Metabolic and physiological studies in a rat model of type 2 diabetes
Abstract
Mild hyperhomocysteinemia is a risk factor for many diseases, including cardiovascular disease. We determined the effects of insulin resistance and of Type 2 diabetes on homocysteine and amino acid metabolism using Zucker diabetic fatty rats (ZDF/Gmi-fa/fa and ZDF/Gmi +/?). Plasma total homocysteine was reduced in ZDF fa/fa rats by 24% in the pre-diabetic insulin-resistant stage while in the frank diabetic stage there was a 59% reduction. Hepatic activities of several enzymes that remove homocysteine: cystathionine β-synthase, cystathionine γ-lyase and betaine:homocysteine methyltransferase were increased as well as methionine adenosyltransferase. Cystathionine β-synthase and betaine:homocysteine methyltransferase mRNA levels and the hepatic level of S-adenosylmethionine were also increased in the ZDF fa/fa rats. Studies with primary hepatocytes showed that homocysteine export and the transsulfuration flux in cells from ZDF fa/fa rats were particularly sensitive to the presence of betaine, which reduced these fluxes. Interestingly, the liver betaine concentration was found to be significantly lower in the ZDF fa/fa rats at both 5 and 11 weeks. We conclude that the decreased insulin action and the elevation of the counter-regulatory hormones observed in diabetes may be responsible for the more efficient homocysteine removal seen in the ZDF fa/fa rats. -- Amino acids were measured in plasma, liver and skeletal muscle and the ratios of plasma: liver and plasma: skeletal muscle,…
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