# The Diversity Outbred Diabetes Project

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $575,411

## Abstract

PROJECT SUMMARY/ABSTRACT
Type 2 diabetes (T2D) is the result of an increased demand for insulin along with an inability of pancreatic β-
cells to meet this demand by secreting sufficient amounts of insulin. The majority of gene loci identified by human
genetic studies of T2D affect β-cell development, mass, and/or function. Yet, there is a great deal that is unknown
about how β-cells secrete insulin in response to nutrient stimuli. We carried out a genetic screen of insulin
secretion in 233,447 pancreatic islets ex vivo that were isolated from 483 Diversity Outbred (DO) mice. The DO
mice were derived from 8 inbred mouse strains representing ~80% of the genetic diversity of all mouse strains.
They have as much genetic diversity as the entire human population; ~40 million single nucleotide
polymorphisms. The DO mice have been maintained for >30 generations, accumulating enough meiotic
recombinations to enable high-resolution mapping of pathophysiological phenotypes. Our genetic screen
identified 30 gene loci that affect insulin secretion or content of insulin or glucagon. Using our pipeline for gene
identification, we chose two genes for further study, Hunk and Zfp148. We derived a whole-body knockout of
Hunk and a β-cell-specific knockout of Zfp148. Islets from both of these knockout mice secreted more insulin in
response to nutrient stimulation than control mice. Hunk is a protein kinase, thus we will identify the substrates
of Hunk to discover how it regulates insulin secretion. Zfp148 is a transcription factor. Thus, we will identify the
direct transcriptional targets of Zfp148. We will apply our bioinformatic pipeline to identify additional genes from
the 30 gene loci identified in our screen and provide them to the research community. Functional studies will be
performed in genetically edited mice, genetically edited human ES-derived β-cells, and human islets. These
studies will discover novel genes and pathways involved in β-cell function and T2D susceptibility.

## Key facts

- **NIH application ID:** 10107803
- **Project number:** 5R01DK101573-08
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Alan D Attie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $575,411
- **Award type:** 5
- **Project period:** 2014-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107803

## Citation

> US National Institutes of Health, RePORTER application 10107803, The Diversity Outbred Diabetes Project (5R01DK101573-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107803. Licensed CC0.

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