotocin.