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. We will first demonstrate the relevant physiology and pathophysiology in the vascularized liver acinus MPS (vLAMPS) and the vascularized pancreatic islets MPS (vPANIS) using primary human cells/tissue (Aim 1). The full power of MPS disease models will utilize patient- derived, adult iPSCs of all of the key cells in the organs and include real-time fluorescent biosensors of key physiological parameters and conditional knock-downs of selected genes. Our proposal has a strategic plan to optimize the migration from primary human cells in the UG3 phase to iPSC-derived cells in the later stages of the UH3 phase, including collaborative integration of relevant progress in the iPSC field (Aim 2 and 4). The initial use of human primary, cell-based MPS?s will define the optimal normal and disease metrics in each MPS model to begin the investigation of the disease and to serve as a functional reference to test the physiological relevance of the iPSC-derived models. We will functionally and then physically couple the vLAMPS to the vPANIS to test the hypothesis that factors from the insulin resistant liver can potentiate beta cell dysfunction in the context of hyperglycemia and hyperinsulemia (Aims 3 and 4). We will use our microphysiology database as a platform for sharing data, protocols, reagents, the vLAMPS and vPANIS models and results (Aim 5).

Public Health Relevance

We propose to further evolve our vascularized, human, 3D microfluidic liver micropysiology system model (vLAMPS) and a vascularized, human pancreatic islet microphysiology system (vPANIS) to investigate the mechanisms of disease progression of type 2 diabetes (T2D), to identify clinically relevant biomarkers and to develop therapeutic strategies that can prevent, mitigate or reverse the morbidity associated with diabetes and improve patient outcomes. We will evolve the models from human primary cells/tissues to iPSC-derived cells that include real-time fluorescence-based biosensors and conditional knock-down of selected genes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZDK1)
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Haft, Carol R
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University of Pittsburgh
Schools of Medicine
United States
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