Type 2 diabetes, characterized by persistent hyperglycemia, arises mostly from beta cell dysfunction and insulin resistance and remains a highly complex metabolic disease due to various stages in its pathogenesis. Glucose homeostasis is primarily regulated by insulin secretion from the beta cells in response to prevailing glycemia. Beta cell populations are dynamic as they respond to fluctuating insulin demand. Beta cell replenishment and death primarily regulate beta cell populations. Beta cells, pancreatic cells, and extra-pancreatic cells represent the three tiers for replenishing beta cells. In rodents, beta cell self-replenishment appears to be the dominant source for new beta cells supported by pancreatic cells (non-beta islet cells, acinar cells, and duct cells) and extra-pancreatic cells (liver, neural, and stem/progenitor cells). In humans, beta cell neogenesis from non-beta cells appears to be the dominant source of beta cell replenishment as limited beta cell self-replenishment occurs particularly in adulthood. Metabolic states of increased insulin demand trigger increased insulin synthesis and secretion from beta cells. Beta cells, therefore, adapt to support their physiology. Maintaining physiological beta cell populations is a strategy for targeting metabolic states of persistently increased insulin demand as in diabetes.