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Diabetes 54:2968-2976, 2005
© 2005 by the American Diabetes Association, Inc.

Effects of Insulin on Methionine and Homocysteine Kinetics in Type 2 Diabetes With Nephropathy

Paolo Tessari1, Anna Coracina1, Edward Kiwanuka1, Monica Vedovato1, Monica Vettore1, Anna Valerio1, Michela Zaramella1, and Giacomo Garibotto2

1 Department of Clinical and Experimental Medicine, Chair of Metabolism, University of Padova, Padova, Italy
2 Division of Nephrology, Department of Internal Medicine, University of Genova, Genova, Italy

Although hyperhomocysteinemia, an independent cardiovascular risk factor, is common in type 2 diabetes with nephropathy, the mechanism(s) of this alteration is not known. In healthy humans, hyperinsulinemia increases methionine transmethylation, homocysteine transsulfuration, and clearance. No such data exist in type 2 diabetes either in the fasting state or in response to hyperinsulinemia. To this purpose, seven male type 2 diabetic patients with albuminuria (1.2 ± 0.4 g/day, three with mild to moderate renal insufficiency) and seven matched control subjects were infused for 6 h with L-[methyl-2H3, 1-13C]methionine. Methionine flux, transmethylation, and disposal into proteins as well as homocysteine remethylation, transsulfuration, and clearance were determined before and after euglycemic hyperinsulinemia (~1,000 pmol/l). In type 2 diabetic subjects, homocysteine concentration was twofold greater (P < 0.01) and methionine transmethylation and homocysteine clearance lower (from ~15 to >50% and from ~40 to >100%, respectively; P < 0.05) than in control subjects. The insulin-induced increments of methionine transmethylation, homocysteine transsulfuration, and clearance were markedly reduced in type 2 diabetic subjects (by more than threefold, P < 0.05 or less vs. control subjects). In contrast, methionine methyl and carbon flux were not increased in the patients. In conclusion, pathways of homocysteine disposal are impaired in type 2 diabetes with nephropathy, both in postabsorptive and insulin-stimulated states, possibly accounting for the hyperhomocysteinemia of this condition.

Address correspondence and reprint requests to Prof. Paolo Tessari, Department of Clinical and Experimental Medicine, Chair of Metabolism, Policlinico Universitario, via Giustiniani 2, 35128 Padova, Italy. E-mail: paolo.tessari{at}unipd.it

Abbreviations: CBS, cystathionine-ß-synthase; MTHFR, methylene-tetrahydrofolate-reductase; OHA, oral hypoglycemic agent; TTR, tracer-to-tracee ratio


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Copyright © 2005 by the American Diabetes Association.