The role of glutamine in pancreatic alpha cells

Active Project Grant Awarded Last action

Award ID
F31DK148143
Recipient
Awarding agency
Obligated
$71,112

Award facts

Completion date 0% complete
Originally
Place of performance
Nashville, TN 37203, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Glucagon (GCG) secreted from pancreatic islet alpha (Α) cells regulates blood glucose, but increasing evidence has evolved our understanding of Α-cells' role as potent amino acid sensors that integrate multiple nutrient signals to modulate GCG secretion and the downstream homeostasis of each macronutrient. Rising circulating amino acids (e.g., after meals) stimulate glucagon secretion, and in turn, glucagon stimulates amino acid transport and catabolism in the liver, increasing hepatic glucose output. As such, hyperglucagonemia contributes to hyperglycemia in diabetes. Blocking GCG receptor signaling in the liver by any means leads to improved glycemia but also hyperaminoacidemia, hyperglucagonemia, and Α-cell proliferation and hyperplasia. These findings support the existence of a classical endocrine feedback loop called the liver-αcell axis. However, the mechanisms linking Α-cell amino acid sensing to Α-cell function remain poorly understood. Studies from our group identify glutamine as a major regulator of Α-cell proliferation and glucagon secretion, but the underlying mechanism has not been studied. Notably, glutaminase (GLS), which catalyzes the conversion of glutamine to glutamate, is highly and selectively expressed in Α-cells compared to other pancreatic cells, suggesting a specialized role in Α-cell metabolism. The overarching objective of this proposal is to define how glutamine metabolism in Α-cells regulates proliferation, signaling, and function. Our preliminary data demonstrate that inhibition of GLS suppresses glutamine-driven Α-cell proliferation, MTORC1 activation, and glucagon secretion, indicating that GLS- derived glutamate may be essential for Α-cell homeostasis. Additionally, emerging evidence suggests that glutamate availability influences MTORC1 activation, redox balance, and mitochondrial function -critical regulators of cell survival and hormone secretion. Therefore, we hypothesize that inhibiting glutaminase activity impairs Α-cell function by decreasing glutamate availability, thereby inhibiting MTORC1 activation, increasing reactive oxygen species, decreasing mitochondrial function, and ultimately decreasing GCG secretion. To test this, we will use a recently generated inducible Α-cell-specific GLS knock-out mouse model to study the role of GLS in Α-cells without impacting other cell types throughout the body. To ensure our findings are relevant to human physiology, we will treat human cadaveric islets with a selective pharmacological inhibitor of GLS. Aim 1 will examine the role of GLS in proliferation, MTORC1 activation, glutamate content and secretion, and glucagon secretion. Aim 2 will test if GLS activity affects redox balance and metabolic flux. Collectively, these studies will define the molecular mechanisms linking glutamine metabolism to Α-cell function and establish the importance of GLS in maintaining Α-cell homeostasis. Given that hyperglucagonemia is a key feature of metabolic dysfunction, these findings could reveal novel therapeutic targets to modulate glucagon secretion.

Transactions

Action Obligated Date
Amendment $35,556
Amendment $35,556
Original award $0

Quick answers

Who received award F31DK148143?

F31DK148143 was awarded to Vanderbilt University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on December 1, 2026.

How much is award F31DK148143 worth?

$71,112 has been obligated on F31DK148143.

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