# Metabolic crosstalks in regulation of beta-cell stress response and adaptation

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $468,839

## Abstract

Abstract
Glucose metabolism generates important signals that regulate several facets of β-cell health, including insulin
secretion, proliferation, survival, and differentiation. We have found that the TCA cycle enzyme pyruvate
carboxylase (PC), which promotes metabolic signals that regulate insulin secretion, has previously
unappreciated roles in β-cell stress mitigation by promoting urea cycle activity and de novo glutathione (GSH)
synthesis. These PC-directed pathways can promote a dual defense mechanism, whereby nitric oxide (NO)
synthesis from arginine is reduced as arginine is utilized for ureagenesis and antioxidant capacity is increased
by de novo GSH synthesis in the face of diabetes-related stress stimuli. Both pathways receive input from
glucose through PC activity and are modulated by phosphorylation of BAD, a GK binding and activating protein
that drives a broad β-cell protective program.
This renewal application addresses key questions that stem from these findings: What are the molecular
mechanistic components of this PC-driven β-cell protective program and how do they contribute to β-
cell mass dynamics? We will address these questions in two aims. First, we will dissect the downstream
effectors of the urea cycle pathway that are required for β-cell protection. Our prediction is that beyond changing
the balance between urea and NO production, urea cycle activation provides biosynthetic intermediates that
promote growth, including ornithine and polyamines. We will also examine how glucose is connected to these
pathways using metabolomics and metabolic tracing studies combined with genetic and pharmacologic
perturbations of these pathways. Similarly, we will examine the route for glucose to GSH synthesis and how this
antioxidant mechanism factors into PC-mediated protection. We will then test the relevance of these pathways
in protecting donor islets in a marginal mass islet transplantation model (Aim 1). Second, we will test the
contributions of these pathways to β-cell mass adaptation in response to high fat diet (HFD) using two
complementary approaches; a β-cell-specific PC knockout mouse model treated with HFD and assessing the
response of donor islet grafts to (HFD) treatment of transplanted mice (Aim 2).
These studies will provide an integrated picture of the pathways connecting phospho-BAD, GK and PC activation
to β-cell stress response and adaptation. In the fullness of time, understanding these connections will yield
valuable insights into the most effective strategies to capture and mimic the protective aspects of glucose
signaling for preservation/restoration of functional β-cell mass.

## Key facts

- **NIH application ID:** 10793593
- **Project number:** 5R01DK078081-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Nika N Danial
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,839
- **Award type:** 5
- **Project period:** 2008-02-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793593

## Citation

> US National Institutes of Health, RePORTER application 10793593, Metabolic crosstalks in regulation of beta-cell stress response and adaptation (5R01DK078081-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10793593. Licensed CC0.

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