# Microphysiological systems to interrogate the Islet-Liver-Adipose Axis in normal physiology and Type-2 Diabetes Mellitus

> **NIH NIH UH3** · UNIVERSITY OF CALIFORNIA BERKELEY · 2022 · $2,287,847

## Abstract

PROJECT SUMMARY/ABSTRACT
Obesity-related disorders, particularly type-2 diabetes mellitus (T2DM), continuously increase in the US and
worldwide with an estimated 1.9 billion overweight adults and over 650 million obese individuals globally. While
the mechanistic underpinnings of obesity-induced T2DM remain a topic of investigation, central features
include a pro-inflammatory environment and dysregulated lipolysis in adipose tissue leading to elevated levels
of circulating free fatty acids with subsequent ectopic accumulation of lipids in multiple tissues. The
combination of nutrient excess and pro-inflammatory signaling in turn results in insulin resistance in multiple
tissues impairing glucose uptake by muscle and adipose tissue and release by the liver as well as ß-cell
function, ultimately resulting in overt diabetes. Interrogation of the complex interplay between these key tissues
has, thus far, only been possible using animal models, which do not lend themselves to high-throughput
approaches and frequently deviate from humans in key metabolic features, thus greatly impeding efforts to
discover treatments for insulin resistance and T2DM. Here we propose to develop an essential set of human
induced pluripotent stem cell (iPSC)-derived key metabolic tissues for glucose and fatty acid uptake/release,
i.e., liver (L) and adipose (A) tissue, and insulin secretion, i.e., islets (I), in conjunction with an immune
component, i.e., macrophages, using interconnected microphysiological systems (MPS). This LAI-MPS will
allow for the pharmacological interrogation of glucose and insulin sensitivity in the context of normal tissue
interactions, lipid overload and chronic inflammation to address the following major current shortfalls. In 6
milestones we will progress from the 1) generation and metabolic characterization of human iPSC-derived
hepatocytes, adipocytes, ß-cells and macrophages – to 2) Development of optimized microfluidic devices for
iPSC-derived hepatocytes, adipocytes and ß-cells – to 3) Establish on-chip insulin and glucose sensitivity
assays for, WAT and islet MPS. As part of the UH3 phase we will then begin integration of MPS platforms by
4) integration of liver and fat MPS with common medium and determination of insulin sensitivity using in-line
sensors – and 5) Use liver and WAT MPS for the generation and quantitation of insulin resistance following
scaling of WAT MPS and inclusion of pro-inflammatory macrophages – and finally 6) integrate islet, liver, and
WAT MPS and determine impact of pharmacological and pro-inflammatory modulation on glucose tolerance
and ß-cell function. Ultimately, this disruptive technology will enable the rapid screening of pharmacological
and environmental compounds for beneficial or detrimental effects on insulin sensitivity and for the detection of
pharmacogenetic interactions.

## Key facts

- **NIH application ID:** 10462610
- **Project number:** 5UH3DK120004-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** KEVIN Edward HEALY
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,287,847
- **Award type:** 5
- **Project period:** 2018-09-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462610

## Citation

> US National Institutes of Health, RePORTER application 10462610, Microphysiological systems to interrogate the Islet-Liver-Adipose Axis in normal physiology and Type-2 Diabetes Mellitus (5UH3DK120004-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10462610. Licensed CC0.

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