Impaired β-cell function and insufficient β-cell mass compensation are twin pathogenic features that underlie type 2 diabetes (T2D). Current therapeutic strategies continue to evolve to improve treatment outcomes in different ethnic populations and include approaches to counter insulin resistance and improve β-cell function. Although the effects of insulin secretion on metabolic organs such as liver, skeletal muscle and adipose is directly relevant for improving glucose uptake and reduce hyperglycemia, the ability of pancreatic β-cells to crosstalk with multiple non-metabolic tissues is providing novel insights into potential opportunities for improving β-cell function and/or mass that could have beneficial effects in patients with diabetes. For example, the role of the gastrointestinal system in the regulation of β-cell biology is well recognized and has been exploited clinically to develop incretin-related antidiabetic agents. The microbiome and the immune system are emerging as important players in regulating β-cell function and mass. The rich innervation of islet cells indicates it is a prime organ for regulation by the nervous system. In this review, we discuss the potential implications of signals from these organ systems as well as those from bone, placenta, kidney, thyroid, endothelial cells, reproductive organs and adrenal and pituitary glands that can directly impact β-cell biology. An added layer of complexity is the limited data regarding the relative relevance of one or more of these systems in different ethnic populations. It is evident that better understanding of this paradigm would provide clues to enhance β-cell function and/or mass in vivo in the long-term goal of treating or curing patients with diabetes.