# Islet alterations in type 2 diabetes

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Type 2 diabetes mellitus (T2D), a formidable and growing challenge to the VA healthcare system, represents a
heterogenous set of hyperglycemic disorders involving impaired insulin secretion, insulin resistance, and
increased hepatic glucose production. Both insufficient insulin secretion from β cells and dysregulated, typically
increased, glucagon secretion from α cells, contribute to the hyperglycemia in T2D. While many hypotheses
and models exist, the molecular mechanisms responsible for human islet dysfunction in T2D are incompletely
defined and largely unknown or unproven. Most models and hypotheses about the T2D β cell arise from
studies of rodent models and have not been confirmed or tested in human samples. Because of the many
differences in human and rodent islets, it is critical to study potential regulators in a human islet context and
that will be a focus of this proposal. This proposed studies are based on evidence that islets from donors with
short-duration T2D have impaired insulin secretion, enhanced glucagon secretion, and reduced expression of
PAX6, an islet-enriched transcription factor recently shown in rodent systems critical to islet β cell identify and
functional maintenance. Very little is known about the role of PAX6 is human islet cells. The proposed studies
will test the hypothesis that PAX6 is required for normal human α and β cell function and that reduced PAX6
expression contributes to T2D islet α and β cell dysfunction in these aims: (1) Determine the functional and
transcriptional consequences of PAX6 transcriptional control normal human islets in vitro; (2) Determine the
functional consequences of PAX6 loss from normal human α or β cells in vivo; (3) Assess whether PAX6 loss
in short-duration T2D islets is reversed by treatment with a Glucagon-like Peptide-1 (GLP-1) agonist. By
employing innovative experimental approaches such as creation of human pseudoislets in which gene
expression can be modified and transplantation of genetically modified human pseudoislets into
immunodeficient, glucagon-less mouse model (NSG-GKO) to allow for the assessment of α and β cell function
in vitro and in vivo, these studies will expand our understanding of the molecular processes regulating human
α and β cell function and islet dysfunction, leading to new clinically actionable information for T2D treatment.

## Key facts

- **NIH application ID:** 10012458
- **Project number:** 2I01BX000666-09
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** ALVIN C POWERS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2010-07-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012458

## Citation

> US National Institutes of Health, RePORTER application 10012458, Islet alterations in type 2 diabetes (2I01BX000666-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10012458. Licensed CC0.

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