The recent failure of immunotherapeutic strategies in the cure of T1D raised questions in considering autoimmunity the sole mechanism responsible for the pathogenesis of T1D. It has been recognized that activation of immune response against self-peptides is essential in the onset of T1D, but its role in the destruction of beta cells, which leads to reduced insulin secretion and glycometabolic control, is a matter of debate. The recent studies demonstrating a relevant role for the environmental factors in the pathogenesis of diabetes, confirmed that non-immunological determinants and beta cell regulating molecules might contribute in initiating and/or perpetrating this process. The increasing body of evidences that autocrine and paracrine signaling pathways control the homeostasis of several type of cells, such as stem cells and pancreatic beta cells, drew the attention of scientists on the possibility that even circulating hormones may be involved. More importantly, altered secretion of factors/hormones during T1D leads us to hypothesize that systemic factors may target pancreatic beta cells and modulate fate/function. Our previous studies showed that a circulating hepatic-released factor IGFBP3, exerts a detrimental effect on intestinal stem cells (ISCs) and induces their apoptosis/death by binding its receptor, TMEM219, expressed on ISCs surface. Interestingly, TMEM219, is expressed in human islets and in a beta cell line. We hypothesize that an overexpression of TMEM219 may favor beta cells destruction and affect beta cell mass, and the consequent hyperglycemia may perpetrate the process, given that TMEM219 expression is sensitive to high glucose exposure.