PROJECT SUMMARY ABSTRACT The exocrine pancreas of patients with type 1 diabetes is smaller than the pancreas of healthy subjects and shows histological anomalies such as fibrosis, fatty degeneration, inflammatory cell infiltration and atherosclerosis. The histological features associated with diabetes are so specific that they have been defined as a distinct entity called diabetic exocrine pancreatopathy, which can be readily distinguished from chronic pancreatitis. The prevalence is high: 35 to 77% of adult patients with type 1 diabetes present with pancreatic exocrine dysfunction. Multiple etiological factors have been proposed, but it is inescapable that type 1 diabetes is defined by the autoimmune attack destroying the beta cells. Our goals are (a) to understand how the beta cell coordinates pancreas function and (b) to determine how the progressive demise of the beta cell impacts this coordination. In preliminary studies, we found that local insulin signaling affects the function of the acinar tissue and the islet microvasculature. We thus propose that locally delivered insulin orchestrates pancreas function by acting on three functional effectors: (1) adjacent acinar tissues, (2) vascular units comprised of pericytes and endothelial cells, and (3) intrapancreatic neurons that provide local cholinergic input. We hypothesize that beta cell control of these effectors deteriorates during the progression of T1D, leading to inadequate coordination of pancreas activity. The long term loss of this coordination produces pathological sequelae across compartments. The rationale for the proposed research is that if we want to develop therapies it is imperative to elucidate the mutual interactions and mechanism that promote the disease state. The proposed research is therefore relevant to the mission of the NIH that pertains to the pursuit of fundamental knowledge about beta cell function and its demise in diabetes. Guided by strong preliminary data, our hypothesis will be tested by pursuing three specific aims (1) Determine the impact of insulin on exocrine tissue function during diabetes development, (2) Determine the impact of insulin on the pancreatic microvasculature, and (3) Determine how insulin impacts neural coordination of pancreas function. We will determine the trophic role of insulin by manipulating insulin signaling and measuring the structural and functional consequences in exocrine, vascular, and neural compartments. The manipulation will be performed in the mouse in vivo, using genetic tools or in diabetes models. We will study the healthy and the diseased state in the human pancreas by using living pancreas slices provided by the network of pancreatic organ donors. The proposed research is significant because it could generate mechanistic insight into how beta cells influence surrounding tissues to coordinate activity across pancreas compartments. By identifying the effectors and principles governing this local regulation, we will be a...