An important concept Dr. David Stephens came up with is the idea of glucose-limiting events. After acute events of increased glucose-requirement (cerebral hyperglycolysis following traumatic brain injury), the brain chronically and permanently lowers it's own glucose consumption, to prevent future damage. At the same time, the glucose consumption of the organs is also lowered, to prioritize the brain. It is some kind of hibernation mode that preserves the body in light of reduced resources. This results in a permanent glucose-limitation of the brain and organs, the amount of glucose reaching the brain and organs is thus lowered. Liver glycogen is also negatively affected, and adrenaline and cortisol increase to provide sufficient energy to the brain, while insulin sensitivity is often lowered (to channel the glucose into the brain instead of the organs).
According to Dr. Stephens, every little stress can act as a glucose-limiting event, not merely pronounced brain injuries and concussions. Many concussions also go completely unnoticed. Most people thus experience several glucose-limiting events every year, with a permanent reduction in brain function.
Chris Masterjohn and Alex Leaf have speculated that the 34% higher risk of diabetes associated with high-dose niacin therapy is due to eating carbohydrates during the free-fatty acid (FFA) rebound phase, which results in impaired glucose metabolism. They use a study by Wang et. al to make their point, where the rebound phase was measured after intake of 500mg niacin.
As we know from Ray Peat, a rise in FFA is always accompanied by a rise in serotonin, adrenaline and other stress hormones.
In the 2 hours following niacin intake, carbohydrate oxidation almost triples. This means niacin is an excellent tool to improve glucose oxidation in the context of taking dextrose. But what happens when the body does not have enough glucose available?
Alex Leaf speculates the FFA rebound indicates a "harder time using carbs for energy", but this is likely not the case. Chris Masterjohn echoes his sentiment.
In the study participants, niacin increased glycogenolysis, which means more glycogen is turned into glucose to fuel the cells and liver glucose stores are lowered. This means ingesting more glucose is essential when using niacin. From the study:
After 3-4 hours, it looks like glycogen stores in the liver are depleted and glycogenolysis is downregulated. The glycogenolysis peak is after 2 hours, so one can assume that the lack of sugar manifests itself most strongly after 2-3 hours, as glycogen levels fall and stress starts to increase.
And indeed, exactly at the point of glycogen utilization decreasing, 3 hours after niacin intake, a rebound phase is observed where large amounts of free fatty acids enter the blood.
I speculate the slight increase in diabetes risk with the use of niacin is not per se in the rebound of fatty acids, but in the depletion of available glucose (glycogen) from the liver. In light with the research and work by Dr. David Stephens, this would in some people lead to a pronounced glucose deficiency and would thus be a glucose-limiting event, downregulating the amount of glucose that can reach the brain. As an adaptive mechanism, insulin sensitivity is lowered. If this is true, simply taking large amounts of dextrose would be the solution to prevent any risks of niacin in relation to diabetes. The FFA rebound itself is not dangerous and it's ok to consume carbohydrates while in the rebound phase.
It's also likely that the increase in FFA (rebound phase) is actually a consequences of depleted glycogen stores in the first place, which results in a lowered carbohydrate oxidation. Comparing the control phase with the niacin phase supports this idea:
As the study shows, it is not that the oxidation of fatty acids increase during the rebound compared to control, but glucose oxidation decreases. As you can see, the carbohydrate oxidation in the 5-6 hour phase is also markedly lower in the control phase, suggesting that the participants hadn't eaten during the previous couple hours. So the reduction in carbohydrate oxidation is not as drastic as Chris Masterjohn and Alex Leaf make it appear, when comparing it to controls. But what can be seen here is that the study participants simply didn't eat the entire time, which increased the fat oxidation even in the control phase.
The control phase happened before the niacin phase in the same participants. The result of taking niacin without adequate glucose is that 5 hours after taking niacin, the glucose oxidation has been limited to less than half the previous amount.
The study merely shows the glycogen-depleting effects of niacin, since boosting carbohydrate oxidation is only good if you actually provide the glucose. Otherwise you deplete glucose and create a stress reaction. The rise in FFA is simply a consequence of this stress reaction due to lowered glycogen stores, resulting in an increase in adrenaline.
