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New Study on NR vs. Diabetic Neuropathy

niagen nicotinamide riboside diabetic neuropathy diabetes

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#1 Michael

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Posted 22 October 2017 - 03:49 AM


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.

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#2 able

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Posted 22 October 2017 - 01:21 PM

Thanks michael, but the link to new study doesn't work for me - shows "forbidden".

 



#3 Michael

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Posted 22 October 2017 - 03:59 PM

Thanks michael, but the link to new study doesn't work for me - shows "forbidden".


Hmm... I think I see the problem. I've just edited the link. Please try it now, and tell me if it works; if so, I'll then delete this little exchange to keep the thread clean.

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#4 able

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Posted 22 October 2017 - 04:03 PM

yes, works now

 

whoops.  it opens "ANA 2017 Program"

 

 

 

not the study


Edited by able, 22 October 2017 - 04:08 PM.


#5 Heisok

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Posted 22 October 2017 - 05:10 PM

Hypophagia related to NR, brings up an interesting thought. Does anybody who is practicing C.R. get more consistent compliance after having been on an NR regimen?

 

Thanks.



#6 Michael

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Posted 22 October 2017 - 05:31 PM

yes, works now
 
whoops.  it opens "ANA 2017 Program"[/size]
 
 
 
not the study


"ANA 2017 Program" is where the study is: as I said, it's a meeting abstract. Use the 'search' function.

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#7 ambivalent

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Posted 23 October 2017 - 04:07 PM

This was kindly posted on another thread by Nikolay:

 

d-ribose as a contributor to glycated haemoglobin

 

https://ncbi.nlm.nih...pubmed/29033370

 

I have recently experienced what I believe to have some kidney injury - the preceding symptoms were sensed by both NR and N+R (some dizziness and extremity pain). These sensations were similar to those observed when my younger self  pursued a diet was horrifically high in sugar. While not obscenely so, my calorie intake has been far higher in sugar content than desired, or I would say at all healthy; I believe the compounding of higher blood-glucose coupled with N+R and some NR compounded (I experienced these symptoms as have others while exclusively on NR too, though not the subsequent kidney pain) caused a rather drastic renal response. 

 

I should add I can't know with certainty it was a kidney related, I've had no scans. In addition it could conceivably have been kidney stones (I've taken high doses of vit D), though, afaik, I've not passed suspecting objects and yet I appear to be recovering. Also the acute kidney pain occurred the day after concluding the N+R due to the somewhat alarming extremity pain. It only occurred to me a few days ago that the classic NR foot problem was something I suffered from many years ago at the height of my poor diet, which I had put down to being overweight with flattish feet.

 

I should add that despite the irritation of extremity pain, I was feeling fantastic the days before my sleep was assaulted in the early hours by this acute left-flank pain; I've been off the painkillers since the weekend, after almost a week on them, but still it is sore and not to be aggravated.

 

Obviously this could well be a dosing problem, although I believe some reported these extremity pains while on low doses and my initial experiences of those symptoms occurred at low doses around a year ago. They have been recurrent on NR but were not persistent.

    







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