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.

NAD and the aging process: Role in life, death and everything in between

“…This supplementation ameliorated metabolic defects of obese mice, boosted their energy expenditure and oxidative performance of skeletal muscle and brown adipose tissue, and, overall, reverted metabolic impairment (Cantó et al, 2012). In pre-diabetic mice NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis, while protecting against sensory neuropathy (Trammell et al, 2016). Additionally, NR was shown to prevent and reverse the development of nonalcoholic fatty liver disease (NAFLD) by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (Gariani et al, 2016).…”

Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme

“…Recently, it became apparent that NAD + levels decline in obesity and aging, and this decline may contribute to the metabolic dysfunction, because restoring tissue NAD + through supplements ameliorates the metabolic dysregulation caused by high fat diet and aging [81,82,87–89]. Although NAD + acts on multiple enzymes, Sirt1 and Sirt3 are considered major effectors of its metabolic actions [81,87].…”

“…Proof of concept should come from the whole body NNMT-KO mouse, when available. This may be important as pharmacological doses of nicotinamide riboside (NR), NAD + precursor, are being tested in preclinical models and in humans as a treatment for a variety of dysfunctions associated with obesity and aging (ClinicalTrials.gov Identifiers: NCT02303483, NCT02950441) [81,82]. Efficient removal of these precursors over time will be essential.…”

NAD+: A key metabolic regulator with great therapeutic potential

“…Enhanced oxidative metabolism in multiple tissues, with a subsequent elevation in lipid usage appeared to underlie these favourable effects . Recently, dietary NR supplementation was also shown to be beneficial in pre‐diabetic and diabetic (STZ‐induced) mice . NR improved markers of glycaemic control, reduced weight gain and hepatic steatosis, and protected against the development of neuropathy, with the neuroprotective effects ascribed to the restoration of NADP(H) levels by NR .…”

“…Recently, dietary NR supplementation was also shown to be beneficial in pre‐diabetic and diabetic (STZ‐induced) mice . NR improved markers of glycaemic control, reduced weight gain and hepatic steatosis, and protected against the development of neuropathy, with the neuroprotective effects ascribed to the restoration of NADP(H) levels by NR . Administration of NMN also reversed the metabolic defects seen in adipose‐specific NAMPT knockout mice .…”