This stress reaction is a traumatic glucose-limiting event, and can permanently lower the glucose oxidation rate in the brain. In some people, this glucose-limitation then leads to diabetes. In other people, different symptoms develop.
I suggest that niacin can be risky without adequate glucose supply and should only be used together with adequate amounts of dextrose. It's possible that in some people the use of niacin during the 6-month dextrose therapy of Dr. Stephens can prevent recovery, since it's easy to accidentally underconsume dextrose.
Liver glycogen should never be reduced in the hours following the intake of niacin. The utilization of glycogen means the body is in a stress and survival mode. All the necessary glucose should come from the diet. The only way to achieve this is by taking some extra dextrose (at least 50g probably) with the niacin.
Conclusion
One in 43 people treated with high-dose niacin will develop diabetes within 5 years due to niacin intake. Leaf and Masterjohn speculate the impaired glucose metabolism happens due to the consumption of carbohydrates during the high FFA rebound phase.
Unfortunately, they get the causality wrong - it's not the suppression of FFA that boosts glucose oxidation and the increase in FFA that suppresses it. Instead, it is the glucose oxidation which lowers the free fatty acids. Depletion of blood sugar (within minutes of taking niacin) leads to glycogenolysis (breakdown of glycogen) in the liver and this creates a massive stress response (adrenaline) following empty liver stores. The rise in FFA is a symptom of this stress response.
Ingestion of additional dextrose every hour following niacin intake will likely prevent the rise in FFA.
Sources:
Chris Masterjohn Video
pubmed.ncbi.nlm.nih.gov
pubmed.ncbi.nlm.nih.gov
alexleaf.com
According to Dr. Stephens, every little stress can act as a glucose-limiting event, not merely pronounced brain injuries and concussions. Many concussions also go completely unnoticed. Most people thus experience several glucose-limiting events every year, with a permanent reduction in brain function.
Chris Masterjohn and Alex Leaf have speculated that the 34% higher risk of diabetes associated with high-dose niacin therapy is due to eating carbohydrates during the free-fatty acid (FFA) rebound phase, which results in impaired glucose metabolism. They use a study by Wang et. al to make their point, where the rebound phase was measured after intake of 500mg niacin.
As we know from Ray Peat, a rise in FFA is always accompanied by a rise in serotonin, adrenaline and other stress hormones.
In the 2 hours following niacin intake, carbohydrate oxidation almost triples. This means niacin is an excellent tool to improve glucose oxidation in the context of taking dextrose. But what happens when the body does not have enough glucose available?
Alex Leaf speculates the FFA rebound indicates a "harder time using carbs for energy", but this is likely not the case. Chris Masterjohn echoes his sentiment.
In the study participants, niacin increased glycogenolysis, which means more glycogen is turned into glucose to fuel the cells and liver glucose stores are lowered. This means ingesting more glucose is essential when using niacin. From the study:
After 3-4 hours, it looks like glycogen stores in the liver are depleted and glycogenolysis is downregulated. The glycogenolysis peak is after 2 hours, so one can assume that the lack of sugar manifests itself most strongly after 2-3 hours, as glycogen levels fall and stress starts to increase.
And indeed, exactly at the point of glycogen utilization decreasing, 3 hours after niacin intake, a rebound phase is observed where large amounts of free fatty acids enter the blood.
I speculate the slight increase in diabetes risk with the use of niacin is not per se in the rebound of fatty acids, but in the depletion of available glucose (glycogen) from the liver. In light with the research and work by Dr. David Stephens, this would in some people lead to a pronounced glucose deficiency and would thus be a glucose-limiting event, downregulating the amount of glucose that can reach the brain. As an adaptive mechanism, insulin sensitivity is lowered. If this is true, simply taking large amounts of dextrose would be the solution to prevent any risks of niacin in relation to diabetes. The FFA rebound itself is not dangerous and it's ok to consume carbohydrates while in the rebound phase.
