Effects of diabetes and insulin on betaine-homocysteineS-methyltransferase expression in rat liver

Abstract

Elevation of plasma homocysteine levels has been recognized as an independent risk factor for the development of cardiovascular disease, a major complication of diabetes. Plasma homocysteine reflects a balance between its synthesis via S-adenosyl-L-methionine-dependent methylation reactions and its removal through the transmethylation and the transsulfuration pathways. Betaine-homocysteine methyltransferase (BHMT, EC 2.1.1.5) is one of the enzymes involved in the remethylation pathway. BHMT, a major zinc metalloenzyme in the liver, catalyzes the transfer of methyl groups from betaine to homocysteine to form dimethylglycine and methionine. We have previously shown that plasma homocysteine levels and the transsulfuration pathway are affected by diabetes. In the present study, we found increased BHMT activity and mRNA levels in livers from streptozotocin-diabetic rats. In the rat hepatoma cell line (H4IIE cells), glucocorticoids (triamcinolone) increased the level and rate of BHMT mRNA synthesis. In the same cell line, insulin decreased the abundance of BHMT mRNA and the rate of de novo mRNA transcription of the gene. Thus the decreased plasma homocysteine in various models of diabetes could be due to enhanced homocysteine removal brought about by a combination of increased transsulfuration of homocysteine to cysteine and increased remethylation of homocysteine to methionine by BHMT.homocysteine; diabetes; insulin; glucocorticoids; remethylation AN ELEVATION OF PLASMA HOMOCYSTEINE is recognized as an independent risk factor for the development of Alzheimer's disease, premature arteriosclerosis, thrombosis, and connective tissue disorders, including skeletal abnormalities, osteoporosis, and fractures (3,19,20,22,38,41). Cardiovascular disease is a major complication of diabetes, and plasma homocysteine levels are often perturbed in patients with diabetes (13-15). Although diabetic patients with nephropathy tend to have elevated plasma homocysteine levels, those with no kidney dysfunction have decreased levels. (15). Plasma homocysteine reflects a balance between its synthesis via S-adenosyl-Lmethionine (SAM)-dependent methylation reactions and its catabolism through the transmethylation and transsulfuration pathways. Methionine synthase (MS) and betaine-homocysteine methyltransferase (BHMT) are the major enzymes involved in the remethylation pathway. BHMT (EC 2.1.1.5) is a zinc metalloenzyme that catalyzes the transfer of methyl groups from betaine to homocysteine to produce dimethylglycine and methionine (21). Betaine, which arises from the oxidation of choline and is also a minor dietary constituent, serves as a folate-independent source of methyl groups for homocysteine remethylation via BHMT. This enzyme is found mainly in the liver and kidney of mammals. A developmentally regulated BHMT is also expressed in the lens of rhesus monkeys and humans (25). BHMT is fairly abundant in the liver and represents 0.5-1.6% of the total soluble protein in the mammalian liver (8).The importance of the BHMT reaction to homocys...

Proteomic changes associated with diabetes in the BB-DP rat

“…These data demonstrate another potential source of the formaldehyde in diabetes that warrants evaluation, and suggest a possible metabolic adaptation that has been unrecognized in the literature. There are studies that have demonstrated upregulation of elements of the methionine cycle (52,66), but these studies were unable to evaluate the entire pathway concurrently and that is a particular strength of the present data.…”

Evaluation of plasma homocysteine level according to the C677T and A1298C polymorphism of the enzyme MTHRF in type 2 diabetic adults

“…Reduced peripheral resistance to insulin has been con sidered responsible for lower plasma homocysteine lev els in the initial phases of experimental diabetes (26,27), due to increased transsulfuration (28). On the other hand, variations in serum homocysteine levels were not related with insulin, proinsulin, and insulin sensitivity among the Parkatêjê Indians (29).…”

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

“…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.…”