Glucose + vitamin B3 combo synergistic for treating mitochondrial disease

haidut

Member
Forum Supporter
Joined
Mar 18, 2013
Messages
19,798
Location
USA / Europe
A very interesting study, which demonstrates the unique synergy between glucose and vitamin B3 in treating deficiencies of function in Complex I & II of the electron transport chain (ETC). Deficiencies on those metabolic steps are the most common causes for the wide varieties of debilitating symptoms (or even death) in people with "inborn" mitochondrial pathologies such as Leigh Syndrome, MERFF, MELAS, etc. The vast majority of those mitochondrial diseases are considered incurable, yet the study below demonstrates that a simple combination of glucose and vitamin B3 is highly effective in restoring mitochondrial function and normalizing a number of biomarkers indicative of mitochondrial dysfunction such as increase lactate/pyruvate ratio, increased NADH/NAD ratio, low ATP, and elevated GSH/GSSG ratio. The aforementioned combination also included N-acetyl-cysteine (NAC), but I don't think it is necessary for the beneficial effects to manifest, and in fact may be harmful considering that all mitochondrial diseases have increased GSH/GSSG ratios and NAC (being a reductant itself) will only further increase said ratio. Interestingly, the study did not test known mitochondrial therapeutic such as aspirin or methylene blue (or for that matter other quinones such as vitamin K, emodin, etc.). Neither did the study test the other vitamin B3 family member niacinamide/nicotinamide, however, they do explain that the rationale for using niacin was its role as a precursor to NAD+, which automatically means niacinamide/nicotinamide will likely have even stronger therapeutic effects. Finally, the study states that mitochondrial dysfunction is often the result of chronic conditions such as diabetes, heart disease, Parkinson, Alzheimer, etc. but I think the study got it backwards. It is those chronic conditions that are caused by mitochondrial dysfunction, so addressing the mitochondrial dysfunction would also likely result in reliable treatments for the myriads of chronic conditions we are constantly told are currently "incurable". I suppose such a statement would be too dangerous to see in the study itself, even for well-funded scientists working at the Children's Hospital of Philadelphia (CHOP) - an institution second probably only to the Mayo Clinic in terms of financial resources.

Combinatorial glucose, nicotinic acid, and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease
Researchers find effective combination of therapies for managing mitochondrial disease
"...Mitochondrial disease describes a collective group of energy deficiency disorders with no FDA-approved treatments or cures. Approximately 350 different gene disorders have been shown to substantially impair mitochondrial respiratory chain function, an essential process for making energy to power our cells. Respiratory chain function can also become severely disrupted by other genetic conditions, certain medications or environmental exposures, as well as common metabolic disorders, strokes, heart attacks, the aging process, and Alzheimer and Parkinson's diseases. In the absence of FDA-approved therapies, many affected patients seek out or are prescribed a wide variety of vitamins, supplements, and enzyme cofactors or "helper molecules" that generally fall into three different treatment classes: antioxidants, metabolic modifiers, and signaling modifiers. However, rigorous clinical trials have not been performed for these compounds to guide the medical community in understanding their comparative safety or benefit in mitochondrial disease patients. Additionally, prior to this study, it was unknown whether the best options were to give specific therapies alone or whether a combination of therapies are actually safe to administer and may work synergistically to provides patients with any direct health benefit. "We wanted to test unique combinatorial treatment regimens in preclinical models of mitochondrial disease to determine whether they showed any objective and measurable benefit to health, and to learn whether some combinations may be more effective than others," said senior study author Marni Falk, MD, Professor in the Division of Human Genetics as well as attending physician and Executive Director of the Mitochondrial Medicine Frontier Program CHOP. "This modeling approach would show us where physiology is most improved and take the guesswork out of developing treatment options for our patients." The study team, including Mitochondrial Medicine team members Sujay Guha, PhD and Neal D. Mathew, PhD, used two translational animal models of mitochondrial respiratory chain complex I disease - the most common biochemical site of dysfunction in mitochondrial disease - to evaluate 11 random combinations of drugs selected from each of the three treatment classes. Of those combinations, only one combination - glucose, nicotinic acid, and N-acetylcysteine - synergistically improved the lifespan of the first model beyond any individual component alone, as well as mitochondrial membrane potential, a quantitative measurement of how well mitochondria perform their essential energy-producing function. Importantly, this combination treatment yielded these survival and cellular physiology improvements without exacerbating any negative side effects, such as oxidative or mitochondrial stress. Validation studies performed in the second model, zebrafish, showed that glucose, nicotinic acid, and N-acetylcysteine combination therapy prevented stress-induced brain death - a sign that this therapy may prevent metabolic strokes such as those that occur with stress in Leigh syndrome and other mitochondrial disease syndromes - and rescued larval zebrafish animal swimming capacity as well as their tissue levels of ATP and glutathione."
 

cjm

Member
Joined
Jul 2, 2013
Messages
664
Location
Baltimore, MD
Interestingly, the study did not test known mitochondrial therapeutic such as aspirin or methylene blue (or for that matter other quinones such as vitamin K, emodin, etc.).

evaluate 11 random combinations of drugs selected from each of the three treatment classes

antioxidants, metabolic modifiers, and signaling modifiers.

