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Effects of Insulin Deprivation and Treatment on Homocysteine Metabolism in People with Type 1 Diabetes

Endocrine Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: K. S. Nair, Endocrine Research Unit, Mayo Clinic, 200 First Street SW, Joseph 5-194, Rochester, Minnesota 55905. E-mail: nair.sree{at}mayo.edu.

Context: Abnormal homocysteine metabolism may contribute to increased cardiovascular death in type 1 diabetes (T1DM). Amino acid metabolism is altered in T1DM. In vitro, insulin reduces hepatic catabolism of homocysteine by inhibiting liver transsulfuration. It remains to be determined whether methionine-homocysteine metabolism is altered in T1DM.

Objective: We sought to determine whether insulin deficiency during insulin deprivation or high plasma insulin concentration after insulin treatment alters homocysteine metabolism in T1DM.

Design: This was an acute interventional study with paired and comparative controls.

Setting: The study was conducted at a general clinical research center.

Patients and Intervention: We used stable isotope tracers to measure methionine-homocysteine kinetics in six patients with T1DM during insulin deprivation (I–) and also during insulin treatment (I+) and compared them with nondiabetic controls (n = 6).

Main Outcome Measures: Homocysteine kinetics (transmethylation, transsulfuration, and remethylation) were from plasma isotopic enrichment of methionine and homocysteine and ¹³CO₂.

Results: T1DM (I–) had lower rates of homocysteine-methionine remethylation (P < 0.05 vs. control and I+). In contrast, transsulfuration rates were higher in I– than controls and I+ (P < 0.05). Insulin treatment normalized transsulfuration and remethylation (P < 0.05 vs. I– and P > 0.8 vs. control). Plasma homocysteine concentrations were lower in T1DM (P < 0.05 vs. control during both I– and I+), which may be explained by increased homocysteine transsulfuration. Thus, significant alterations of methionine-homocysteine metabolism occur during insulin deprivation in humans with T1DM.

Conclusions: Insulin plays a key role in the regulation of methionine-homocysteine metabolism in humans, and altered homocysteine may occur during insulin deficiency in type 1 diabetic patients.

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