The PI3K/Akt pathway is a common pathway activated by a variety of growth factors to stimulate cell growth and survival. In particular, Akt activation has been shown to induce b cell proliferation, survival, mass and function. Thus, factors able to stimulate Akt have gained relevance in the search of new antidiabetic strategy. We showed in this paper that the observed T3- induced anti-apoptotic LY2109761 effects are associated with activation of the Akt signalling pathway in the islets. This is consistent with recent data showing the ability of the thyroid hormone to stimulate Akt in neurons, in vascular myocytes and in other cell types. In addition, we previously demonstrated that T3 stimulates Akt in pancreatic b cells in vitro, leading to the activation of mTOR, GSK3B, B-catenin and others ; in the present study we did not deepen into the Akt pathway, but considering our in vitro data, it is conceivable that the survival action of T3 in mice might involve mainly the same mechanisms. The important outcome of the observed T3 protective effects in b cell survival and function is the preservation of pancreatic metabolic activity. Indeed, we showed that T3 administration actually preserves an intact response to glucose, and keeps plasma insulin levels in STZtreated mice comparable to those in control mice; moreover, we showed that both STZ and STZ+T3 treated mice do not develop insulin resistance. While b cell loss by apoptosis is a recognized feature of both type 1 and type 2 diabetes, approaches to block this process are limited, so far. Currently, the main goal for diabetes treatment is the maintenance of glucose homeostasis as close to normal as possible in order to avoid the devastating complications of this disease. These treatments include oral hypoglycemics and insulin sensitizers, different insulin preparations administered daily by multiple injections, continuous insulin pumps and, in some T1D patients, transplantation of the whole pancreas or islets. None of these approaches is focused on the maintenance of endogenous b cell mass, though it has been shown that even a small amount of preserved endogenous insulin secretion has great Everolimus abmole bioscience benefits in terms of clinical outcome. Therefore, finding a molecule that could be useful to block b cell apoptosis and thereby preserve and enhance endogenous b cell mass would represent a major breakthrough. The results presented in this study suggest that T3 may actually be a good candidate. To this aim, however, therapeutic protocol should be accurately designed, in terms of both doses and time intervals, to avoid side effects. It is known indeed that excess of thyroid hormones production by the thyroid gland or by exogenous thyroid hormones administration, results in hyperthyroidism or thyrotoxicosis, characterized by tachycardia, with possible atrial arrythmias and heart failure, muscle wasting, osteoporosis in post-menopausal women, and other symptoms.