A Signaling Role of Glutamine in Insulin Secretion

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

doi:10.1074/jbc.m311502200

Cited by 145 publications

(172 citation statements)

References 22 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…The insulin response in Slc6a19 nullizygous mice was blunted both during fasting and feeding, demonstrating that nutritional protein levels have a modulatory role of the insulin response. This is consistent with the observed role of glutamine in the release of insulin from pancreatic ␤-cells (38). We could detect B 0 AT1 mRNA in pancreas but do not know whether it is expressed in ␤-cells, where the B 0 AT1 trafficking subunit collectrin has been found (39,40).…”

Section: Discussionsupporting

confidence: 73%

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

Bröer

Juelich

Vanslambrouck

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B 0 AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na ؉ -dependent uptake of neutral amino acids into the intestine and renal brushborder membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B 0 AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B 0 AT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.In a typical Western diet humans consume about 80 -100 g of protein per day. Proteins are hydrolyzed by the action of secreted and membrane-bound peptidases into individual amino acids, di-and tripeptides (1). Individual amino acids are taken up by a variety of amino acid transporters, whereas diand tripeptides are absorbed by the peptide transporter PepT1 (SLC15A1) (2). Together this digestive process makes 90 -95% of ingested proteins available to the body. Protein demand is particularly high during growth and development when new proteins are required to build up body mass. In the adult, protein recycling is quite efficient, and only 50 g of protein is needed per day to replace protein lost through urine and feces.The bulk of neutral amino acids is absorbed in the intestine by the neutral amino acid transporter B 0 AT1 (SLC6A19), which is also expressed in the kidney where it mediates reabsorption of neutral amino acids (3). Expression studies in heterologous systems have shown that B 0 AT1 accepts all neutral amino acids with a preference for large neutral amino acids such as branched-chain amino acids and methionine (4, 5). These amino acids are taken up with a K m of about 1 mM, whereas smaller amino acids are taken up with higher K m values. Glycine and proline are poor substrates of B 0 AT1. As a result additional transporters are involved in the uptake of imino acids and glycine, such as PAT1 (SLC36A1), PAT2 (SLC36A2), and IMINO (SLC6A20) (6). Additional transport systems for other neutral amino acids in the kidney and intestine have been proposed; these include a specific intestinal transporter for methionine and phenylalanine (7) and the amino acid antiporter ASCT2 (SLC1A5) as a mediator of small neutral amino acids and glutamine uptake in kidney and intestine (8).Efficient trafficking and sur...

show abstract

Section: Discussionsupporting

confidence: 73%

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

Bröer

Juelich

Vanslambrouck

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A full explanation for the complexity of the results is yet to be achieved, although there is clear evidence that glutamine and other amino acids can potently stimulate secretion in these SUR1 KO islets [37,38]. These mice also exhibit near-normal insulin secretion in response to feeding, which could account for the euglycaemia [12].…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinism in mice with heterozygous loss of KATP channels

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis ATP-sensitive K + (K ATP ) channels couple glucose metabolism to insulin secretion in pancreatic beta cells. In humans, loss-of-function mutations of beta cell K ATP subunits (SUR1, encoded by the gene ABCC8, or Kir6.2, encoded by the gene KCNJ11) cause congenital hyperinsulinaemia. Mice with dominant-negative reduction of beta cell K ATP (Kir6.2[AAA]) exhibit hyperinsulinism, whereas mice with zero K ATP (Kir6.2 −/− ) show transient hyperinsulinaemia as neonates, but are glucose-intolerant as adults. Thus, we propose that partial loss of beta cell K ATP in vivo causes insulin hypersecretion, but complete absence may cause insulin secretory failure. Materials and methods Heterozygous Kir6.2 +/− and SUR1 +/− animals were generated by backcrossing from knockout animals. Glucose tolerance in intact animals was determined following i.p. loading. Glucose-stimulated insulin secretion (GSIS), islet K ATP conductance and glucose dependence of intracellular Ca 2+ were assessed in isolated islets. Results In both of the mechanistically distinct models of reduced K ATP (Kir6.2 +/− and SUR1 +/− ), K ATP density is reduced by ∼60%. While both Kir6.2 −/− and SUR1 −/− mice are glucose-intolerant and have reduced glucose-stimulated insulin secretion, heterozygous Kir6.2 +/− and SUR1 +/− mice show enhanced glucose tolerance and increased GSIS, paralleled by a left-shift in glucose dependence of intracellular Ca 2+ oscillations. Conclusions/interpretation The results confirm that incomplete loss of beta cell K ATP in vivo underlies a hyperinsulinaemic phenotype, whereas complete loss of K ATP underlies eventual secretory failure.

show abstract

“…This metabolic shift towards glutaminolysis may help to maintain both the higher basal mitochondrial membrane potential and NADPH levels in LABKO β cells in which respiration is attenuated. Glutamine itself is known to amplify GSIS and enhance K ATP channel-independent release [40], and may serve as a coupling factor to amplify metabolism-secretion coupling in LABKO beta cells. This idea is consistent with recent work using beta cells in which Lkb1 is deleted (using the Ins1-Cre system), wherein loss of LKB1 or AMPK results in a metabolic switch favouring glutamine metabolism [27].…”

Section: Discussionmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

show abstract

A Signaling Role of Glutamine in Insulin Secretion

Cited by 145 publications

References 22 publications

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

Impaired Nutrient Signaling and Body Weight Control in a Na+ Neutral Amino Acid Cotransporter (Slc6a19)-deficient Mouse

Hyperinsulinism in mice with heterozygous loss of KATP channels

LKB1 couples glucose metabolism to insulin secretion in mice

Contact Info

Product

Resources

About