Effects of streptozotocin-induced diabetes and of insulin treatment on homocysteine metabolism in the rat.

Jacobs, René L.; House, James D.; Brosnan, Margaret E.; Brosnan, John T.

doi:10.2337/diabetes.47.12.1967

Cited by 174 publications

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“…Hyperhomocysteinaemia is known to be associated with impaired endotheliumdependent vasodilation [36,37]. Plasma homocysteine concentrations were, however, lower in the diabetic than in the control rats, as described previously [38], and were not influenced by treatment with 5-MTHF. Accordingly, folate has been shown to restore endothelial dysfunction during a methionine load test in healthy volunteers without affecting the rise in plasma homocysteine concentrations [17].…”

Section: Basalmentioning

confidence: 62%

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

et al. 2000

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Dysfunction of the endothelium is an early and key event in the development of microvascular and macrovascular complications [1], which account for most of the morbidity and mortality of diabetes. Endothelial integrity is generally assessed by evaluating the vasodilator response of a blood vessel or a vascular bed to an endothelium-dependent agonist [2]. Endothelial cells relax the tone of the underlying vascular smooth muscle cells by releasing a number of vasodi- Diabetologia (2000) Abstract Aims/hypothesis. Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. Methods. Endothelium-dependent and endotheliumindependent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor l-N G -nitroarginine methylester HCI (l-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. Results. The l-NAME-and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) and to the K + -channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. Conclusion-interpretation. Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes. [Diabetologia (2000

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Section: Basalmentioning

confidence: 62%

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

et al. 2000

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“…Studies in our laboratory have shown that plasma homocysteine is decreased in the streptozotocin-diabetic rat (a model for Type 1 diabetes mellitus). Insulin treatment increased plasma homocysteine in these diabetic animals (9). We have also shown that enzyme activities of the hepatic transsulfuration pathway are increased during uncontrolled diabetes.…”

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confidence: 60%

Hyperglucagonemia in Rats Results in Decreased Plasma Homocysteine and Increased Flux through the Transsulfuration Pathway in Liver

Jacobs¹,

Stead²,

Brosnan

et al. 2001

Journal of Biological Chemistry

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An elevated plasma level of homocysteine is a risk factor for the development of cardiovascular disease. The purpose of this study was to investigate the effect of glucagon on homocysteine metabolism in the rat. Male Sprague-Dawley rats were treated with 4 mg/kg/day (3 injections per day) glucagon for 2 days while control rats received vehicle injections. Glucagon treatment resulted in a 30% decrease in total plasma homocysteine and increased hepatic activities of glycine N-methyltransferase, cystathionine ␤-synthase, and cystathionine ␥-lyase. Enzyme activities of the remethylation pathway were unaffected. The 90% elevation in activity of cystathionine ␤-synthase was accompanied by a 2-fold increase in its mRNA level. Hepatocytes prepared from glucagon-injected rats exported less homocysteine, when incubated with methionine, than did hepatocytes of saline-treated rats. Flux through cystathionine ␤-synthase was increased 5-fold in hepatocytes isolated from glucagon-treated rats as determined by production of 14 CO 2 and ␣-[1-14 C]ketobutyrate from L-[1-14 C]methionine. Methionine transport was elevated 2-fold in hepatocytes isolated from glucagon-treated rats resulting in increased hepatic methionine levels. Hepatic concentrations of S-adenosylmethionine and S-adenosylhomocysteine, allosteric activators of cystathionine ␤-synthase, were also increased following glucagon treatment. These results indicate that glucagon can regulate plasma homocysteine through its effects on the hepatic transsulfuration pathway.An elevated plasma concentration of homocysteine, a sulfurcontaining amino acid derived from methionine, has been recognized as an independent risk factor for the development of vascular disease (1). Methionine is adenylated by methionine adenosyltransferase to form S-adenosylmethionine, an important biological methyl donor. Numerous methyltransferases catalyze the transfer of a methyl group from S-adenosylmethionine to a methyl acceptor, producing a methylated product and S-adenosylhomocysteine, which is subsequently hydrolyzed to form adenosine and homocysteine. Homocysteine has several possible fates: 1) remethylation to form methionine via either the cobalamin-dependent methionine synthase (using N 5 -methyltetrahydrofolate as a methyl donor) or betaine:homocysteine methyltransferase (using betaine as a methyl donor); 2) catabolism by the transsulfuration pathway, ultimately forming cysteine; 3) export to the extracellular space. Two vitamin B 6 -dependent enzymes comprise the transsulfuration pathway: cystathionine ␤-synthase, which condenses homocysteine with serine to form cystathionine, and cystathionine ␥-lyase, which cleaves cystathionine to cysteine, NH 4 ϩ , and ␣-ketobutyrate.Altered flux through the remethylation or transsulfuration pathways as a result of genetic mutations or impaired vitamin status has been shown to affect plasma homocysteine levels (2, 3). In recent years it has also become apparent that certain hormones can affect homocysteine metabolism. It has been shown that hypothyroid ...

