Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance toN-acetylcysteine supplementation

Abstract

Blood glutathione concentrations represent a measure of protection against oxidative damage. In earlier studies, we observed that, in adolescents with poorly controlled type 1 diabetes mellitus (T1DM), blood glutathione is significantly depleted because of increased rates of glutathione utilization. To determine whether increased availability of cysteine - one of the three constitutive amino acids of glutathione - would attenuate the alterations in glutathione metabolism, ten 16 +/- 1 yr-old adolescents with poorly controlled T1DM [hemoglobin A1c (HbA1c): 9.9 +/- 1.3%] received 5-h infusions of l-[3,3-(2)H(2)] cysteine and d-[6,6-(2)H(2)]glucose on two occasions, 3 wk apart, after a 10-d oral supplementation with (i) N-acetylcysteine (NAC, 30-45 mg/kg/d) or (ii) L-alanine, in randomized order, and with a 3-wk 'washout' interim period. Blood glucose was maintained in the same hyperglycemic range on both infusion study days, using intravenous insulin. Glutathione fractional synthesis rate (FSR) was determined from (2)H(2)-cysteine incorporation into blood glutathione. NAC supplementation failed to raise erythrocyte cysteine concentrations (23 +/- 6 vs. 17 +/- 1 micromol/L, p = 0.853) and did not alter erythrocyte glutathione concentrations (838 +/- 106 vs. 793 +/- 111 micromol/L, p = 0.220) or glutathione FSR (96 +/- 20 vs. 89 +/- 19%/d, p = 0.974). We conclude that in adolescents with poorly controlled T1DM, dietary cysteine supplementation alone cannot correct glutathione status. In the presence of relative insulinopenia, either higher amino acid doses or aggressive insulin therapy may be needed to achieve this goal. This would require further study.

Treatment with N-acetylcysteine does not alter blood glucose levels and the oxidative stress status in diabetic rats

“…In our experiment, NAC supplementation in diabetic rats was not able to decrease the significant blood glucose and glycated hemoglobin levels [ Table 1] when compared to the diabetic/saline group, as has been shown in other studies on humans [18,28] and diabetic animals. [29] Possibly the destruction of pancreatic beta cells by alloxan-induced ROS generation [19] hindered the potentially therapeutic effect of NAC on these cells, and consequently on the hyperglycemia status.…”

“…Furthermore, poor conversion of NAC to cysteine, excess urinary NAC, and decreased uptake of plasma cysteine by red blood cells could be the cause for the lack of effect of NAC on the GSH levels in a diabetic state. [28] In other studies, diabetic rats treated with NAC showed lower levels of glycemia than untreated diabetic rats, but hyperglycemia is common to both groups of animals, in spite of the improvement in the GSH status after NAC supplementation. [13,35,40] Darmaun et al, [28] demonstrated high levels of blood glucose after NAC supplementation in diabetes type I, but erythrocyte GSH levels were still decreased, similar to our study [ Table 4].…”

“…[28] In other studies, diabetic rats treated with NAC showed lower levels of glycemia than untreated diabetic rats, but hyperglycemia is common to both groups of animals, in spite of the improvement in the GSH status after NAC supplementation. [13,35,40] Darmaun et al, [28] demonstrated high levels of blood glucose after NAC supplementation in diabetes type I, but erythrocyte GSH levels were still decreased, similar to our study [ Table 4]. We suggested that NAC transport to the interior of the cells, where it was deacylated and converted to cysteine, [41] could be injured in diabetes type I. Consequently, cysteine was not provided as a substrate for GSH synthesis.…”

Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes

“…Glutathione (GSH) plays an important role in a multitude of cellular processes and its deficiency is implicated in the etiology and progression of a number of human diseases including cardiovascular, immune, diseases of aging, and diabetes (1-7). GSH is a cofactor of many enzymes that are involved in the detoxification of oxygen radicals and the detoxification of drugs.…”

Hydrogen Sulfide and l-Cysteine Increase Phosphatidylinositol 3,4,5-Trisphosphate (PIP3) and Glucose Utilization by Inhibiting Phosphatase and Tensin Homolog (PTEN) Protein and Activating Phosphoinositide 3-Kinase (PI3K)/Serine/Threonine Protein Kinase (AKT)/Protein Kinase Cζ/λ (PKCζ/λ) in 3T3l1 Adipocytes

“…Recent studies report lower blood levels of LC and altered cysteine homeostasis (15,16) as well as lower H 2 S levels in diabetic patients (17,18). Along with a host of proteins, LC is a precursor of glutathione, which is considered essential for the reduction of cellular oxidative stress (19).…”