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

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Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase. / Andersson, Lotta E.; Shcherbina, Liliya; Al-Majdoub, Mahmoud; Vishnu, Neelanjan; Arroyo, Claudia Balderas; Carrara, Jonathan Aste; Wollheim, Claes B.; Fex, Malin; Mulder, Hindrik; Wierup, Nils; Spégel, Peter.

In: Diabetes, Vol. 67, No. 3, 01.03.2018, p. 372-384.

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T1 - Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase

AU - Andersson, Lotta E.

AU - Shcherbina, Liliya

AU - Al-Majdoub, Mahmoud

AU - Vishnu, Neelanjan

AU - Arroyo, Claudia Balderas

AU - Carrara, Jonathan Aste

AU - Wollheim, Claes B.

AU - Fex, Malin

AU - Mulder, Hindrik

AU - Wierup, Nils

AU - Spégel, Peter

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85042590210&partnerID=8YFLogxK

U2 - 10.2337/db16-1441

DO - 10.2337/db16-1441

M3 - Article

VL - 67

SP - 372

EP - 384

JO - Diabetes

T2 - Diabetes

JF - Diabetes

SN - 1939-327X

IS - 3

ER -