Mice deficient in the zinc-sensor GPR39, which has been demonstrated to protect cells against endoplasmatic stress and cell death in vitro, display moderate glucose intolerance and impaired glucose-induced insulin secretion. Here, we use the Tet-On system under the control of the proinsulin promoter to selectively overexpress GPR39 in the ß cells in a double transgenic mouse strain and challenge them with multiple low doses of streptozotocin, which in the wild-type littermates leads to a gradual increase in nonfasting glucose levels and glucose intolerance observed during both food intake and OGTT. Although the overexpression of the constitutively active GPR39 receptor in animals not treated with streptozotocin appeared by itself to impair the glucose tolerance slightly and to decrease the ß-cell mass, it nevertheless totally protected against the gradual hyperglycemia in the steptozotocin-treated animals. It is concluded that GPR39 functions in a ß-cell protective manner and it is suggested that it is involved in some of the beneficial, ß-cell protective effects observed for Zn(++) and that GPR39 may be a target for antidiabetic drug intervention.