Parp Activation

Increased oxidative stress, presumably from polyol pathway activity, AGE and its interaction with RAGE, PKC activation, and hyperactivity of mitochondrial respiratory chain, damages lipids, proteins, and DNA (49). DNA strand breaks activate PARP, which is an enzyme that transfers ADP-ribose from NAD+ to nuclear proteins as part of the DNA repair process (50). However, overactivation of PARP has deleterious consequences, including the activation of the proinflammatory transcription factors NF-kB and activating protein-1 (AP-1), and the induction of the apoptosis-inducing factor, which might lead to cell death (51-53). PARP has been shown to be involved in the diabetes-induced endothelial dysfunction of the aorta (54,55).

The PARP-1 gene KO mice were used to determine if PARP contributes to diabetic neuropathy. These mice showed no obvious abnormality. Under normal rearing condition, the MNCV of their sciatic nerve, the SNCV of their digital nerve, and the morphology of their sciatic nerve all appeared normal (56). When the WT mice were induced to become diabetic by streptozotocin, their MNCV and SNCV decreased significantly. In the sciatic nerve of the diabetic WT mice there was significant increase in immunostaining of PAR, the product of PARP activity, indicating that hyperglycemia activates PARP. The PARP-1 null mice on the other hand, showed no reduction in MNCV and SNCV when induced to become diabetic. The blood glucose level in the diabetic PARP null mice was not different from that of the diabetic WT mice, indicating that PARP did not affect diabetes, but plays an important role in the diabetes-induced functional impairment in the peripheral nerves. When fed a high galactose diet, which simulates and exaggerates the AR-mediated glucose toxicity, the WT mice showed even higher reduction in sciatic nerve MNCV and digital nerve SNCV than that of diabetic WT mice. PARP deficiency partially protected these mice against galactosemia-induced MNCV reduction, and completely protected them against galactosemia-induced SNCV reduction, suggesting that hyperglycemia-induced activation of PARP is mediated by AR activity. This was confirmed by experiments that showed that ARI blocked the hyper-glycemia-induced oxidative stress and activation of PARP in the sciatic nerve (57). The deleterious effect of overactivation of PARP is because of the depletion of its cofactor NAD+, which leads to the depletion of ATP. In the sciatic nerve of the diabetic and galactosemic WT mice, the ratio of phosphocreatine (PCr)/Cr, an indicator of cytosolic ATP/ADP ratio, was significantly decreased. There was no change in PCr/Cr ratio in the sciatic nerve of the diabetic or galactosemic PARP-deficient mice. These results indicate that hyperglycemia activation of PARP depletes cellular PCr level, and by inference, energy stores.

Two structurally unrelated inhibitors of PARP were administered to diabetic rats. Both drugs were able to normalize diabetes-induced reduction in MNCV, SNCV, nerve blood flow, blood pressure, and vascular conductance in rats, confirming the findings in PARP-1 null mice (56). These PARP inhibitors are potential drugs for the prevention and treatment of diabetic neuropathy and other complications. However, studies are needed to determine if inhibition of PARP activity would leave unrepaired the hyperglycemia-induced DNA breaks that might lead to mutations and cancers.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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