Can't seem to find the full study through Sci-Hub but I was curious what combinations they used.

Edit: why were the combinations random?
 

Texon

Member
Joined
Nov 28, 2016
Messages
668
A very interesting study, which demonstrates the unique synergy between glucose and vitamin B3 in treating deficiencies of function in Complex I & II of the electron transport chain (ETC). Deficiencies on those metabolic steps are the most common causes for the wide varieties of debilitating symptoms (or even death) in people with "inborn" mitochondrial pathologies such as Leigh Syndrome, MERFF, MELAS, etc. The vast majority of those mitochondrial diseases are considered incurable, yet the study below demonstrates that a simple combination of glucose and vitamin B3 is highly effective in restoring mitochondrial function and normalizing a number of biomarkers indicative of mitochondrial dysfunction such as increase lactate/pyruvate ratio, increased NADH/NAD ratio, low ATP, and elevated GSH/GSSG ratio. The aforementioned combination also included N-acetyl-cysteine (NAC), but I don't think it is necessary for the beneficial effects to manifest, and in fact may be harmful considering that all mitochondrial diseases have increased GSH/GSSG ratios and NAC (being a reductant itself) will only further increase said ratio. Interestingly, the study did not test known mitochondrial therapeutic such as aspirin or methylene blue (or for that matter other quinones such as vitamin K, emodin, etc.). Neither did the study test the other vitamin B3 family member niacinamide/nicotinamide, however, they do explain that the rationale for using niacin was its role as a precursor to NAD+, which automatically means niacinamide/nicotinamide will likely have even stronger therapeutic effects. Finally, the study states that mitochondrial dysfunction is often the result of chronic conditions such as diabetes, heart disease, Parkinson, Alzheimer, etc. but I think the study got it backwards. It is those chronic conditions that are caused by mitochondrial dysfunction, so addressing the mitochondrial dysfunction would also likely result in reliable treatments for the myriads of chronic conditions we are constantly told are currently "incurable". I suppose such a statement would be too dangerous to see in the study itself, even for well-funded scientists working at the Children's Hospital of Philadelphia (CHOP) - an institution second probably only to the Mayo Clinic in terms of financial resources.

Combinatorial glucose, nicotinic acid, and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease
Researchers find effective combination of therapies for managing mitochondrial disease
"...Mitochondrial disease describes a collective group of energy deficiency disorders with no FDA-approved treatments or cures. Approximately 350 different gene disorders have been shown to substantially impair mitochondrial respiratory chain function, an essential process for making energy to power our cells. Respiratory chain function can also become severely disrupted by other genetic conditions, certain medications or environmental exposures, as well as common metabolic disorders, strokes, heart attacks, the aging process, and Alzheimer and Parkinson's diseases. In the absence of FDA-approved therapies, many affected patients seek out or are prescribed a wide variety of vitamins, supplements, and enzyme cofactors or "helper molecules" that generally fall into three different treatment classes: antioxidants, metabolic modifiers, and signaling modifiers. However, rigorous clinical trials have not been performed for these compounds to guide the medical community in understanding their comparative safety or benefit in mitochondrial disease patients. Additionally, prior to this study, it was unknown whether the best options were to give specific therapies alone or whether a combination of therapies are actually safe to administer and may work synergistically to provides patients with any direct health benefit. "We wanted to test unique combinatorial treatment regimens in preclinical models of mitochondrial disease to determine whether they showed any objective and measurable benefit to health, and to learn whether some combinations may be more effective than others," said senior study author Marni Falk, MD, Professor in the Division of Human Genetics as well as attending physician and Executive Director of the Mitochondrial Medicine Frontier Program CHOP. "This modeling approach would show us where physiology is most improved and take the guesswork out of developing treatment options for our patients." The study team, including Mitochondrial Medicine team members Sujay Guha, PhD and Neal D. Mathew, PhD, used two translational animal models of mitochondrial respiratory chain complex I disease - the most common biochemical site of dysfunction in mitochondrial disease - to evaluate 11 random combinations of drugs selected from each of the three treatment classes. Of those combinations, only one combination - glucose, nicotinic acid, and N-acetylcysteine - synergistically improved the lifespan of the first model beyond any individual component alone, as well as mitochondrial membrane potential, a quantitative measurement of how well mitochondria perform their essential energy-producing function. Importantly, this combination treatment yielded these survival and cellular physiology improvements without exacerbating any negative side effects, such as oxidative or mitochondrial stress. Validation studies performed in the second model, zebrafish, showed that glucose, nicotinic acid, and N-acetylcysteine combination therapy prevented stress-induced brain death - a sign that this therapy may prevent metabolic strokes such as those that occur with stress in Leigh syndrome and other mitochondrial disease syndromes - and rescued larval zebrafish animal swimming capacity as well as their tissue levels of ATP and glutathione."
Haidut I would dearly love to try this combo. However I have to deal with significant methylation and homocysteine issues. Plus the niacin tend to give me gouty sensations primarily in my feet and ankles. This is a real struggle for me and I have tried everything I can think of as a workaround. Do you think I could just throw in the towel and use allopurinol to keep uric acid lower (recently increased from 5.7 to 6.3) so I might get away with the nmd/glucose combo? Can I assume honey and/or regular table sugar would work as well? I have seen recently that the current thinking is that fructose is really the main trigger for gout.
 

