Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells.

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes. In human umbilical vein endothelial cells (HUVECs), the risk allele "C" is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and the γ-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17-58% increase/allele copy, P = 0.046-0.002), including five γ-glutamyl amino acids, ß-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate-a marker of γ-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione-to-glutamate ratio (-9%, P = 0.012), decreased S-lactoylglutathione (-41%, P = 0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, P = 0.008). GLUL downregulation by shRNA caused a 40% increase in the methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the γ-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.

Percutaneous ethanol injection plus radioiodine versus radioiodine alone in the treatment of large toxic thyroid nodules.

UNLABELLED: Therapeutic options for toxic thyroid nodules (TTNs) are surgery, radioiodine (RAI), and percutaneous ethanol injection (PEI). Surgery is generally considered for TTNs larger than 4 cm. However, some patients may be at high surgical risk. The purpose of the study was to evaluate the efficacy of 2 nonsurgical modalities for these TTNs. METHODS: Twenty-two patients with TTNs larger than 4 cm were randomly assigned to 2 different treatments: to 11 (subgroup A), RAI was administered at a dose of 12,580 kBq/mL of nodular volume (NV) and was corrected for 100% 24-h (131)I uptake (RAIU); to 11 (subgroup B), 2-4 PEI sessions (ethanol injected = 30% NV) preceded 2 mo of 24-h RAIU and RAI dosing. Inclusion criteria were clinical and biochemical hyperthyroidism; a single palpable, hot nodule at (99m)Tc scintigraphy; and high surgical risk or refusal to have surgery. Patients gave informed consent. Local symptoms were evaluated by a previously validated score (symptom score, or SYS). RESULTS: Both treatments were well tolerated. Subgroup B showed a significant reduction of NV 2 mo after PEI: 33.6 +/- 18.5 versus 60.8 +/- 29.5 mL. Their 24-h RAIU was similar to that of subgroup A: 53.9 +/- 13.9 versus 61.8% +/- 11.0%. Consequently, the administered RAI dose was significantly lower for subgroup B (730 +/- 245 MBq) than for subgroup A (1,048 +/- 392 MBq). Twelve months after RAI, subgroup B had a higher NV reduction and a lower SYS than did subgroup A. In subgroup A, 1 patient was subclinically hyperthyroid, 2 showed a slight increase of thyroid-stimulating hormone, and 1 was clinically hypothyroid. In subgroup B, 1 patient had a slight increase of thyroid-stimulating hormone. CONCLUSION: We demonstrated that RAI, alone or with PEI, can be considered a valid alternative for TTNs larger than 4 cm when surgery is either refused or contraindicated. PEI plus RAI can be considered when marked shrinkage of a nodule is required or when reduction of the RAI dose can prevent hospitalization.