# Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $454,815

## Abstract

ABSTRACT
While evaluating the potential for glucagon receptor antagonists (GRAs) to maintain glucose homeostasis in
T1D rodents, we noted that GRAs promote β−cell survival and regeneration. Remarkably, GRA-treated mice
maintained normal blood glucose, even after the treatment was withdrawn. Our recently published data
suggest that: 1) ablation or antagonism of the glucagon receptor (GcgR) blunts apoptosis and stimulates
regeneration of functional β-cell mass in mice; 2) much of this new insulin+ mass derives from the conversion
of α−cell precursors into insulin-producing cells; and 3) GRAs restore sustainable euglycemia and insulin
production in diabetic NOD mice and in mice grafted with human islets. Our preliminary results suggest that the
β-cytotrophic effects of GRAs occur through both islet autonomous effects and through a well described liver-
α-cell axis4-7 which triggers α-cell hyperplasia through AA-dependent mechanisms (Figure 1). We have
identified Foxn3, a glucagon-responsive transcriptional repressor and novel mediator of glycemia8-11, as the
previously-undefined integrator by which glucagon alters amino acid metabolism. In parallel, we have
identified the GRA-driven upregulation of fibroblast growth factor 2 (FGF2), a target of the proliferative
transcriptional co-factor Yes-associated protein 1 (YAP1) that is expressed in Sox9+ ductal cells, as a key
contributor to GRA-mediated revival of a regenerative niche within the islet. We hypothesize that impaired
glucagon action promotes hepatic Foxn3-mediated α-cell hyperplasia via changes in amino acid metabolism
and an FGF2-mediated regenerative niche within the islet to allow α-cell to β-cell conversion in T1D. We will
evaluate our hypothesis using a cadre of novel, validated, and uniquely-suited mouse models which facilitate
our genetic dissection of the mechanisms linking the loss of glucagon signaling to altered hepatic utilization of
amino acids, α-cell hyperplasia, and the restoration of functional β-cell mass via two aims. 1) Using PANIC-
ATTAC diabetic mice, cultured murine islets, and cultured human islets, we will examine the islet-autonomous
effects of glucagon receptor antagonism or ablation on β-cell survival and β-cell regeneration. 2) We will
examine α-cell hyperplasia, β-cell survival and the regeneration of functional β−cell mass after liver-specific
deletion or overexpression of Foxn3.

## Key facts

- **NIH application ID:** 10540191
- **Project number:** 2R01DK112826-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** WILLIAM L HOLLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $454,815
- **Award type:** 2
- **Project period:** 2017-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540191

## Citation

> US National Institutes of Health, RePORTER application 10540191, Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration (2R01DK112826-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10540191. Licensed CC0.

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