Motorneuron

Member
Joined
Jan 29, 2021
Messages
444
What dosages of B3 are used? but doesn't it create problems with blood sugar?
 

Texon

Member
Joined
Nov 28, 2016
Messages
668
Haidut I would dearly love to try this combo. However I have to deal with significant methylation and homocysteine issues. Plus the niacin tend to give me gouty sensations primarily in my feet and ankles. This is a real struggle for me and I have tried everything I can think of as a workaround. Do you think I could just throw in the towel and use allopurinol to keep uric acid lower (recently increased from 5.7 to 6.3) so I might get away with the nmd/glucose combo? Can I assume honey and/or regular table sugar would work as well? I have seen recently that the current thinking is that fructose is really the main trigger for gout.
Bump
 

Candeias

Member
Joined
Apr 29, 2018
Messages
217
Haidut I would dearly love to try this combo. However I have to deal with significant methylation and homocysteine issues. Plus the niacin tend to give me gouty sensations primarily in my feet and ankles. This is a real struggle for me and I have tried everything I can think of as a workaround. Do you think I could just throw in the towel and use allopurinol to keep uric acid lower (recently increased from 5.7 to 6.3) so I might get away with the nmd/glucose combo? Can I assume honey and/or regular table sugar would work as well? I have seen recently that the current thinking is that fructose is really the main trigger for gout.

Did you try niacinamide?
 

Texon

Member
Joined
Nov 28, 2016
Messages
668
Did you try niacinamide?
I have recently started again somewhat out of desperation. 500-1,000 mgs/day balanced with the same amount of trimethylglycine because NMD jacks my homocysteine higher very quickly if I don't use the TMG. I also take a multi b vitamin with methylated b's except b12 is a mix of adenosyl and hydroxocobalamin instead of the methyl form of b12.
 

Candeias

Member
Joined
Apr 29, 2018
Messages
217
I have recently started again somewhat out of desperation. 500-1,000 mgs/day balanced with the same amount of trimethylglycine because NMD jacks my homocysteine higher very quickly if I don't use the TMG. I also take a multi b vitamin with methylated b's except b12 is a mix of adenosyl and hydroxocobalamin instead of the methyl form of b12.
Are you prone to having elevated homocysteine? I ask because I have been taking high doses of niacinamide to treat a recent problem, people here have reported taking a few grams without problems
 

Texon

Member
Joined
Nov 28, 2016
Messages
668
Are you prone to having elevated homocysteine? I ask because I have been taking high doses of niacinamide to treat a recent problem, people here have reported taking a few grams without problems
Yes I am due to a few sub optimal homozygous genetic factors that control HCY conversion to a non toxic molecule...methionine I think.
 

Dr. B

Member
Joined
Mar 16, 2021
Messages
4,316
I have recently started again somewhat out of desperation. 500-1,000 mgs/day balanced with the same amount of trimethylglycine because NMD jacks my homocysteine higher very quickly if I don't use the TMG. I also take a multi b vitamin with methylated b's except b12 is a mix of adenosyl and hydroxocobalamin instead of the methyl form of b12.
What is your diet like? Dont most people have more methylation than needed? And niacinamide can help that. I thought restricting methionine had similar benefits to fasting or something- so couldnt niacinamide help since it could deplete methyl groups
 

Texon

Member
Joined
Nov 28, 2016
Messages
668
What is your diet like? Dont most people have more methylation than needed? And niacinamide can help that. I thought restricting methionine had similar benefits to fasting or something- so couldnt niacinamide help since it could deplete methyl groups
Diet is fine. I just have certain genetic issues that need attention to methylation.
 

Similar threads

Back
Top Bottom