Diabetic ketoacidosis and its treatment increase plasma 3-deoxyglucosone.

OBJECTIVES: Highly reactive dicarbonyl compounds are known to be increased by hyperglycemia, ketone bodies and lipid peroxidation. This study was carried out to investigate the effect of diabetic ketoacidosis (DKA) and its treatment on the plasma concentration of 3 deoxyglucosone (3-DG) one of the dicarbonyl compounds. DESIGN AND METHODS: 3-DG was measured in 7 children before, during and following correction of severe DKA. 3-DG was elevated before treatment (610 nmol/L +or/- 70) in comparison to baseline (120 h) (200 nmol/L+/or- 17) (p < 0.05). At 6 to 24 h into treatment 3-DG was further elevated (1080 nmol/L +or/- 80) in comparison to both pretreatment (p < 0.05) and baseline (p < 0.05). CONCLUSION: 3-DG is significantly elevated before the treatment of DKA and increases further during the treatment of DKA. The time course of the increase of 3-DG coincides with the time of progression of subclinical brain edema, which occurs in DKA.

Meglumine exerts protective effects against features of metabolic syndrome and type II diabetes.

Metabolic syndrome, diabetes and diabetes complications pose a growing medical challenge worldwide, accentuating the need of safe and effective strategies for their clinical management. Here we present preclinical evidence that the sorbitol derivative meglumine (N-methyl-D-glucamine) can safely protect against several features of metabolic syndrome and diabetes, as well as elicit enhancement in muscle stamina. Meglumine is a compound routinely used as an approved excipient to improve drug absorption that has not been ascribed any direct biological effects in vivo. Normal mice (SV129) administered 18 mM meglumine orally for six weeks did not display any gastrointestinal or other observable adverse effects, but had a marked effect on enhancing muscle stamina and at longer times in limiting weight gain. In the established KK.Cg-Ay/J model of non-insulin dependent diabetes, oral administration of meglumine significantly improved glycemic control and significantly lowered levels of plasma and liver triglycerides. Compared to untreated control animals, meglumine reduced apparent diabetic nephropathy. Sorbitol can improve blood glucose uptake by liver and muscle in a manner associated with upregulation of the AMPK-related enzyme SNARK, but with undesirable gastrointestinal side effects not seen with meglumine. In murine myoblasts, we found that meglumine increased steady-state SNARK levels in a dose-dependent manner more potently than sorbitol. Taken together, these findings provide support for the clinical evaluation of meglumine as a low-cost, safe supplement offering the potential to improve muscle function, limit metabolic syndrome and reduce diabetic complications.

Two dicarbonyl compounds, 3-deoxyglucosone and methylglyoxal, differentially modulate dermal fibroblasts.

Advanced glycation endproducts accumulate on long-lived proteins such as collagens as a function of diet and age and mediate the cross-linking of those proteins causing changes in collagen pathophysiology resulting in the disruption of normal collagen matrix remodeling. Two commonly studied advanced glycation endproduct precursors 3-deoxyglucosone and methylglyoxal were investigated for their role in the modification of collagen and on extracellular matrix expression. Fibroblasts cultured on methylglyoxal cross-linked matrices increased the expression of collagen, active TGF-beta1, beta1-integrin, and decreased Smad7; whereas 3-deoxyglucosone decreased collagen, active TGF-beta1, beta1-integrin but increased Smad7. Purified collagen modified by 3-deoxyglucosone or methylglyoxal had different molecular weights; methylglyoxal increased the apparent molecular weight by approximately 20 kDa, whereas 3-deoxyglucosone did not. The differences in collagen expression by 3-deoxyglucosone and methylglyoxal raise the provocative idea that a genetic or environmental background leading to the predominance of one of these advanced glycation endproduct precursors may precipitate a fibrotic or chronic wound in susceptible individuals, particularly in the diabetic.