Patients with diabetes would benefit from therapies that increase functional β-cell mass. β-cells naturally adapt to increased metabolic demand and insulin resistance by expanding their functional mass, a process that decreases with aging. We have recently demonstrated a critical role for Myc in adaptive expansion of functional β-cells in young but not old mice. Despite multiple studies describing the effect of Myc overexpression in beta cells, there is a knowledge gap about how this crucial anabolic transcription factor perceives and responds to nutrients and increased insulin demand in its native context. How do nutrients regulate Myc expression in β-cells? How does Myc participate in the regulation of GSIS and mitochondrial function in the β-cell, how does Myc fail to increase adaptive proliferation in aged β-cells or will targeted demethylation of specific Myc binding sites increase β-cell proliferation in metabolically-stressed aged β-cells? These important questions about the physiological role of Myc in the β-cell need to be answered to advance our knowledge and find therapeutic means to treat diabetes. Our overarching hypothesis is that Myc is critical for adaptive β-cell growth and function, and reversing Myc resistance in the T2D-prone or metabolically-stressed aged β-cell can lead to an enhanced adaptive response. We will test our hypothesis by completing the following specific aims: 1) To elucidate how nutrients physiologically upregulate Myc in β-cells and whether Myc upregulation is required for adaptive glucose and β-cell homeostasis in insulin resistance; 2) To determine the physiological role of Myc on insulin secretion and mitochondrial bioenergetics in the β-cell; and, 3) To uncover and modify the mechanisms impairing Myc action in the metabolically-stressed, aged, and T2D β-cells. These studies will deliver unprecedented insight into how Myc is regulated by nutrients, how Myc regulates β-cell function and how to overcome Myc resistance in the metabolically-stressed aged β-cell, which will provide a crucial basic platform for designing and testing novel therapeutic strategies for the treatment of diabetes.