Effects of insulin on methionine and homocysteine kinetics in type 2 diabetes with nephropathy.
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-(2)H(3), 1-(13)C]methionine. Methionine flux, transmethylation, and disposal into proteins as well as homocysteine remethylation, transsulfuration, and clearance were determined before and after euglycemic hyperinsulinemia (approximately 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 approximately 15 to >50% and from approximately 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.
Tessari
Paolo
P
Department of Clinical and Experimental Medicine, University of Padova, Italy. paolo.tessari@unipd.it
Coracina
Anna
A
Kiwanuka
Edward
E
Vedovato
Monica
M
Vettore
Monica
M
Valerio
Anna
A
Zaramella
Michela
M
Garibotto
Giacomo
G
D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications; D003928:Diabetic Nephropathies / Q000097:blood*; D005215:Fasting; D005502:Food; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000032:analysis; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood*; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008715:Methionine / Q000097:blood*; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D013455:Sulfur / Q000378:metabolism
D001786:Blood Glucose; D002245:Carbon Dioxide; D006442:Glycated Hemoglobin; D006710:Homocysteine; D007328:Insulin; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013455:Sulfur