I have read with great interest the comments of Drs. Liu and Xia. Their study on a similar model of streptozotocine-induced diabetic rats1confirmed my findings that myocardial signal transducer and activator of transcription 3 (STAT3) concentrations are significantly decreased in the diabetic heart, whereas normal STAT3 concentrations are essential for initiation of the protective process of sevoflurane postconditioning (postC) in diabetes. They also described their findings that STAT3 concentrations might recover in diabetic hearts in the presence of N -acetylcysteine. They suggest that N -acetylcysteine and allupurinol promote tolerance of the myocardium to ischemic injury by restoring adinopectin concentration, and thus, they propose that N -acetylcysteine might be effective in restoring sevoflurane postC in the diabetic heart.

The animal model used in the study2was type I diabetes, i.e. , uncorrected hyperglycemia for 1 month. Insulin was given in the last 48 h to bring the animals into a state of normoglycemia at the time of the experiment. I did not give insulin therapy to alleviate the symptoms of diabetes, but to perform the experiments in a normoglycemic state, with a goal to reduce blood sugar to less than 135 mg/dl, but I actually achieved better control as reflected in the study. The diabetic irresponsiveness of the myocardium is more complex than that expected by the hyperglycemic state alone. It might be attributed to multiple cellular changes in mitochondrial membrane potentials, which lead to certain degrees of mitochondrial uncoupling.3This in turn leads to a glycation reaction, causing cellular injury and accumulation of glycation end products,4depression of more signal transduction components such as phosphatidylinositol 3-kinase, STAT3,2and nitric oxide synthase, as well as glycogen synthase kinase-3β activation,5all leading to lipid accumulation, inflammation, and remodeling.6Therefore, I do not agree with the comment that strict preservation of normoglycemia during the experiment might eliminate all changes accumulated during the month of diabetic state. The changes in the heart are too substantial to be prevented by a single maneuver of replenishing antioxidant state.

From a practical view, giving higher doses of insulin to an animal would be irresponsible, because hypoglycemia in animals who are not observed closely most of the time would be detrimental. I am not aware of any animal study evaluating diabetes for long-term outcome that used conventional glucose control levels. Extrapolating from human data that use conventional glucose control, as suggested in the current letter to the editor, on patient postoperative long-term outcome, is controversial at best. Strict control of diabetes at normal levels was found hazardous due to severe side effects.7,8Attributing changes in sensitive cellular pathways, such as STAT3 and phosphatidylinositol 3-kinase, only to the natural lack of antioxidants seems simplistic. As discussed in the previous paragraph, diabetes effects on the heart are profound and the mechanism of injury is at multiple levels.

The authors claim that a longer period of insulin therapy might have a beneficial effect on restoring postC in diabetes. Unfortunately, I suggested differently, that changes in the heart caused by diabetes were not restored by a short period of normoglycemia. Insulin administration before complete ischemia may carry the risk of enhanced cellular metabolism in the no-flow state, a situation that may bring about accumulation of high tissue levels of lactate, which inhibits glycolysis and prevents any glycolytic stimulation by insulin.9,10Therefore, until proved experimentally, I cannot agree with the authors' final statement that insulin administration before ischemia may produce beneficial effects.

1.
Wang T, Qiao S, Lei S, Liu Y, Ng KF, Xu A, Lam KS, Irwin MG, Xia Z: N -acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats. PLoS ONE 2011; 6:e23967
2.
Drenger B, Ostrovsky IA, Barak M, Nechemia-Arbely Y, Ziv E, Axelrod JH: Diabetes blockade of sevoflurane postconditioning is not restored by insulin in the rat heart: Phosphorylated signal transducer and activator of transcription 3- and phosphatidylinositol 3-kinase-mediated inhibition. ANESTHESIOLOGY 2011; 114:1364–72
3.
Hassouna A, Loubani M, Matata BM, Fowler A, Standen NB, Galiñanes M: Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium. Cardiovasc Res 2006; 69:450–8
4.
Negre-Salvayre A, Salvayre R, Auge′ N, Pamplona R, Portero-Ot M: Hyperglycemia and glycation in diabetic complications. Antioxid Redox Signal 2009; 11:3071–109
5.
Gross ER, Hsu AK, Gross GJ: Diabetes abolishes morphine-induced cardioprotection via  multiple pathways upstream of glycogen synthase kinase-3beta. Diabetes 2007; 56:127–36
6.
Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L: Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 2009; 58:1391–402
7.
Nunnally ME: Tight perioperative glycemic control: Poorly supported and risky. J Cardiothor Vasc Anesth 2005; 19:689–90
8.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hbert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ: Intensive versus  conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283–97
9.
Apstein CS, Gravino FN, Haudenschild CC: Determinants of a protective effect of glucose and insulin on the ischemic myocardium. Effects on contractile function, diastolic compliance, metabolism, and ultrastructure during ischemia and reperfusion. Circ Res 1983; 52:515–26
10.
Shimizu I, Minamino T, Toko H, Okada S, Ikeda H, Yasuda N, Tateno K, Moriya J, Yokoyama M, Nojima A, Koh GY, Akazawa H, Shiojima I, Kahn CR, Abel ED, Komuro I: Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J Clin Invest 2010; 120:1506–14