Human Microphysiology Systems Disease Model of Type 2 Diabetes Starting with Liver and Pancreatic Islets. Over 30 million Americans have diabetes, constituting about 9.4% of the adult population. An additional 84 million adult Americans have pre-diabetes, both amounting to an economic cost of $322 billion annually. The underlying cause of all forms of diabetes is an inadequate insulin secretion relative to the metabolic needs. While there is an absolute loss of beta cells in type 1 diabetes (T1D) due to an autoimmune destruction, the pathogenesis of type 2 diabetes (T2D) is much more heterogeneous with preceding insulin resistance being present in many tissues, principally the liver, ?-cells in pancreatic islets, white adipose tissue and skeletal muscle. The insulin resistance and the metabolic consequences vary between tissues and more importantly, vary enormously in the population. Furthermore, evidence from human and model organism studies has demonstrated the importance of organ crosstalk including the role of myokines, adipokines, hepatokines and cytokines from inflammatory cells, as well as the exosomal transfer of miRNA in the pathophysiology of diabetes. Interspecies differences between human and model organism physiology limits the translatability of many findings (e.g. from transgenic mouse studies), such as those from beta cells. All of these make it necessary to devise in vitro systems to study human physiology that allow organ crosstalk interrogation. Understanding the pathophysiology of T2D in a human microphysiology system (MPS) will help understand the progression of the disease, identify biomarkers and develop therapeutic strategies that can prevent, mitigate or reverse the morbidity associated with diabetes and improve patient outcomes. Our proposal focuses on two of the critical organs: liver and pancreatic islets.