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“…This shift is also reflected in other 270 gluconeogenic states, such as diabetes. We and others have demonstrated that a diabetic state or 271 administration of synthetic glucocorticoid compounds has a major impact on methyl group and 272 homocysteine metabolism [23][24][25][26][49][50][51][52]. A consistent finding from these reports is a reduction 273 in circulating homocysteine concentrations owing to an increase in folate-independent 274 remethylation (i.e., BHMT) and catabolism of homocysteine through the transsulfuration 275 pathway.…”

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confidence: 88%

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

Neuman¹,

Albright²,

Schalinske³

2013

Nutrition Research

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Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is associated with numerous pathological conditions. A number of nutritional and hormonal factors have been shown to influence circulating homocysteine concentrations; however, the impact of exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-independent manner. The purpose of this study was to determine the influence of exercise on homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate hyperhomocysteinemia. Female outbred mice (12 weeks old) were assigned to either a sedentary or free-access wheel exercise group. Following a 4-week acclimation period, half of the mice in each group were provided a folate-restricted diet for 7-weeks prior to euthanasia and tissue collection. As expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total homocysteine concentrations; however, exercise completely prevented the increase in circulating homocysteine concentrations. Moreover, exercise reduced plasma homocysteine concentrations 36% within the group fed only the control diet. The prevention of hyperhomocysteinemia by exercise appears, at least in part, to be the result of increased folate-independent homocysteine remethylation owing to a 2-fold increase in renal betaine homocysteine S-methyltransferase. To our knowledge, this is the first report demonstrating the prevention of hyperhomocysteinemia by exercise in a dietary folate-restriction model. Future research will be directed at determining if exercise can have a positive impact on other nutritional, hormonal, and genetic models of hyperhomocysteinemia relevant to humans. Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is 30 associated with numerous pathological conditions. A number of nutritional and hormonal factors 31 have been shown to influence circulating homocysteine concentrations; however, the impact of 32 exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was 33 that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-34 independent manner. The purpose of this study was to determine the influence of exercise on 35 homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate 36 hyperhomocysteinemia. Female outbred mice (12 wk old) were assigned to either a sedentary or 37 free-access wheel exercise group. Following a 4-wk acclimation period, half of the mice in each 38 group were provided a folate-restricted diet for 7-wk prior to euthanasia and tissue collection. As 39 expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total 40 homocysteine concentrations; however, exercise completely prevented the increase in circulating 41 homocysteine concentrations. Moreover, exercise reduced plasma homocysteine c...

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Effects of streptozotocin-induced diabetes and of insulin treatment on homocysteine metabolism in the rat.

Cited by 174 publications

References 0 publications

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

Hyperglucagonemia in Rats Results in Decreased Plasma Homocysteine and Increased Flux through the Transsulfuration Pathway in Liver

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

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