Insulin resistant states such as obesity are generally characterized by an increase in beta cell mass as a form of compensation to maintain normoglycemia in mammals. The factors that promote the growth of beta cells and the mechanisms and signaling pathways that mediate these effects have been a focus of investigation for several decades. This presentation will include a discussion on inter-organ cross talk and the role of circulating factors, such as Serpinb1, that are able to enhance beta cell proliferation and mass in insulin resistant states. The discussion will include the role of growth factor signaling (e.g. insulin and insulin-like growth factor 1) proteins and the emerging importance of epitranscriptomics (RNA methylation) in the regulation of islet cell biology and metabolism with therapeutic significance.