A Signaling Role of Glutamine in Insulin Secretion

Changhong Li,Carol Buettger,Jae Kwagh,Andrea Matter,Yevgeny Daikhin,Ilana B Nissim,Heather W Collins,Marc Yudkoff,Charles A Stanley,Franz M Matschinsky

doi:10.1074/jbc.m311502200

Changhong Li, Carol Buettger + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m311502200

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Abstract

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.

Highlights

Children with hypoglycemia due to recessive loss of function mutations of the ␤-cell ATP-sensitive potassium (KATP) channel can develop hypoglycemia in response to protein feeding
acid stimulated insulin secretion (AASIS) of SURϪ/Ϫ and Control Islets—We studied the molecular basis of pancreatic ␤-cell hypersensitivity to amino acids that had been observed in patients with loss of function mutations of the KATP channel by perifusing isolated and cultured islets of SUR1Ϫ/Ϫ and control mice with an amino acid mixture
The present study shows that isolated pancreatic islets from SUR1 knockout mice respond briskly to a physiological mixture of 20 amino acids even though these islets cannot be stimulated by glucose or by leucine

Summary

Introduction

Children with hypoglycemia due to recessive loss of function mutations of the ␤-cell ATP-sensitive potassium (KATP) channel can develop hypoglycemia in response to protein feeding. The elucidation of a novel hyperinsulinism syndrome associated with mild hyperammonemia and linked to overactivity the glutamate dehydrogenase enzyme (GDH-HI) has led to the identification of a prominent role of glutaminolysis in the regulation of insulin secretion [3, 4, 5] These successful studies in human biochemical genetics of insulin secretion motivated the present investigation to find an explanation for the striking clinical observation that the patients with hyperinsulinism caused by inactivating mutations of the ␤-cell ATP-sensitive potassium channel (KATPHI) [6, 7] exhibit hypoglycemia following a protein meal [6, 8, 9], while the ␤-cell response to glucose is impaired [10]. This glutamine effect emerges to be central for the understanding of fuel stimulated insulin release from the ␤-cell

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