A signaling role of glutamine in insulin secretion.
Children with hypoglycemia due to recessive loss of function mutations of the beta-cell ATP-sensitive potassium (K(ATP)) channel can develop hypoglycemia in response to protein feeding. We hypothesized that amino acids might stimulate insulin secretion by unknown mechanisms, because the K(ATP) channel-dependent pathway of insulin secretion is defective. We therefore investigated the effects of amino acids on insulin secretion and intracellular calcium in islets from normal and sulfonylurea receptor 1 knockout (SUR1-/-) mice. Even though SUR1-/- mice are euglycemic, their islets are considered a suitable model for studies of the human genetic defect. SUR1-/- islets, but not normal islets, released insulin in response to an amino acid mixture ramp. This response to amino acids was decreased by 60% when glutamine was omitted. Insulin release by SUR1-/- islets was also stimulated by a ramp of glutamine alone. Glutamine was more potent than leucine or dimethyl glutamate. Basal intracellular calcium was elevated in SUR1-/- islets and was increased further by glutamine. In normal islets, methionine sulfoximine, a glutamine synthetase inhibitor, suppressed insulin release in response to a glucose ramp. This inhibition was reversed by glutamine or by 6-diazo-5-oxo-l-norleucine, a non-metabolizable glutamine analogue. High glucose doubled glutamine levels of islets. Methionine sulfoximine inhibition of glucose stimulated insulin secretion was associated with accumulation of glutamate and aspartate. We hypothesize that glutamine plays a critical role as a signaling molecule in amino acid- and glucose-stimulated insulin secretion, and that beta-cell depolarization and subsequent intracellular calcium elevation are required for this glutamine effect to occur.
Li
Changhong
C
Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Buettger
Carol
C
Kwagh
Jae
J
Matter
Andrea
A
Daikhin
Yevgeny
Y
Nissim
Ilana B
IB
Collins
Heather W
HW
Yudkoff
Marc
M
Stanley
Charles A
CA
Matschinsky
Franz M
FM
D018528:ATP-Binding Cassette Transporters; D000643:Ammonium Chloride / Q000493:pharmacokinetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009587:Nitrogen Isotopes; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D000643:Ammonium Chloride; D002118:Calcium; D005973:Glutamine; D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009587:Nitrogen Isotopes; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C577507:ABCC8 protein, human; C577508:Abcc8 protein, mouse