Amazoniac
Member
I shall keep going. Almost nothing intimidates anymore, only these.
- Nicotinamide overload may play a role in the development of type 2 diabetes
- [9] Nicotinamide: A double edged sword - ScienceDirect
The adaptations that take the places when the metabolism slows down, must reflect in slow processing and disposing unwanted stuff. Perhaps this is linked to having trouble handling caffeine. Xanthin oxidase requires similar nutrients as aldehyd oxidase, so riboflavin and molybdenum must be involved. It must stem from liver inflammation, which is odd since it's just ornamental. But if you have trouble with detoxification, it's possible that you are more prone to the adverse effects of niacin, especially as nicotinamide.
There are people blaming N-methylnicotinamide for the problems, but I don't know if that's correct. Copper seems to decrease the activity of Nicotinamide N-methyltransferase (the enzyme that methylates it) and manganese in excess increase it. However maybe the focus should be on improving the activity of aldehyd oxidase, which processes it further for excretion and prevents the accumulation of N-methylnicotinamide.
It's also possible that this is a protective mechanism, and not methylating it would be more damaging as suggested by the first quote from the second link. If that's the case, lowering it would be a nicht, nicht for sure. But I'm just making the thoughts out of the loud.
And what happens to tryptophan when niacin is in excess?
Check out what are the best food sources of niacin and their cholin content. Even though niacin supplementation in lower doses should not be a problem, it can be when the rest of the diet is poor.
- Nicotinamide overload may play a role in the development of type 2 diabetes
"The main findings of this study were that: (1) nicotinamide overload elevates plasma levels of N1-methylnicotinamide associated with oxidative stress and insulin resistance; (2) the skin plays an important role in expelling excess nicotinamide and detoxifying N1-methylnicotinamide; and (3) diabetic subjects have slow plasma N1-methylnicotinamide clearance. These findings may contribute to explain the mechanism of oxidative stress and insulin resistance in a variety of clinical conditions."
"Importantly, diabetic subjects exhibited significantly higher plasma N1-methylnicotinamide levels than non-diabetic subjects after nicotinamide loading, which suggests its involvement in the toxic effects of nicotinamide overload. Indeed, this study demonstrated that N1-methylnicotinamide mimicked the effect of nicotinamide overload, which suggested N1-methylnicotinamide mediation of the toxic effect."
"Consistent with previous research, this study found that N1-methylnicotinamide not only elevated plasma H2O2 levels in vivo, but also directly stimulated H2O2 generation of human erythrocytes in vitro at physiological concentrations, which indicates that N1-methylnicotinamide is a potent trigger of diabetic oxidative stress."
"Oxidative stress may induce NAD depletion, a marker of cell injury[34,35]. Indeed, this study found that N1-methylnicotinamide-induced high plasma H2O2 level was associated with a significant reduction in NAD content in the muscle and liver of rats. Then came the vital question: where did the excess systemic ROS originate? NADH-dependent ROS generation is an important source of intracellular ROS[34]. Accumulating evidence has indicated that diabetes shows a decreased cytosolic NAD+/NADH ratio in a variety of tissues[21]. Importantly, this study demonstrates that N1-methylnicotinamide decreases NAD/NADH ratio in rat erythrocytes in vivo and human erythrocytes in vitro. Thus, it is likely that diabetic oxidative stress is initiated by high plasma N1-methylnicotinamide-induced imbalance in the NAD+/NADH redox couple. Many cellular processes are governed by the enzymes using NAD+/NADH as a cofactor[6,21,34], therefore, it is not difficult to understand why a set of metabolic abnormalities happen in type 2 diabetes."
