All:
There are several reports out there finding that NR improves glycemia in obesogenic diabetes, particularly on postprandial glycemia — notably the Cantó/Auwerx NR vs. diet-induced obesity study (PMID: 22682224)) and the Trammell/Brenner NR diabetic neuropathy study (PMID 27230286). Both studies also find that it increases energy expenditure and decreases weight gain; the latter study also finds it to be protective against diabetic neuropathy.
A new report presented at the 142nd Annual Meeting of the American Neurological Association confirms a protective effect against diabetic neuropathy — but, somewhat surprisingly, finds no effect on body weight.
Trammel and Brenner first:
Sixty male C57Bl/6J mice [were used].. At 12 weeks of age, when mice weighed ~23 g, 40 mice were transferred to [high-fat diet (HFD)] to render them [prediabetic (PD)], while 20 mice remained on [normal chow (NC)]. After 8 weeks on HFD, 20 of 40 mice were given ... STZ [streptozotocin, a toxin that destroys beta-cells, thus reducing or eliminating insulin production] to induce [type 2 diabetes (T2D)]. PD and T2D mice remained on HFD for the duration of the experiment.
Five weeks after STZ administration to create the T2D population, 10 of 20 mice in each of the three groups (NC, HFD and HFD + STZ) were supplemented with 3 g of NR chloride per kg of their diet, thereby creating six groups of 10 mice (NC, NC + NR, HFD, HFD + NR, HFD + STZ, HFD + STZ + NR ... PD mice were effectively on HFD for 21 weeks without supplementation whereas NR-supplemented PD mice were fed HFD enriched with NR for the last 8 weeks. All T2D mice were non-supplemented for five weeks post STZ administration and 10 out of 20 were supplemented with NR from week 13 to 21 on HFD.
[M]ice on HFD gained ~27 g of body weight while mice in the HFD + STZ treatment group gained ~16 g. Though supplementation was for only 8 weeks, NR blunted weight gain in PD by ~7 g (P = 0.007) and by ~6 g in the T2D group (P = 0.031). ...
[NR] tended to normalize hemoglobin A1c (HbA1c) and significantly improved nonfasting glucose (P < 0.001) in T2D. As shown in Fig. 1i, NR had a powerful effect on fasting glucose, depressing levels from 210 mg/dl to 161 mg/dl in PD mice (P = 0.008) and from 345 mg/dl to 194 mg/dl in T2D mice (P < 0.001). Finally, as shown in Fig. 1j and Supplementary Fig. 2, NR significantly improved glucose tolerance in PD (P = 0.018) and tended to improve glucose tolerance in T2D. These data indicate that NR has profound effects on whole body metabolism in PD and T2D mouse models....
As shown in Fig. 2a,b, PD mice retained their [motor neuron conduction velocity (MNCV)] but had significantly depressed [sensory neuron conduction velocity (SNCV)] (P < 0.001). This sensory deficit was not evident in mice supplemented with NR. T2D mice had significantly depressed MNCV (P < 0.001) and SNCV (P < 0.001) that were prevented by NR supplementation. Thermal insensitivity, a particularly dangerous aspect of human [diabetic polyneuropathy], was strikingly evident in the PD (P < 0.001) and T2D (P < 0.001) models and was significantly reduced by NR in PD (P = 0.003) and T2D (P < 0.001). ...
neuroprotection cannot be explained by glycemic control alone. For example, T2D mice supplemented with NR have higher nonfasting glucose than PD mice without NR (P = 0.0012). Nonetheless, PD mice without NR have SNCV deficits, whereas T2D mice supplemented with NR do not. Thus, NR is presumed to have neuronal and hepatic targets.
Now, the abstract of the new meeting presentation:
Nicotinamide Riboside Is a Potential Therapy for Diabetic Neuropathy
Pranith H. Kumar, Neda Najimi, Krish Chandrasekaran, Chen Chen and James W. Russell. 142nd Annual Meeting of the American Neurological Association. Ann Neurol. October 2017; Volume 82, Issue S21, Abstract S309. doi:10.1002/ana.25024
... Adult C57BL6 mice were fed a high fat diet (HFD) for two months until they developed neuropathy. Then, 150 mg/kg or 300 mg/kg NR was added to the HFD for a further 2 mo. ...
Results: Both [mechanical allodynia (MA) — ie, painful hypersensitivity to a light touch] and [motor sciatic-fibular nerve conduction velocities (MCV)] improve in HFD mice with NR treatment (P<0.001 mice at 4 months compared to the 2 month time point). There was no change in control diet (CD) animals. HFD animals continued to develop neuropathy over the 4 mo. period. At 4 mo., the [intraepidermal nerve fiber density (IENFD)] was decreased in the HFD but not the NR group (P<0.001 HFD mice at 4 months vs baseline). ... In HFD mice, there was a parallel decrease in the NAD+ level, in SIRT1 activity, and in PGC-1 alpha levels in [dorsal root ganglion neurons]. NR normalized these measurements. ...
NR treatment did not significantly affect glucose and insulin measurements in HFD animals, but decreased HFD-induced increase in triglycerides and non-esterified fatty acids, and normalized impaired glucose tolerance test. ...
The most consistent effect across all studies is on glucose tolerance, with less or no effect on fasting glucose or insulin. But Trammel & Brenner, as other papers, find an effect on weight gain; none such in the new report. Neither did the less-is-more nicotinamide riboside dose-ranging study (PMID 28211258), which also tested NR in mice fed an obesogenic diet, albeit in a strain of mouse without the NNT mutation.
I also note that the new report says they tried two different doses, but don't say anything about either being better than the other. I wonder if that means there was no further benefit at 300 vs. 150 mg/kg. Trammel & Brenner unfortunately report the dose in mg/kg diet, not mg/kg mouse, and failed to report on food intake in the mice — which, it must be said, is rather sloppy, especially in a study focused on body weight and glycemic control. The closest they come is saying "mice supplemented with NR are neither hyperactive nor hypophagic [that is, they aren't gaining weight more slowly than controls because they're undereating] (data not shown)."
As a very, very rough ballpark, consider the NR dose-ranging study Here NR did not impede weight gain when given to younger animals on an obesogenic chow at 900 mg NR per kg diet for 15 weeks. This amounted to 102 mg NR/kgmouse/day at the start of the experiment to 65 mg NR/kg mouse/day in the end, when they weighed 40-45 g. These are not the same mice, not the same age, and not fed the same chow (both studies used high-fat, obesogenic chows, but the Trammel/Brenner chow was 60% Calories from fat, vs. 40% in the dose-ranging study, so the Trammel/Brenner animals would have had to consume fewer grams of food to gain the same amount of weight). Looking at the plateau weights of NR-supplemented animals, it's unlikely Trammel/Brenner's PD animals got more than 225 mg/kg NR, and the T2D animals may have gotten less in turn, both because their peak weights were lower and because their ostensibly isocaloric weight deficit relative to controls was less than for the PD animals.
I also note that even in Trammel & Brenner, animals fed normal rodent chow were no lighter with NR supplementation than unsupplemented animals.
Edited by Michael, 22 October 2017 - 03:57 PM.