Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

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.

Figure 1. NR Improves Metabolic Parameters in PD and T2D.

(a) NR reduces weight gain on HFD independent of STZ. (b–d) NR reduces hepatic steatosis in the PD and T2D models. NR lowers circulating cholesterol (e) and circulating alanine aminotransferase (f) in PD. In T2D, NR tends to lower HbA1C (g) and depresses nonfasting glucose (h). NR depresses fasting glucose in both models (i). NR improves GTT in PD (j). Statistics were by two-way ANOVA. n = 10. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 2. NR Opposes PDPN and T2DPN.

(a) NR protects against a decline in MNCV in T2D. (b) NR protects against declines in SNCV in PD and T2D. (c) NR protects against loss of thermal sensitivity in both models. (d,e) NR improves INFD on NC and in both disease models. Statistics were by two-way ANOVA. n = 10. **P < 0.01; ***P < 0.001.

Figure 3. Neuroprotective Activity of NR in DPN Can be Monitored by Corneal Confocal Microscopy.

(a,b) CCM is a sensitized assay for PD and T2D nerve loss. (c) and (d) By post-mortem class III β-tubulin staining, NR protects against corneal sub-epithelial nerve loss in T2D. Statistics were by two-way ANOVA. n = 10. *P < 0.05; **P < 0.01; ***P < 0.001.