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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase

Author

  • Lotta E. Andersson
  • Liliya Shcherbina
  • Mahmoud Al-Majdoub
  • Neelanjan Vishnu
  • Claudia Balderas Arroyo
  • Jonathan Aste Carrara
  • Claes B. Wollheim
  • Malin Fex
  • Hindrik Mulder
  • Nils Wierup
  • Peter Spégel

Summary, in English

Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.

Department/s

  • Diabetes - Molecular Metabolism
  • Neuroendocrine Cell Biology
  • Centre for Analysis and Synthesis
  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2018-03-01

Language

English

Pages

372-384

Publication/Series

Diabetes

Volume

67

Issue

3

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Molecular Metabolism
  • Neuroendocrine Cell Biology
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 0012-1797