Type 1 and Type 2 Diabetes differ in their pathogenesis, but both are characterized by loss of β-cells. Most of the current therapies act on the symptoms rather than on the causes of the disease and they do not irreversibly cure it. Here, to uncover factors predisposing to the development of diabetes, we studied whether single nucleotide polymorphisms (SNPs) in the gene encoding for the human Cx36 alter the β-cells function. We found that SNP rs3743123 is associated with altered function of β-cells, possibly contributing to T2D pathogenesis. Next, we concentrated on strategies aimed at replenishing the β-cell mass once lost and, more specifically, we investigated the ability of pancreatic α-cells to give rise to new insulin producing cells. We show that the plasticity potential of α-cells is restricted by constitutive local regulatory signals originating from several endocrine cells within the pancreatic islet niche. Plasticity resistance of α-cells is mediated, among others, by constitutive intra-islet insulin and Hedgehog (Hh) signaling pathways and interfering with them primes α-cell for conversion into insulin producers.