# Pancreatic islet alpha cell response to insulin resistance and type 2 diabetes

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Type 2 diabetes (T2D) is a chronic disease that affects nearly 25% of U.S. Veterans, a prevalence that
exceeds that among the civilian population, and represents a growing challenge to the VA healthcare system.
T2D comprises a heterogeneous set of metabolic disorders that commonly arises from obesity-associated
insulin resistance, inadequate insulin production and secretion from pancreatic islet beta cells, and
dysregulated (often increased) secretion of glucagon from pancreatic islet alpha cells that collectively lead to
hyperglycemia. Although it has been recognized for decades that diabetes is a bi-hormonal disease reflecting
pathology in both pancreatic islet beta and alpha cells, the mechanisms governing human alpha cell function in
physiological or pathological settings are virtually unknown. Therefore, discovery of molecular mechanisms
that control human alpha cell gene regulation and hormone secretion are urgently needed. Islet-enriched
transcription factors (TF) are critical regulators of alpha and beta cell development and function, with
alterations in their activity leading to diabetes. One such TF, MAFB, was shown to be compromised early on in
human islets in response to diabetes-relevant cellular stressors, including oxidative stress, high fat dietinduced
insulin resistance, and hyperglycemia. Furthermore, both type 1 diabetes and T2D are associated with
marked downregulation of MAFB expression in human alpha and beta cells, implicating compromised MAFB
activity with islet cell dysfunction. I hypothesize that MAFB is a critical regulator in human alpha cells, with its
loss contributing to dysregulated g/ucagon secretion and glucose homeostasis pathophysiologically. To test
this hypothesis, I will use genetic manipulation of MAFB levels in a human pseudoislet system combined with
advanced transplantation, functional, and transcriptomic analyses to determine how loss of MAFB impacts
human alpha cell gene regulation and function in vitro and in vivo (Aim 1 ). In addition, I will comprehensively
define the functional and molecular changes that occur in transplanted human alpha cells in vivo under
conditions of chronic insulin resistance, an acquired pathological state that impacts MAFB (Aim 2). A key
component of my strategy is use of a new transplant-tolerant glucagon knockout mouse model (i.e., GKONSG),
allowing for the first-time longitudinal examination of (patho)physiologic changes in human alpha cells
and glucagon secretion in vivo in response to conditions that mimic the genetic and metabolic milieu of human
T2D. These experiments should provide fundamental new insights into the physiologic and genetic
mechanisms controlling human alpha cell activity in healthy and diseased pancreatic islets and may lead to
new clinically actionable information to treat the underlying causes of T2D. Additionally, the structured training
and mentored research of this career development award will form a strong foundation for my independent
research...

## Key facts

- **NIH application ID:** 10696298
- **Project number:** 1IK2BX006210-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Kathryn Colbert Coate
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10696298

## Citation

> US National Institutes of Health, RePORTER application 10696298, Pancreatic islet alpha cell response to insulin resistance and type 2 diabetes (1IK2BX006210-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10696298. Licensed CC0.

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