# Novel Regulators of Beta Cell Proliferation and Function

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Diabetes is one of the leading causes of morbidity and mortality in the veteran population. The Veteran
population are particularly susceptible for diabetes, with a staggering 70% of Veterans at risk for diabetes. 25%
of all Veterans have diabetes, similar to that seen in older Americans from the general population. A failure to
increase the β-cell proliferation and functional β-cell mass in response to increasing metabolic demand from
insulin resistance associated with obesity and aging, underlies most causes of adult onset diabetes in
veterans. It is, therefore, imperative to identify pathways that regulate functional β-cell mass that could be
leveraged for treating β-cell failure and diabetes. Our data demonstrate that Tead1, a critical transcriptional
effector of the mammalian Hippo pathway, is robustly expressed in mouse and human islets and has a non-
redundant role in regulating β-cell proliferation and function. The mammalian Hippo-Tead1 pathway consists of
a core kinase cascade, culminating with Lats1&2, inhibitory kinases, that phosphorylate coactivators, Yap and
Taz, preventing their nuclear translocation and co-activation of Tead1-mediated transcription regulating cell
proliferation and apoptosis. The premise for this proposal rests on our preliminary data that strongly suggest
that Tead1 is the switch regulating the proliferation restriction, while promoting mature function in adult β-cells.
Recent reports have found some contrasting results, wherein, (a) Yap-Tead1 act as an enhancer in many β-
cell maturation genes in human embryonic pancreatic progenitors, (b) Yap has also been shown to inhibit
endocrinogenesis in mice, and acquisition of mature function during differentiation of human iPS cells
(hIPSCs), but (d) sufficient to induce proliferation in human islets, ex vivo. Preliminary data shows that β-cell
specific Tead1 deletion leads to diabetes and glucose intolerance. Tead1-null islets display a decrease in
expression of mature β-cell markers and a loss of glucose stimulated insulin secretion. Furthermore, our data
indicates that embryonic Tead1 deletion in β-cells also led to profound diabetes suggesting that Tead1 is
required in the endocrine progenitors for normal differentiation. To comprehensively test the regulation of β-cell
differentiation, proliferation and function by the Hippo-tead1 pathway, we hypothesize that Tead1 regulates
β-cell proliferation and acquisition of mature function via context-dependent co-factor specific,
transcriptional regulation of a network of proliferation and mature-phenotype defining genes. The
broad goal is to mechanistically delineate key pathways regulating functional β-cell mass that can be
harnessed to promote human β-cell proliferation with preserved function, through genetic loss- and gain-of-
function studies using in vivo mouse models and ex vivo mouse and human islets and human iPSCs. We will
specifically 1. To test if enhancing Yap activity in adult β-cells in vivo is sufficient f...

## Key facts

- **NIH application ID:** 10726591
- **Project number:** 5I01BX002678-09
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Vijay K Yechoor
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-01-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726591

## Citation

> US National Institutes of Health, RePORTER application 10726591, Novel Regulators of Beta Cell Proliferation and Function (5I01BX002678-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10726591. Licensed CC0.

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