# A High Throughput Screening to Identify Compounds Rescuing Human Pancreatic Beta Cell Function in Diabetic Conditions

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $423,750

## Abstract

Abstract
Diabetes is a polygenetic and chronic disease affecting approximately 346 million people worldwide. In 2004, an
estimated 3.4 million people died from the consequences of high blood glucose. The World Health Organization
projects that deaths caused by diabetes will double between 2005 and 2030. Uncontrolled diabetes results in
hyperglycemia, which over time leads to serious damage to many organs. More than 90% of the diabetic
population has type 2 diabetes mellitus (T2DM). The classic pathogenesis of T2DM involves insulin resistance
and pancreatic beta cell dysfunction, marked by impaired, glucose-stimulated insulin secretion. Only 40-50% of
individuals with insulin resistance progress to T2DM. The pivotal defect in those who progress is that pancreatic
beta cells fail to compensate for insulin resistance, become dysfunctional, and eventually die. Thus, pancreatic
beta cell dysfunction is a key step in the progression from metabolic impairments to a disease state.
Most of the current efforts on anti-diabetes drug discovery focus on either protecting pancreatic beta cells from
cell death or inducing beta cell proliferation. Only a few drugs have been developed to improve pancreatic beta
cell function. It is well known that the same compound may have opposite effects on healthy and diseased cells,
since different mechanisms may be involved in the regulation of cellular physiology versus pathophysiology.
Therefore, a critical gap in anti-diabetes drug discovery is the lack of drugs rescuing human beta cell
function in a diabetic condition. This deficit is mainly due to the lack of a high-throughput screening
(HTS) platform to directly monitor human pancreatic beta cell function.
In our preliminary studies, we created a luminescence-based HTS assay to identify compounds that rescue
human pancreatic beta cell function in a diabetic condition. After completing a pilot screen using a library with
more than 2,000 small molecules, we identified hit compounds that potentially rescue the impaired, glucose-
stimulated insulin secretion of human pancreatic beta cells exposed to glucolipotoxicity. Here, we propose to
perform a large-scale HTS using our established platform on multiple chemical libraries containing
~240,000 compounds, validate the hit compounds using follow-up assays, optimize lead compounds through
simple structure activity relationship analyses, and evaluate the function of the identified chemical probes in
diabetic-humanized mouse models. Finally, we will perform target identification and study the mechanism of
action of the chemical probes. The identified chemical probes can be directly used for anti-diabetes drug
development or serve to discover novel disease targets for future drug discovery.

## Key facts

- **NIH application ID:** 9905514
- **Project number:** 5R01DK116075-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Shuibing Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905514

## Citation

> US National Institutes of Health, RePORTER application 9905514, A High Throughput Screening to Identify Compounds Rescuing Human Pancreatic Beta Cell Function in Diabetic Conditions (5R01DK116075-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9905514. Licensed CC0.

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