# Transcriptional and Translational Mechanisms Governing Beta Cell Function

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $380,912

## Abstract

PROJECT SUMMARY/ABSTRACT
 The prevalence of diabetes and pre-diabetes in the US is now a staggering 51%. It has become
increasingly clear that development of both type 1 and type 2 diabetes depends upon the ability or inability of
the islet β cell to adapt to prevailing stresses in either disease. Elucidating the molecular mechanisms of the β
cell response in diabetes has remained a long-standing objective of this R01 award over the years. My
laboratory has recently focused on defining how mRNA translation in the β cell is regulated in response to
diabetogenic stresses. The translation factor eIF5A functions as an acute response factor in the β cell that
either activates translation of specific mRNAs, enabling the requisite cellular response. Notably, eIF5A is the
only protein containing the unique amino acid hypusine. When “hypusinated,” eIF5A permits translation of
specific mRNAs; when “unhypusinated,” eIF5A is dysfunctional. The formation of hypusine is governed by two
rate-limiting enzymes, ornithine decarboxylase (ODC) and deoxyhypusine synthase (DHS). ODC generates
intracellular polyamines from ornithine, and DHS utilizes the polyamine spermidine to form hypusine on eIF5A.
Because polyamines and hypusine can be manipulated by diet or clinically available small molecule inhibitors,
they represent real-world targets to intervene in human diabetes pathogenesis. This application takes a
distinctly disease-specific approach to understand better the role of the polyamine/hypusine pathway in type 1
and type 2 diabetes. We hypothesize that the pathway that generates polyamines and hypusine integrates
extracellular diabetogenic signals to promote stress-specific mRNA translation in the islet β cell. We believe we
are uniquely positioned with the expertise in β cell biology and mRNA translation and with unique reagents––
including novel conditional KO mice, mRNA translation assessment tools, and access to clinical trial samples–
–to test this hypothesis. We propose the following 3 aims
Aim 1: Interrogate the mechanism by which the polyamine/hypusine pathway contributes to the translation of
specific mRNAs in islet β cells.
Aim 2: Determine the adaptive and maladaptive roles of the polyamine/hypusine pathway in β cell
compensation and dysfunction, respectively, in insulin resistance.
Aim 3: Define the roles of hypusine and polyamines during the pathogeneses of mouse and human type 1
diabetes.
We believe the major impact of these studies will be to identify a new tractable pathway that contributes to the
adaptive and maladaptive responses of the β cell to inflammatory, ER, and oxidative stresses. Because
manipulation of this pathway is achievable with small molecule inhibitors, these studies will provide the first
evidence for the feasibility of these inhibitors in the treatment of diabetes.

## Key facts

- **NIH application ID:** 9955250
- **Project number:** 7R01DK060581-18
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Raghavendra G Mirmira
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,912
- **Award type:** 7
- **Project period:** 2002-03-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955250

## Citation

> US National Institutes of Health, RePORTER application 9955250, Transcriptional and Translational Mechanisms Governing Beta Cell Function (7R01DK060581-18). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9955250. Licensed CC0.

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