"Mammalian AOX is a molybdo-flavo enzyme involved in the detoxification of various endogenous and exogenous N-heterocyclic compounds[22,23]. N1-methylnicotinamide is one of the substrates of AOX by which N1-methylnicotinamide is oxidized to pyridones[7], and thus, detoxified. AOX is expressed predominantly in the liver. Therefore, severe liver disease might be expected to reduce plasma N1-methylnicotinamide clearance and subsequent insulin resistance. In fact, it is well known that liver cirrhosis is associated with high incidence of diabetes[36,37]. Pumpo et al[38] have found that cirrhotic patients have high serum N1-methylnicotinamide levels, both in basal values and after nicotinamide loading."
"Tamoxifen, a well-known inducer of non-alcoholic steatohepatitis[24], is found to inhibit strongly AOX activity[23] and its expression (Figure (Figure5C).5C). Collectively, it seems that the decrease in N1-methylnicotinamide detoxification may be involved in hepatogenic insulin resistance."
"AOX is also expressed in the skin[26], which suggests skin involvement in N1-methylnicotinamide detoxification. Moreover, as found in this study, human sweat glands can excrete excess nicotinamide. Therefore, decreased skin function may be implicated in N1-methylnicotinamide-induced insulin resistance. In fact, severe burns may induce long-lasting insulin resistance, a well-documented but poorly understood phenomenon[31,39]. The present study demonstrated that severe burns significantly delayed N1-methylnicotinamide clearance, which suggests that long-lasting post-burn insulin resistance may involve a decrease in nicotinamide detoxification and excretion."
"Sweat gland activity fluctuates according to ambient temperature; the most significant feature of the gland. Therefore, sweat gland inactivity is expected to slow nicotinamide catabolism and thereby increase the danger of developing insulin resistance."
?
"Importantly, diabetic subjects exhibited significantly higher plasma N1-methylnicotinamide levels than non-diabetic subjects after nicotinamide loading, which suggests its involvement in the toxic effects of nicotinamide overload. Indeed, this study demonstrated that N1-methylnicotinamide mimicked the effect of nicotinamide overload, which suggested N1-methylnicotinamide mediation of the toxic effect."
"Consistent with previous research, this study found that N1-methylnicotinamide not only elevated plasma H2O2 levels in vivo, but also directly stimulated H2O2 generation of human erythrocytes in vitro at physiological concentrations, which indicates that N1-methylnicotinamide is a potent trigger of diabetic oxidative stress."
"Oxidative stress may induce NAD depletion, a marker of cell injury[34,35]. Indeed, this study found that N1-methylnicotinamide-induced high plasma H2O2 level was associated with a significant reduction in NAD content in the muscle and liver of rats. Then came the vital question: where did the excess systemic ROS originate? NADH-dependent ROS generation is an important source of intracellular ROS[34]. Accumulating evidence has indicated that diabetes shows a decreased cytosolic NAD+/NADH ratio in a variety of tissues[21]. Importantly, this study demonstrates that N1-methylnicotinamide decreases NAD/NADH ratio in rat erythrocytes in vivo and human erythrocytes in vitro. Thus, it is likely that diabetic oxidative stress is initiated by high plasma N1-methylnicotinamide-induced imbalance in the NAD+/NADH redox couple. Many cellular processes are governed by the enzymes using NAD+/NADH as a cofactor[6,21,34], therefore, it is not difficult to understand why a set of metabolic abnormalities happen in type 2 diabetes."
"Mammalian AOX is a molybdo-flavo enzyme involved in the detoxification of various endogenous and exogenous N-heterocyclic compounds[22,23]. N1-methylnicotinamide is one of the substrates of AOX by which N1-methylnicotinamide is oxidized to pyridones[7], and thus, detoxified. AOX is expressed predominantly in the liver. Therefore, severe liver disease might be expected to reduce plasma N1-methylnicotinamide clearance and subsequent insulin resistance. In fact, it is well known that liver cirrhosis is associated with high incidence of diabetes[36,37]. Pumpo et al[38] have found that cirrhotic patients have high serum N1-methylnicotinamide levels, both in basal values and after nicotinamide loading."
