Elevated plasma total homocysteine levels in hyperinsulinemic obese subjects

Sanchez-Margalet, V.; Valle, Miguel; Ruz, Francisco J.; Gascón, Félix; Mateo, J; Goberna, R.

doi:10.1016/s0955-2863(01)00197-8

Cited by 75 publications

(57 citation statements)

References 28 publications

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“…Homocysteine. Elevated plasma homocysteine levels have been reported in hyperinsulinemic obese subjects and in subjects with type 2 diabetes with preexisting coronary vascular disease (74). In contrast to all the amino acids discussed above, homocysteine has a negative impact on insulin secretion in pancreatic ␤-cells.…”

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

confidence: 99%

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

confidence: 99%

Amino Acid Metabolism, β-Cell Function, and Diabetes

2006

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“…Raised plasma HC is now generally accepted as an important biological marker for arterial and venous vascular disease (Eikelboom et al 1999). Elevated plasma HC levels have been reported in patients suffering from diseases associated with the metabolic syndrome (Sanchez-Margalet et al 2002). Increased HC levels have also been detected in obese diabetic patients (Sanchez-Margalet et al 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Elevated plasma HC levels have been reported in patients suffering from diseases associated with the metabolic syndrome (Sanchez-Margalet et al 2002). Increased HC levels have also been detected in obese diabetic patients (Sanchez-Margalet et al 2002). HC exerts detrimental effects on a number of cell lineages including endothelial cells (Blundell et al 1996) and neuronal cells (Kim & Pae 1996), at least partially mediated through production of reactive oxygen species (ROS; Skurk & Walsh 2004), which induce DNA damage and apoptosis (Suhara et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of homocysteine toxicity to insulin-secreting BRIN-BD11 cells in combination with alloxan

Scullion

Gurgul-Convey

Lenzen

et al. 2012

Journal of Endocrinology

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Previous studies have shown that homocysteine (HC) has a detrimental impact on insulin secretion and pancreatic beta cell function. The aim of the present study was to determine the role of reactive oxygen species (ROS) in the in vitro toxic effects of HC on insulin secretion and function of BRIN-BD11 insulin-secreting cells. In this study, insulin secretion from BRIN-BD11 cells was determined radioimmunologically, cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and glucokinase activity by a glucose phosphorylation assay following culture with HC plus alloxan (Alx). Treatment with HC resulted in concentrationdependent inhibition of insulin secretion induced by glucose and other insulinotropic agents. HC in combination with Alx resulted in a more pronounced decline in insulin secretion, including that induced by 20 mM alanine, by 43% (P!0 . 001) and 30 mM KCl by 60% (P!0 . 001), compared with control culture. The glucokinase phosphorylating capacity in cells cultured with HC plus Alx was significantly lower, compared with control cells. The cells also displayed a significant 84% (P!0 . 001) decline in cell viability. Prolonged, 72-h culture of insulin-secreting cells with HC followed by 18-h culture without HC did not result in full restoration of beta cell responses to insulinotropic agents. In vitro oxygen consumption was enhanced by a combination of Alx with HC. The study arrived at the conclusion that HC generates ROS in a redox-cycling reaction with Alx that explains the decline in viability of insulin-secreting cells, leading to reduced glucokinase phosphorylating ability, diminished insulin secretory responsiveness and cell death.

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“…But insulin resistance (IR) appears as a key factor for oxidative risk. Hyperinsulinemia, correlated with the fat overload, contributes to a metabolic disorder of sulfur amino acids, leading to elevated homocysteine levels (Gallistl et al, 2000;Sanchez-Margalet et al, 2002) which increases the risk of cardiovascular disease. Moreover, in children (Morinobu et al, 2002), adolescents (Neuhouser et al, 2001) and adults obese (Wallstrom et al, 2001), it has been reported low plasma levels of α-tocopherol, vitamin C and carotenoids that are major micronutrients for the secondary antioxidant defense.…”

Section: Obesitymentioning

confidence: 99%