# Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis

> **NIH NIH F31** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $18,371

## Abstract

Project Summary
 Type 2 diabetes (T2D) is an extremely prevalent disease in the United States, affecting approximately 1
in 10 adults, and it is estimated that 640 million people will be diagnosed with diabetes by 2040. While T2D is
associated with β-cell failure, defects in both insulin and glucagon secretion from the pancreatic islet contribute
to dysregulated blood glucose. As current therapies that target β-cells to increase insulin secretion have limited
success, innovative ideas that focus on novel mechanisms for regulation of blood glucose are necessary to
create new therapeutics to combat T2D. Glucagon secretion by α-cells has strong control over the magnitude of
insulin secretion, making α-cells an attractive target for new therapies. The second messenger cAMP is a strong
determinant of glucagon secretion. Glucose has been shown to regulate α-cell cAMP intrinsically and
extrinsically. Preliminary studies show that leucine strongly reduces α-cell cAMP independently of islet paracrine
signaling, KATP channel effects, or calcium. Furthermore, in a similar fashion, glucose and leucine can dampen
amino acid-stimulated glucagon secretion. Glucose and leucine are both strongly anaplerotic, and preliminary
data suggests that the mitochondrial enzyme phosphoenolpyruvate carboxykinase (PCK2), an essential effector
of mitochondrial anaplerosis-cataplerosis, plays an important role in the regulation of amino acid-dependent
glucagon secretion. We hypothesize that anaplerotic fuels such as leucine and glucose will decrease cAMP
through PCK2 to inhibit glucagon release. To study this hypothesis we will: 1) Determine the intrinsic vs.
paracrine (via β/δ-cells) effects of leucine on α-cell cAMP and 2) Determine whether α-cell PCK2 mediates the
inhibitory effects of anaplerotic fuels. These aims will be studied by TIRF and lightsheet microscopy in
combination with novel genetic mouse models and biosensors, to examine role of anaplerotic fuels on α-cell
cAMP and glucagon secretion. Successful completion of this project will characterize new connections between
anaplerosis and cAMP signaling, train the PI in state of the art techniques for the study of metabolism, and
potentially unlock a new pathway to target for the treatment of T2D.

## Key facts

- **NIH application ID:** 10761719
- **Project number:** 5F31DK134171-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Emily Knuth
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $18,371
- **Award type:** 5
- **Project period:** 2022-12-12 → 2024-05-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10761719

## Citation

> US National Institutes of Health, RePORTER application 10761719, Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis (5F31DK134171-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10761719. Licensed CC0.

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