"Tamoxifen, a well-known inducer of non-alcoholic steatohepatitis[24], is found to inhibit strongly AOX activity[23] and its expression (Figure (Figure5C).5C). Collectively, it seems that the decrease in N1-methylnicotinamide detoxification may be involved in hepatogenic insulin resistance."
"AOX is also expressed in the skin[26], which suggests skin involvement in N1-methylnicotinamide detoxification. Moreover, as found in this study, human sweat glands can excrete excess nicotinamide. Therefore, decreased skin function may be implicated in N1-methylnicotinamide-induced insulin resistance. In fact, severe burns may induce long-lasting insulin resistance, a well-documented but poorly understood phenomenon[31,39]. The present study demonstrated that severe burns significantly delayed N1-methylnicotinamide clearance, which suggests that long-lasting post-burn insulin resistance may involve a decrease in nicotinamide detoxification and excretion."
"Sweat gland activity fluctuates according to ambient temperature; the most significant feature of the gland. Therefore, sweat gland inactivity is expected to slow nicotinamide catabolism and thereby increase the danger of developing insulin resistance."
?
- [9] Nicotinamide: A double edged sword - ScienceDirect
"[..]catabolism is predominately N-methylation to N-methyl nicotinamide catalyzed by the enzyme Nicotinamide N-methyl transferase (NNMT) [11]. This enzyme barely exists in herbivores suggesting that it has been developed by evolution to deal with the higher nicotinamide intake of carnivores and omnivores [12]."
"Around 1980 a mini-epidemic that involved a different pyridine, MPTP, occurred again in extreme circumstances [13,14]. Drug addicts took the compound parentrally and gave themselves acute Parkinsonism. Both in patients and in subsequent animal models there are striking similarities with idiopathic Parkinson’s and only arguable differences many of which may be explained by the acuteness of the situation in the drug addicts and animal model and the chronic nature of the condition in idiopathic Parkinson’s. There is no other known source of MPTP. However, under experimental conditions, it can be produced from 4-phenylpyridine known to be present in diet and to form MPPC directly using the same enzyme that is involved with Nicotinamide catabolism, NNMT [15] (Fig. 1). S-adenosyl methionine (SAM) is the methyl donor. This reaction can produce a range of N-methyl pyridines and also N-methylated beta-carbolines and isoquinolines that are potential or proven dopaminergic toxins [16,17]. So there are some plausible protoxins present in diet and more than one may well be involved."
"Once charged with the N-methyl group, no toxin [on its way out] can cross the blood/brain barrier, so the toxication step has to take place in the brain. The enzyme NNMT has recently been shown to be present in the brain of humans [26] and rats [27]. The enzyme’s activity, protein and RNA levels are increased in the brain of patients with PD [26,28]."
"N-methyl nicotinamide has useful functions, for instance, in inhibiting the export of choline [34] and may confer an early biologic advantage to high methylators [35] and their developing brain, perhaps affecting personality type and cognition and put them on a different trajectory for Alzheimer’s Disease. However, choline may further boost methylation in dopaminergic neurones, as it is a methyl donor, and increased acetylcholine would not help pharmacologically in the parkinsonian brain. N-methyl nicotinamide is toxic under certain experimental conditions using the same mechanisms as MPPC but having between 1/5th and 1/50th of the toxicity [27,36]."
"The dose of the protoxin MPTP required to cause acute Parkinsonism is approximately 500 mg to 2 g in more chronic year long experiments. The average nicotinamide intake in Western populations is around 35 mg a day. The recommended daily allowance is around 15 mg a day. About 20 mg a day, if an overdose equates to 350 g over 50 years. Even at 1/50th of the toxicity and accepting that very chronic exposure would be safer, that is a lot of MPPC equivalents that we now know will reach neurones."
"[..]alcoholics who are likely to be nicotinamide deficient tend not to get PD [46]."
