Type 1 diabetes (T1D) is a chronic metabolic disease characterized by autoimmune destruction of β cells of the insulin producing pancreatic islets. The different immunological approaches implemented to date to treat T1D have obtained a negligible number of insulin-independent individuals. The initial stages of diabetic disease are characterized by the massive and progressive infiltration of T cells and autoantibodies within the tissue with the consequent development of insulitis and subsequently, the destruction of pancreatic beta cells. The onset of T1D has been mainly associated to a dysregulation of the immune response. However, data are emerging on the importance of non-immunological factors responsible for the damage to pancreatic beta cells. The investigators have recently shown that the expression of the TMEM219 death factor is an essential factor in controlling the fate of stem cells in diabetes.

The aim of the study is to identify new markers in the mechanism of damage to pancreatic beta cells in the onset of type 1 diabetes, with particular reference to apoptotic factors such as TMEM219.

METHODS OF RECRUITING THE SUBJECTS Healthy subjects, individuals with type 1 and type 2 diabetes and those who are at risk of developing diabetes will be enrolled. Enrollment was approved by the University of Florida Ethics Committee within the NPOD project, Network for the Pancreatic Organ Donors with Diabetes.

Duration of the study: 5 years.

EXPERIMENTAL PROCEDURE:

The following analyses will be performed on the collected and received samples:

• Study of TMEM219 expression and of other TMEM219-related markers by immunohistochemistry and immunofluorescence and western blot
• Study of TMEM219 expression and of other TMEM219-related markers by molecular biology analysis
• Analysis of the proteomic profile on collected biological liquids The above analyses will be performed at the Pediatric Clinical Research Center Romeo ed Enrica Invernizzi at the Sacco Hospital - University of Milan.

PREVIOUS EXPERIENCES The investigatore expertise in manipulating / studying the signaling involved in the pathogenesis of type 1 diabetes has been widely recognized in several publications in recent years (Diabetes 2013, Diabetes 2014, Diabetes 2015, Science Translational Medicine 2017) as well as the characterization of marker expression including TMEM219 (Cell Stem Cell 2015).

RELEVANCE OF THE STUDY The study offers the possibility to acquire new information on the pathogenesis of diabetes and to identify new target mechanisms for designing innovative therapeutic strategies in the treatment of diabetes.

Inclusion Criteria:

• Reported in the NPOD protocol

Exclusion Criteria:

• Reported in the NPOD protocol

The study already approved at the local Ethical Committee provides for the enrollment of the following groups of subjects:

• subjects affected by diabetes (type 1, type 2, MODY)
• subjects at risk of developing diabetes (positive screening for autoantibodies)
• subjects not affected by diabetes Enrollment is coordinated by the University of Florida as part of the NPOD project, Network for the Pancreatic Organ Donors with Diabetes.