It's also likely that the increase in FFA (rebound phase) is actually a consequences of depleted glycogen stores in the first place, which results in a lowered carbohydrate oxidation. Comparing the control phase with the niacin phase supports this idea:
As the study shows, it is not that the oxidation of fatty acids increase during the rebound compared to control, but glucose oxidation decreases. As you can see, the carbohydrate oxidation in the 5-6 hour phase is also markedly lower in the control phase, suggesting that the participants hadn't eaten during the previous couple hours. So the reduction in carbohydrate oxidation is not as drastic as Chris Masterjohn and Alex Leaf make it appear, when comparing it to controls. But what can be seen here is that the study participants simply didn't eat the entire time, which increased the fat oxidation even in the control phase.
The control phase happened before the niacin phase in the same participants. The result of taking niacin without adequate glucose is that 5 hours after taking niacin, the glucose oxidation has been limited to less than half the previous amount.
The study merely shows the glycogen-depleting effects of niacin, since boosting carbohydrate oxidation is only good if you actually provide the glucose. Otherwise you deplete glucose and create a stress reaction. The rise in FFA is simply a consequence of this stress reaction due to lowered glycogen stores, resulting in an increase in adrenaline.
This stress reaction is a traumatic glucose-limiting event, and can permanently lower the glucose oxidation rate in the brain. In some people, this glucose-limitation then leads to diabetes. In other people, different symptoms develop.
I suggest that niacin can be risky without adequate glucose supply and should only be used together with adequate amounts of dextrose. It's possible that in some people the use of niacin during the 6-month dextrose therapy of Dr. Stephens can prevent recovery, since it's easy to accidentally underconsume dextrose.
Liver glycogen should never be reduced in the hours following the intake of niacin. The utilization of glycogen means the body is in a stress and survival mode. All the necessary glucose should come from the diet. The only way to achieve this is by taking some extra dextrose (at least 50g probably) with the niacin.
Conclusion
One in 43 people treated with high-dose niacin will develop diabetes within 5 years due to niacin intake. Leaf and Masterjohn speculate the impaired glucose metabolism happens due to the consumption of carbohydrates during the high FFA rebound phase.
Unfortunately, they get the causality wrong - it's not the suppression of FFA that boosts glucose oxidation and the increase in FFA that suppresses it. Instead, it is the glucose oxidation which lowers the free fatty acids. Depletion of blood sugar (within minutes of taking niacin) leads to glycogenolysis (breakdown of glycogen) in the liver and this creates a massive stress response (adrenaline) following empty liver stores. The rise in FFA is a symptom of this stress response.
Ingestion of additional dextrose every hour following niacin intake will likely prevent the rise in FFA.
Sources:
Treatment of Brain Injuries and Mental Illness in Colorado Springs, CO | Peak Neuropsychology and Brain Rehabilitation
Dr. David Stephens provides Concussion Assessment, Couples Counseling, Concussion Rehabilitation, Depression Treatment, Anxiety Treatment, Grief Counseling, and Substance Abuse Counseling in Colorado Springs, CO.
www.peakneuropsych.com
Chris Masterjohn Video
Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women - PubMed
Chronic nicotinic acid (NA) ingestion effectively lowers lipid levels, but adverse effects on glucose metabolism have been reported. Our goal was to investigate acute and chronic effects of NA on lipolysis and glucose metabolism in women. Healthy normolipidemic volunteers (n = 5) were studied...
pubmed.ncbi.nlm.nih.gov
Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials - PubMed
Niacin therapy is associated with a moderately increased risk of developing diabetes regardless of background statin or combination laropiprant therapy.
pubmed.ncbi.nlm.nih.gov
Niacin, heart disease, liver toxicity, and diabetes - Alex Leaf, MS, CISSN
Niacin therapy is effective at reduce heart disease risk due to lowering LDL particle numbers and triglyceride levels, not due to increasing HDL. The risk of diabetes can be minimized by eating within 2 hours of taking niacin and avoiding digestible carbohydrates 3–6 hours after, unless another...
alexleaf.com
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