"High N-methylator status, largely on a genetic basis, is present in 25% of the population and may be over represented in the PD population. One would predict that high N-methylator status could have been a risk factor for Pellagra as well as it would drive nicotinamide levels down at the same time as increasing N-methylated derivatives. High methylation may alter the dynamics of cognition and perhaps personality toward that seen with PD patients who stereotypically are industrious and puritanical premorbidly rather than risk takers. Nicotinamide and stress induce (as do presumably other substrates) the enzyme NNMT creating a more indirect way to toxicity by accelerating the conversion of all protoxins into toxins (Fig. 1). Excess methylation in one pathway might reduce available SAM for other methylation reactions such as that of dopamine (and vice versa when there is exogenous levodopa) and DNA giving links to behavior, mood and carcinogenesis. Nicotine and probably caffeine are substrates for NNMT [11] and are protective factors for Parkinson’s [46]. Nicotine may act as a competitive inhibitor of NNMT boosting intraneuronal nicotinamide thereby protecting against dopaminergic neurodegeneration. Two substrates caffeine and nicotine that are addictive and link with limbic reward mechanisms and dopamine metabolism would be quite a coincidence especially as several drugs of addiction such as cocaine, heroin, meperidine and amphetamine derivatives like ecstasy are N-methyl compounds and therefore may affect this pathway so it will be important to understand the role of NNMT/nicotinamide in this context. One could speculate that evolution has developed a drive mechanism for more nicotinamide to aid brain and physical development and that long latency toxicity is just an accident of nature."
"More careful scrutiny of diet in future case control studies need to be aware of a possible ‘U’ shape curve [tut] with toxicity of nicotinamide in the middle to high range but perhaps leveling off or becoming protective at higher dosages. These should be combined with assessments of other vitamins that affect nicotinamide levels, such as pyridoxine, riboflavin, thiamin, and other compounds that influence the amount of methyl donor SAM, such as methionine and choline intake, B12 and folate, studied if possible in combination with assessing nicotinamide/tryptophan and methylator status biochemically, and factoring in the effects of inhibitors such as nicotine, caffeine and other methylxanthines such as theobromine (in chocolate)."
"Around 1980 a mini-epidemic that involved a different pyridine, MPTP, occurred again in extreme circumstances [13,14]. Drug addicts took the compound parentrally and gave themselves acute Parkinsonism. Both in patients and in subsequent animal models there are striking similarities with idiopathic Parkinson’s and only arguable differences many of which may be explained by the acuteness of the situation in the drug addicts and animal model and the chronic nature of the condition in idiopathic Parkinson’s. There is no other known source of MPTP. However, under experimental conditions, it can be produced from 4-phenylpyridine known to be present in diet and to form MPPC directly using the same enzyme that is involved with Nicotinamide catabolism, NNMT [15] (Fig. 1). S-adenosyl methionine (SAM) is the methyl donor. This reaction can produce a range of N-methyl pyridines and also N-methylated beta-carbolines and isoquinolines that are potential or proven dopaminergic toxins [16,17]. So there are some plausible protoxins present in diet and more than one may well be involved."
"Once charged with the N-methyl group, no toxin [on its way out] can cross the blood/brain barrier, so the toxication step has to take place in the brain. The enzyme NNMT has recently been shown to be present in the brain of humans [26] and rats [27]. The enzyme’s activity, protein and RNA levels are increased in the brain of patients with PD [26,28]."
"N-methyl nicotinamide has useful functions, for instance, in inhibiting the export of choline [34] and may confer an early biologic advantage to high methylators [35] and their developing brain, perhaps affecting personality type and cognition and put them on a different trajectory for Alzheimer’s Disease. However, choline may further boost methylation in dopaminergic neurones, as it is a methyl donor, and increased acetylcholine would not help pharmacologically in the parkinsonian brain. N-methyl nicotinamide is toxic under certain experimental conditions using the same mechanisms as MPPC but having between 1/5th and 1/50th of the toxicity [27,36]."
