# Human Microphysiology Systems Disease Model of Type 2 Diabetes Starting with Liver and pancreatic Islets

> **NIH NIH UH3** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $2,133,247

## Abstract

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, β-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...

## Key facts

- **NIH application ID:** 10216387
- **Project number:** 4UH3DK119973-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** D. Lansing Taylor
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,133,247
- **Award type:** 4N
- **Project period:** 2018-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216387

## Citation

> US National Institutes of Health, RePORTER application 10216387, Human Microphysiology Systems Disease Model of Type 2 Diabetes Starting with Liver and pancreatic Islets (4UH3DK119973-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216387. Licensed CC0.

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