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Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling

Muñoz, Felipe LU ; Gao, Qian ; Mattanovich, Matthias ; Trost, Kajetan ; Hodek, Ondřej ; Lindqvist, Andreas LU ; Wierup, Nils LU ; Fex, Malin LU ; Moritz, Thomas and Mulder, Hindrik LU orcid , et al. (2026) In Metabolism: Clinical and Experimental 174.
Abstract

Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1 , and HADH , were downregulated in... (More)

Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1 , and HADH , were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass -KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.

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publishing date
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publication status
published
subject
keywords
AASS, Amino acids, GABA, GABA shunt, GDH, Glutamate, Insulin secretion, Lysine, Mitochondrial metabolism, TCA cycle, Type 2 diabetes
in
Metabolism: Clinical and Experimental
volume
174
article number
156423
publisher
Elsevier
external identifiers
  • scopus:105022417059
  • pmid:41167553
ISSN
0026-0495
DOI
10.1016/j.metabol.2025.156423
language
English
LU publication?
yes
id
29df9213-304a-4531-84e0-b72da26b5724
date added to LUP
2026-02-11 11:30:52
date last changed
2026-02-12 03:26:22
@article{29df9213-304a-4531-84e0-b72da26b5724,
  abstract     = {{<p>Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1 , and HADH , were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass -KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.</p>}},
  author       = {{Muñoz, Felipe and Gao, Qian and Mattanovich, Matthias and Trost, Kajetan and Hodek, Ondřej and Lindqvist, Andreas and Wierup, Nils and Fex, Malin and Moritz, Thomas and Mulder, Hindrik and Cataldo, Luis Rodrigo}},
  issn         = {{0026-0495}},
  keywords     = {{AASS; Amino acids; GABA; GABA shunt; GDH; Glutamate; Insulin secretion; Lysine; Mitochondrial metabolism; TCA cycle; Type 2 diabetes}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Metabolism: Clinical and Experimental}},
  title        = {{Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling}},
  url          = {{http://dx.doi.org/10.1016/j.metabol.2025.156423}},
  doi          = {{10.1016/j.metabol.2025.156423}},
  volume       = {{174}},
  year         = {{2026}},
}