Abstract Type 2 diabetes (T2D) is a major health problem in the US and worldwide, causing high morbidity and mortality. According to the CDC, in 2017, ~32.5 million had T2D, and an estimated 88 million adults in the United States had prediabetes. Diabetes is the seventh leading cause of death and has become the number one biomedical financial burden in the US, with an estimated national economic cost of $327 billion in 2017. Currently, there is no radical cure for T2D. Studies have demonstrated that glucose induces insulin secretion in a biphasic pattern: an initial first-phase, which develops rapidly but lasts only a few minutes, followed by a nadir, then a sustained second-phase. Loss of first-phase insulin secretion and reduced second-phase secretion are characteristic features of T2D. It is well known that a decrease in the first-phase insulin secretion is the earliest and detrimental defect detected in impaired glucose tolerance (prediabetes) and T2D. Although studies have highlighted the existence of two intra- pancreatic axes of communication between the endocrine and exocrine pancreas (the insular–acinar axis and the acinar–insular axis), little attention has been paid to any direct effect of the exocrine pancreas on β-cell function. We recently designed a surgical mouse model wherein a pancreatic ductal infusion of 1% acetic acid (AcA) led to complete ablation of the exocrine pancreas, but importantly with complete sparing of the islets. This model allows us to study β-cell function in-situ in the pancreas, with the islets retaining their native innervation and vasculature, but in the absence of the exocrine pancreas. We also established a genetic model that uses the diphtheria toxin receptor selectively expressed in acinar cells via the elastase promoter to quickly ablate acinar cells using diphtheria toxin. Our preliminary data in mice, and now in non-human primates, show a significant improvement in glucose tolerance and first-phase insulin secretion to supranormal levels following exocrine pancreas ablation. Observing a similar phenotype with both acinar-only ablation in the genetic model and global exocrine (acini and ducts) ablation in the surgical model supports our hypothesis that it is the acinar cells that are specifically detrimental to the β-cells. This proposal aims to understand the improvements in the physiology of glucose homeostasis in this model by performing the hyperglycemic clamp. It also aims to test the potential translatability of this study by examining the effect of exocrine pancreas loss in a mouse model of obesity-induced hyperglycemia and identifying the underlying causes of the improved insulin secretion following the loss of the exocrine tissue. Also, an important aim of this study is to try to identify the acinar-secreted factor that has an adverse effect on β-cell function. Successful completion of this project will provide the basis for the ultimate objective of this study of generating a therapeutic tar...