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Conversion of glutamate into proline by the leucine analog BCH enhances biphasic insulin secretion in pancreatic β-cells

Gheibi, Sevda LU ; Cataldo, Luis Rodrigo LU orcid ; Ardalani, Hamidreza LU ; Nocquet, Lisa LU ; Spégel, Peter LU ; Straub, Susanne G. ; Sharp, Geoffrey W.G. ; Fex, Malin LU and Mulder, Hindrik LU orcid (2025) In Journal of Biological Chemistry 301(5).
Abstract

Biphasic insulin secretion, which fails in type 2 diabetes, can be provoked by various nutrient stimuli, glucose being the superior physiological one. To identify pathways that may play a role in β-cell stimulus-secretion coupling, we compared β-cell and islet functional, secretory, and metabolic responses to glucose and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), a leucine analog, that acts as an allosteric activator of glutamate dehydrogenase. We employed a range of techniques, including insulin secretion assays, mitochondrial activity measurements, ATP/ADP ratio assessments, and cytosolic Ca2+ level quantifications. Metabolomics was used to analyze cellular metabolite profiles in response to glucose and BCH.... (More)

Biphasic insulin secretion, which fails in type 2 diabetes, can be provoked by various nutrient stimuli, glucose being the superior physiological one. To identify pathways that may play a role in β-cell stimulus-secretion coupling, we compared β-cell and islet functional, secretory, and metabolic responses to glucose and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), a leucine analog, that acts as an allosteric activator of glutamate dehydrogenase. We employed a range of techniques, including insulin secretion assays, mitochondrial activity measurements, ATP/ADP ratio assessments, and cytosolic Ca2+ level quantifications. Metabolomics was used to analyze cellular metabolite profiles in response to glucose and BCH. Additionally, we investigated the role of proline synthesis by silencing ALDH18A1, encoding proline 5-carboxylate synthase, in both clonal β-cells and human islets. BCH and glucose similarly induced a biphasic insulin response in INS-1 832/13 cells, paralleled by increased mitochondrial activity and raised ATP/ADP ratios, plasma membrane depolarization, and elevated cytosolic Ca2+ levels. Metabolomics revealed that proline levels increased significantly only in BCH-stimulated β-cells. Silencing ALDH18A1 disrupted insulin secretion in response to both glucose and BCH, accompanied by reduced cytosolic Ca2+ levels, ATP/ADP ratios, and mitochondrial activity. Our findings demonstrated that BCH-induced activation of glutamate dehydrogenase leads to the conversion of glutamate into proline, which apparently enhances β-cell stimulus-secretion coupling. This work identifies a previously unrecognized role of proline metabolism in β-cell function and provides novel insights into the complex regulation of insulin secretion.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BCH, glutamate dehydrogenase, insulin secretion, proline, β-cells
in
Journal of Biological Chemistry
volume
301
issue
5
article number
108449
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • scopus:105003373638
  • pmid:40154614
ISSN
0021-9258
DOI
10.1016/j.jbc.2025.108449
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Authors
id
87546a12-880d-42f7-b360-a12712c438af
date added to LUP
2025-08-06 15:44:47
date last changed
2025-10-15 22:46:09
@article{87546a12-880d-42f7-b360-a12712c438af,
  abstract     = {{<p>Biphasic insulin secretion, which fails in type 2 diabetes, can be provoked by various nutrient stimuli, glucose being the superior physiological one. To identify pathways that may play a role in β-cell stimulus-secretion coupling, we compared β-cell and islet functional, secretory, and metabolic responses to glucose and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), a leucine analog, that acts as an allosteric activator of glutamate dehydrogenase. We employed a range of techniques, including insulin secretion assays, mitochondrial activity measurements, ATP/ADP ratio assessments, and cytosolic Ca<sup>2+</sup> level quantifications. Metabolomics was used to analyze cellular metabolite profiles in response to glucose and BCH. Additionally, we investigated the role of proline synthesis by silencing ALDH18A1, encoding proline 5-carboxylate synthase, in both clonal β-cells and human islets. BCH and glucose similarly induced a biphasic insulin response in INS-1 832/13 cells, paralleled by increased mitochondrial activity and raised ATP/ADP ratios, plasma membrane depolarization, and elevated cytosolic Ca<sup>2+</sup> levels. Metabolomics revealed that proline levels increased significantly only in BCH-stimulated β-cells. Silencing ALDH18A1 disrupted insulin secretion in response to both glucose and BCH, accompanied by reduced cytosolic Ca<sup>2+</sup> levels, ATP/ADP ratios, and mitochondrial activity. Our findings demonstrated that BCH-induced activation of glutamate dehydrogenase leads to the conversion of glutamate into proline, which apparently enhances β-cell stimulus-secretion coupling. This work identifies a previously unrecognized role of proline metabolism in β-cell function and provides novel insights into the complex regulation of insulin secretion.</p>}},
  author       = {{Gheibi, Sevda and Cataldo, Luis Rodrigo and Ardalani, Hamidreza and Nocquet, Lisa and Spégel, Peter and Straub, Susanne G. and Sharp, Geoffrey W.G. and Fex, Malin and Mulder, Hindrik}},
  issn         = {{0021-9258}},
  keywords     = {{BCH; glutamate dehydrogenase; insulin secretion; proline; β-cells}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Conversion of glutamate into proline by the leucine analog BCH enhances biphasic insulin secretion in pancreatic β-cells}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2025.108449}},
  doi          = {{10.1016/j.jbc.2025.108449}},
  volume       = {{301}},
  year         = {{2025}},
}