Neuroprotective Activity of NR in DPN Can be Monitored by Corneal Confocal Microscopy.
A naturally occurring vitamin, nicotinamide riboside (NR), can lower BSL, reduce fatty liver, and prevent peripheral nerve damage in mouse models of prediabetes and type 2 diabetes (T2D), according to a new study. The findings provide a scientific rationale for conducting human trials to test the effects of NR on metabolic disorders including prediabetes and T2D, as well as obesity, fatty liver disease, and neuropathies.
NR is a vitamin precursor of NAD+, an important cellular metabolite that is required for cells to convert fuel into energy, but which declines with age. NR is currently attracting a great deal of attention for its potential role in improving metabolic health and healthy aging. “NR has emerged as the lead molecule to elevate NAD+ metabolites,” says Prof Charles Brenner, PhD.
nicotinamide riboside
The team studied 6 groups of mice: control mice on a normal chow diet with or without NR supplementation, prediabetic mice on a high-fat diet with or without NR supplementation, and T2D mice on a high-fat diet with or without NR supplement. The mice receiving NR were fed the supplement for the last 8 weeks of the 21-week experiment.
Results:As had been shown in previous studies, NR greatly protected the prediabetic and T2D mice from weight gain due to the high-fat diet. But the new study also showed that NR had other beneficial effects on whole body metabolism in the prediabetic and T2D mice. It protected high-fat fed mice from hepatic steatosis – the build-up of fat globules in the liver – which was severe in the prediabetic and T2D mice that did not receive NR. NR also reduced liver damage in the mice on high-fat diets, and greatly improved blood sugar levels in the prediabetic and T2D mice.
NR also protected against neuropathy, a common, serious complication of prediabetes and T2D. About 60 to 70% of people with diabetes have some form of neuropathy, a leading cause of diabetic foot ulcers and limb amputation in people with T2D.
Metabolic control of vascular redox signaling. The redox status of cytosolic NADH generated primarily by the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in glycolysis and cytosolic NADPH derived from glucose-6-phosphate (G-6-P) metabolism by glucose-6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP) are hypothesized to control signaling mechanisms through their influence in providing NAD(P)H to support ROS generation by Nox oxidases and processes directly regulated by NADP(H) redox. Note that the lactate dehydrogenase (LDH) reaction and mitochondrial shuttles normally function to maintain very low levels of cytosolic NADH, allowing high levels of lactate (Lac) to regulate signaling through increasing NADH and ROS generation by Nox oxidases. Some of the signaling mechanisms we have observed to be regulating contractile function in bovine arteries by these metabolic redox control systems, including cGMP signaling, extracellular signal-regulated kinase (ERK), potassium (K+) channels, and processes controlled by NADP(H) redox (NADP/NADPH) that coordinate the lowering of cytosolic calcium (Ca2+), are included in the model shown.
The study showed that a non-invasive test measuring nerve density in the mouse corneas was a sensitive and accurate biomarker of neuropathy. This test, known as corneal confocal microscopy, is already used on people in the clinic and could, therefore, be a useful tool for researchers to track the neuroprotective effects of NR in human trials. They also developed technology that allows researchers to accurately measure levels of all the NAD+ metabolites in tissues or body fluids. This technology was, for the first time, applied to a disease model and revealed that prediabetes and T2D produced unexpected deficits in NAD+ metabolites in the liver, which were partially restored by the NR supplement.
“NAD+ metabolomics shows that NAD+ itself goes down in prediabetes and T2D, but it is not depressed as strikingly as two other metabolites: NADP+ and NADPH,” Brenner explains. “When we supplement with NR, the NAD+ bounces back but the NADP+ and NADPH levels don’t fully recover, suggesting that the disease process specifically targets these metabolites, which are required for natural resistance to reactive oxygen species (ROS). These results are consistent with research showing that the development of insulin-insensitivity is related to ROS damage and that NR boosts the body’s natural anti-oxidant defenses.” http://www.eurekalert.org/pub_releases/2016-05/uoih-vnr052616.php
http://www.nature.com/articles/srep26933
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