Abstract
Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.
Highlights
The global epidemic of obesity and diabetes has created severe economic stresses on health systems and intense neuropathic complications for affected individuals
Though the mechanisms accounting for resistance to weight gain and improved glycemic control for mice on high fat diet (HFD) as well as resistance to diet-induced fatty liver are not fully understood, nicotinamide riboside (NR) elevates NAD+ levels in skeletal muscle, liver and brown adipose tissue and appears to increase activity of nuclear and mitochondrial NAD+-dependent protein lysine deacetylases including sirtuins SIRT1 and SIRT38,9
At 12 weeks of age, when mice weighed ~23 g, 40 mice were transferred to HFD (Research Diets 12492, 60% calories from fat) to render them PD, while 20 mice remained on normal chow (NC)
Summary
The global epidemic of obesity and diabetes has created severe economic stresses on health systems and intense neuropathic complications for affected individuals. Though pellagra has been nearly eliminated, there are indications that supplementation with nicotinamide riboside (NR), a recently discovered NAD+ precursor vitamin[5,6] found in milk[7], can improve metabolic health in overfed mice[8,9]. Though the mechanisms accounting for resistance to weight gain and improved glycemic control for mice on high fat diet (HFD) as well as resistance to diet-induced fatty liver are not fully understood, NR elevates NAD+ levels in skeletal muscle, liver and brown adipose tissue and appears to increase activity of nuclear and mitochondrial NAD+-dependent protein lysine deacetylases including sirtuins SIRT1 and SIRT38,9. Though hepatic steatosis and hyperglycemia were not fully corrected by NR, supplemented mice have greatly reduced neuropathic symptoms in both models. Our data indicate that corneal confocal microscopy (CCM) can be used as a minimally invasive and translational assay to monitor NR-dependent improvements in PDPN and DPN in future clinical investigations
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