Thyroid hormone and diabetes:an anti-apoptotic pro-survival opportunity for pancreatic b cells.

Pancreatic β cell loss is the key factor in the pathogenesis of both type 1 and type 2 diabetes, being mainly due to apoptosis of the β cell. Therefore, it is conceivable that a valuable approach to treat or even to prevent the onset of diabetes may imply an anti-apoptotic pro-survival therapy of β cell. Ex vivo islet cell culture in the presence of stimulating factors prior to transplantation is considered a good strategy in contrast to the short conclusion of islets transplantation. Previously, I demonstrated how T3 can increase β cell function via specific activation of Akt; therefore I, firstly, hypothesized that thyroid hormone T3 can be considered a promising candidate for the in vitro expansion of islet cell mass. Rat pancreatic islets have been isolated by collagenase digestion and cultured in the presence or not of T3 10⁻⁷ M. Islets viability has been evaluated by two different dyes, one cell-permeable green fluorescent and propidium iodide, and by the analysis of core cell damage upcoming. Moreover, islets function has been evaluated by insulin secretion. The ability of β cells to counteract apoptosis induced by streptozotocin has been analyzed by TUNEL assay. In addition, core cell damage was sensibly reduced by T3, suggesting the preservation of the β cells integrity during the culture period. I demonstrated that treatment of primary cultures of rat pancreatic islets with T3 results in augmented β-cell vitality and function. Since even insulin secretion was sensibly augmented by T3 stimulation. Moreover the strong increment shown in Akt activation suggests the involvement of this pathway in the observed phenomena. This study indicate T3 as a good factor to improve ex vivo islets cell culture. In the second part of my study I demonstrated that the thyroid hormone T3 counteracts the onset of a Streptozotocin (STZ) induced diabetes in wild type mice. To test my hypothesis diabetes has been induced in Balb/c male mice by multiple low dose Streptozotocin injection and a group of mice was contemporaneously injected with T3. After 48 h mice were tested for glucose tolerance test, insulin serum levels and then sacrificed. Whole pancreata were utilized for morphological and biochemical analyses, while protein extracts and RNA were utilized for expression analyses of specific molecules. The results showed that islets from T3 treated mice were comparable to age- and sex-matched control, untreated mice in number, shape, dimension, consistency, ultrastructure, insulin and glucagon levels, TUNEL positivity and caspases activation, while all the cited parameters and molecules were altered by STZ alone. The T3-induced pro survival effect was associated with a strong increase in phosphorylated Akt. Moreover, T3 administration prevented the STZ-dependent alterations in glucose blood level, both during fasting and after glucose challenge, as well as in insulin serum level. In conclusion I demonstrated that T3 could act as a protective factor against STZ induced diabetes.