Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic β-cell glucose metabolism and insulin secretion

Patterson, Steven; Flatt, Peter R.; Brennan, Lorraine; Newsholme, Philip; McClenaghan, Neville H.

doi:10.1677/joe.1.06537

Cited by 55 publications

(44 citation statements)

References 44 publications

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“…The mechanism of insulin secretion inhibited by homocysteine remains unclear. However, the following explanations are possible [19]: 1. It may act on key regulatory steps of the TCA cycle in betacells, possibly via NAD depletion and reduction of glucose oxidation.…”

Section: Discussionmentioning

confidence: 99%

Dose- and Glucose-Dependent Effects of Amino Acids on Insulin Secretion from Isolated Mouse Islets and Clonal INS-1E Beta-Cells

Liu

Jeppesen²,

Gregersen³

et al. 2008

Rev Diabet Stud

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■ AbstractBACKGROUND: The influence of glucose and fatty acids on beta-cell function is well established whereas little is known about the role of amino acids (AAs). METHODS: Islets isolated from NMRI mice were incubated overnight. After preincubation, isolated islets as well as clonal INS-1E beta-cells were incubated for 60 min in a modified Krebs Ringer buffer containing glucose and AAs. RESULTS: At 16.7 mmol/l (mM) glucose, L-arginine, L-lysine, L-alanine, L-proline, L-leucine, and L-glutamine potentiated glucosestimulated insulin secretion dose-dependently, while DLhomocysteine inhibited insulin secretion. Maximal insulin stimulation was obtained at 20 mM L-proline, L-lysine, Lalanine, L-arginine (islets: 2.5 to 6.7 fold increase; INS-1E cells: 1.6 to 2.2 fold increase). L-glutamine and L-leucine only increased glucose-stimulated (16.7 mM) insulin secretion (INS-1E cells: 1.5 and 1.3 fold, respectively) at an AA concentration of 20 mM. Homocysteine inhibited insulin secretion both at 5.6 mM and 16.7 mM glucose. At glucose levels ranging from 1.1 to 25 mM, the equimolar concentration of 10 mM, L-proline, L-lysine, L-arginine increased insulin secretion from mouse islets and INS-1E cells at all glucose levels applied, with a maximal effect obtained at 25 mM glucose. At a concentration of 10 mM, L-arginine and Llysine had the highest insulinotropic potency among the AAs investigated. CONCLUSION: L-arginine, L-lysine, Lalanine, L-proline, L-leucine and L-glutamine acutely stimulate insulin secretion from mouse islets and INS-1E cells in a dose-and glucose-dependent manner, whereas DLhomocysteine inhibits insulin release.

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Section: Discussionmentioning

confidence: 99%

Dose- and Glucose-Dependent Effects of Amino Acids on Insulin Secretion from Isolated Mouse Islets and Clonal INS-1E Beta-Cells

Liu

Jeppesen²,

Gregersen³

et al. 2008

Rev Diabet Stud

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“…Homocysteine also inhibited insulinotrophic responses to tolbutamide and KCl hinting of possible K-ATP channel involvement (Patterson et al 2006b) in this inhibitory process. Endogenous CBS liberates H 2 S from homocysteine.…”

Section: Introductionmentioning

confidence: 92%

Hydrogen sulphide reduces insulin secretion from HIT-T15 cells by a KATP channel-dependent pathway

Ali¹,

Whiteman²,

Low³

et al. 2007

Journal of Endocrinology

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Hydrogen sulphide (H 2 S), a naturally occurring gas exerts physiological effects by opening K ATP channels. Anti-diabetic drugs (e.g. glibenclamide) block K ATP channels and abrogate H 2 S-mediated physiological responses which suggest that H 2 S may also regulate insulin secretion by pancreatic b-cells. To investigate this hypothesis, insulin-secreting (HIT-T15) cells were exposed to NaHS (100 mM) and the K ATP channeldriven pathway of insulin secretion was tracked with various fluorescent probes. The concentration of insulin released from HIT-T15 cells decreased significantly after NaHS exposure and this effect was reversed by the addition of glibenclamide (10 mM). Cell viability and intracellular ATP and glutathione (GSH) levels remained unchanged, suggesting that changes in insulin secretion were not ATP linked or redox dependent. Through fluorescence imaging studies, it was found that K C efflux occurs in cells exposed to NaHS. The hyperpolarised cell membrane, a result of K C leaving the cell, prevents the opening of voltage-gated Ca 2C channels. This subsequently prevents Ca 2C influx and the release of insulin from HIT-T15 cells. This data suggest that H 2 S reduces insulin secretion by a K ATP channel-dependent pathway in HIT-T15 cells. This study reports the molecular mechanism by which H 2 S reduces insulin secretion and provides further insight into a recent observation of increased pancreatic H 2 S production in streptozotocin-diabetic rats.

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“…In contrast to all the amino acids discussed above, homocysteine has a negative impact on insulin secretion in pancreatic ␤-cells. A recent study has revealed that homocysteine inhibits insulin section from the BRIN-BD11 cell line (75). In particular, homocysteine caused a significant and dosedependent inhibition of insulin secretion with initial effects at 50 mol/l.…”

Section: Mechanisms Of Amino Acid-dependent Stimulation Of Insulin Sementioning

confidence: 98%

Amino Acid Metabolism, β-Cell Function, and Diabetes

2006

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Specific amino acids are known to acutely and chronically regulate insulin secretion from pancreatic ␤-cells in vivo and in vitro. Mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to exocytosis of insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling messenger in insulin secretion, and other coupling factors, which serve as sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the key amplifying pathway over the Ca 2؉ signal in nutrient-stimulated insulin secretion. Predominantly, these factors are nucleotides (ATP, GTP, cAMP, and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. This scenario further highlights the importance of the key enzymes or transporters, e.g., glutamate dehydrogenase, the aspartate and alanine aminotransferases, and the malate-aspartate shuttle in the control of insulin secretion. In addition, after chronic exposure, amino acids may influence gene expression in the ␤-cell, which subsequently alters levels of insulin secretion. Therefore, amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion. Diabetes 55 (Suppl. 2)

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Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic β-cell glucose metabolism and insulin secretion

Cited by 55 publications

References 44 publications

Dose- and Glucose-Dependent Effects of Amino Acids on Insulin Secretion from Isolated Mouse Islets and Clonal INS-1E Beta-Cells

Dose- and Glucose-Dependent Effects of Amino Acids on Insulin Secretion from Isolated Mouse Islets and Clonal INS-1E Beta-Cells

Hydrogen sulphide reduces insulin secretion from HIT-T15 cells by a KATP channel-dependent pathway

Amino Acid Metabolism, β-Cell Function, and Diabetes

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