"The dose of the protoxin MPTP required to cause acute Parkinsonism is approximately 500 mg to 2 g in more chronic year long experiments. The average nicotinamide intake in Western populations is around 35 mg a day. The recommended daily allowance is around 15 mg a day. About 20 mg a day, if an overdose equates to 350 g over 50 years. Even at 1/50th of the toxicity and accepting that very chronic exposure would be safer, that is a lot of MPPC equivalents that we now know will reach neurones."
"[..]alcoholics who are likely to be nicotinamide deficient tend not to get PD [46]."
"High N-methylator status, largely on a genetic basis, is present in 25% of the population and may be over represented in the PD population. One would predict that high N-methylator status could have been a risk factor for Pellagra as well as it would drive nicotinamide levels down at the same time as increasing N-methylated derivatives. High methylation may alter the dynamics of cognition and perhaps personality toward that seen with PD patients who stereotypically are industrious and puritanical premorbidly rather than risk takers. Nicotinamide and stress induce (as do presumably other substrates) the enzyme NNMT creating a more indirect way to toxicity by accelerating the conversion of all protoxins into toxins (Fig. 1). Excess methylation in one pathway might reduce available SAM for other methylation reactions such as that of dopamine (and vice versa when there is exogenous levodopa) and DNA giving links to behavior, mood and carcinogenesis. Nicotine and probably caffeine are substrates for NNMT [11] and are protective factors for Parkinson’s [46]. Nicotine may act as a competitive inhibitor of NNMT boosting intraneuronal nicotinamide thereby protecting against dopaminergic neurodegeneration. Two substrates caffeine and nicotine that are addictive and link with limbic reward mechanisms and dopamine metabolism would be quite a coincidence especially as several drugs of addiction such as cocaine, heroin, meperidine and amphetamine derivatives like ecstasy are N-methyl compounds and therefore may affect this pathway so it will be important to understand the role of NNMT/nicotinamide in this context. One could speculate that evolution has developed a drive mechanism for more nicotinamide to aid brain and physical development and that long latency toxicity is just an accident of nature."
"More careful scrutiny of diet in future case control studies need to be aware of a possible ‘U’ shape curve [tut] with toxicity of nicotinamide in the middle to high range but perhaps leveling off or becoming protective at higher dosages. These should be combined with assessments of other vitamins that affect nicotinamide levels, such as pyridoxine, riboflavin, thiamin, and other compounds that influence the amount of methyl donor SAM, such as methionine and choline intake, B12 and folate, studied if possible in combination with assessing nicotinamide/tryptophan and methylator status biochemically, and factoring in the effects of inhibitors such as nicotine, caffeine and other methylxanthines such as theobromine (in chocolate)."
The adaptations that take the places when the metabolism slows down, must reflect in slow processing and disposing unwanted stuff. Perhaps this is linked to having trouble handling caffeine. Xanthin oxidase requires similar nutrients as aldehyd oxidase, so riboflavin and molybdenum must be involved. It must stem from liver inflammation, which is odd since it's just ornamental. But if you have trouble with detoxification, it's possible that you are more prone to the adverse effects of niacin, especially as nicotinamide.
There are people blaming N-methylnicotinamide for the problems, but I don't know if that's correct. Copper seems to decrease the activity of Nicotinamide N-methyltransferase (the enzyme that methylates it) and manganese in excess increase it. However maybe the focus should be on improving the activity of aldehyd oxidase, which processes it further for excretion and prevents the accumulation of N-methylnicotinamide.
It's also possible that this is a protective mechanism, and not methylating it would be more damaging as suggested by the first quote from the second link. If that's the case, lowering it would be a nicht, nicht for sure. But I'm just making the thoughts out of the loud.
And what happens to tryptophan when niacin is in excess?
Check out what are the best food sources of niacin and their cholin content. Even though niacin supplementation in lower doses should not be a problem, it can be when the rest of the diet is poor.