Glycemic control modulates arginine and asymmetrical-dimethylarginine levels during critical illness by preserving dimethylarginine-dimethylaminohydrolase activity

In the context of the hypercatabolic response to stress, critically ill patients reveal hyperglycemia and elevated levels of asymmetrical-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases. Both hyperglycemia and elevated ADMA levels predict increased morbidity and mortality. Tight glycemic control by intensive insulin therapy lowers circulating ADMA levels, and improves morbidity and mortality. Methylarginines are released from proteins during catabolism. ADMA is predominantly cleared by the enzyme dimethylarginine-dimethylaminohydrolase (DDAH) in different tissues, whereas its symmetrical isoform (SDMA) is cleared via the kidneys. Therefore, glycemic control or glycemia-independent actions of insulin on protein breakdown and/or on DDAH activity resulting in augmented ADMA levels may explain part of the clinical benefit of intensive insulin therapy. Therefore, we investigated in our animal model of prolonged critical illness the relative impact of maintaining normoglycemia and of glycemia-independent action of insulin over 7 d in a four-arm design on plasma and tissue levels of ADMA and SDMA, on proteolysis as revealed by surrogate parameters as changes of body weight, plasma urea to creatinine ratio, and plasma levels of SDMA, and on tissue DDAH activity. We found that ADMA levels remained normal in the two normoglycemic groups and increased in hyperglycemic groups. SDMA levels in the investigated tissues remained largely unaffected. The urea to creatinine ratio indicated reduced proteolysis in all but normoglycemic/normal insulin animals. DDAH activity deteriorated in hyperglycemic compared with normoglycemic groups. Insulin did not affect this finding independent of glycemic control action. Conclusively, maintenance of normoglycemia and not glycemia-independent actions of insulin maintained physiological ADMA plasma and tissue levels by preserving physiological DDAH activity.