Lactate is a key driver of diabetes/obesity, by promoting inflammation

[haidut]

A great study, demonstrating that in diabetes (just as in cancer) the so-called Warburg Effect (aerobic glycolysis) is as much a cause of those degenerative conditions as it is an effect of. The study below demonstrated that increased intracellular lactate results in robust increase in systemic release of inflammatory cytokines, resulting in aggravation of systemic insulin resistance. In other words, metabolic effects considered peripheral and unrelated to the core disease (e.g. diabetes type II) are, in fact, major driving factors of that core disease. The study may also explain why not all obese people develop diabetes type II and why some lean people have severe insulin resistance. And, yes, metabolic rate is once again the likely distinguishing factor. Intracellular lactate accumulation, barring cofactor (thiamine, vitamin B2/B3, biotin, etc) deficiencies and/or presence of cancer, is a reliable sign (and also a cause) of low metabolic rate (RMR). Thus, an obese person with higher RMR (per kg of bodyweight) is likely to fare better and be healthier than a leaner person with lower RMR (per kg of bodyweight). On a bit of side note, this discrepancy of RMR (often in favor of the obese/overweight) is the likely explanation of the so-called "Obesity Paradox". In corroboration, up to 60% of hospitalized patients (with any condition) who eventually succumb while in the hospital have lactic acidosis at the time of hospital admission. So, it looks like lactate is no joke and a major factor in both acute (yes, it is involved in COVID-19 mortality as well) and chronic pathologies alike. As such, reducing lipolysis (to limit lactate synthesis due to Randle cycle) and providing a bit extra of the important enzymatic cofactors listed above can go a long way in preventing the chronic, low-grade hyperlactaemia which can apparently wreak havoc on the organism if left unchecked. The more I learn about it, the more lactate starts to sounds like the more evil twin of the already evil endotoxin (LPS). Namely, since endotoxemia in blood is a widely recognized factor in sepsis doctors will check for it and try to address it, while high intracellular lactate is very hard to diagnose (short of a biopsy, which is usually only done for cancers) and will likely go unaddressed as it won't be suspected as a cause of the increased blood levels of the inflammatory cytokines.

Now, while the study does not say it, I'd also venture a guess that lactate is also a promoter/driver of the obesity often seen in type II diabetics. If lactate is a robust promoter of inflammation, as a consequence cortisol would also be elevated (and indeed it is, when measured in such patients). Cortisol is a confirmed obesogen, and the increase in fatty tissue it causes will also result in synthesizing more estrogen (another obesogen). So, the humble lactate that really does not get on anybody's (medical) radar may turn out to be one of the most fundamental driver's of chronic conditions related to inflammation...which is basically all of them. PUFA called and wants its "evil mastermind" title back

Lactate is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue

"...Numerous evidences indicate that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, what triggers obesity-induced inflammation is poorly understood. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of pro-inflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of pro-inflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this deadly link."

 

[L_C]

A great study, demonstrating that in diabetes (just as in cancer) the so-called Warburg Effect (aerobic glycolysis) is as much a cause of those degenerative conditions as it is an effect of. The study below demonstrated that increased intracellular lactate results in robust increase in systemic release of inflammatory cytokines, resulting in aggravation of systemic insulin resistance. In other words, metabolic effects considered peripheral and unrelated to the core disease (e.g. diabetes type II) are, in fact, major driving factors of that core disease. The study may also explain why not all obese people develop diabetes type II and why some lean people have severe insulin resistance. And, yes, metabolic rate is once again the likely distinguishing factor. Intracellular lactate accumulation, barring cofactor (thiamine, vitamin B2/B3, biotin, etc) deficiencies and/or presence of cancer, is a reliable sign (and also a cause) of low metabolic rate (RMR). Thus, an obese person with higher RMR (per kg of bodyweight) is likely to fare better and be healthier than a leaner person with lower RMR (per kg of bodyweight). On a bit of side note, this discrepancy of RMR (often in favor of the obese/overweight) is the likely explanation of the so-called "Obesity Paradox". In corroboration, up to 60% of hospitalized patients (with any condition) who eventually succumb while in the hospital have lactic acidosis at the time of hospital admission. So, it looks like lactate is no joke and a major factor in both acute (yes, it is involved in COVID-19 mortality as well) and chronic pathologies alike. As such, reducing lipolysis (to limit lactate synthesis due to Randle cycle) and providing a bit extra of the important enzymatic cofactors listed above can go a long way in preventing the chronic, low-grade hyperlactaemia which can apparently wreak havoc on the organism if left unchecked. The more I learn about it, the more lactate starts to sounds like the more evil twin of the already evil endotoxin (LPS). Namely, since endotoxemia in blood is a widely recognized factor in sepsis doctors will check for it and try to address it, while high intracellular lactate is very hard to diagnose (short of a biopsy, which is usually only done for cancers) and will likely go unaddressed as it won't be suspected as a cause of the increased blood levels of the inflammatory cytokines.

Now, while the study does not say it, I'd also venture a guess that lactate is also a promoter/driver of the obesity often seen in type II diabetics. If lactate is a robust promoter of inflammation, as a consequence cortisol would also be elevated (and indeed it is, when measured in such patients). Cortisol is a confirmed obesogen, and the increase in fatty tissue it causes will also result in synthesizing more estrogen (another obesogen). So, the humble lactate that really does not get on anybody's (medical) radar may turn out to be one of the most fundamental driver's of chronic conditions related to inflammation...which is basically all of them. PUFA called and wants its "evil mastermind" title back

Lactate is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue

"...Numerous evidences indicate that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, what triggers obesity-induced inflammation is poorly understood. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of pro-inflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of pro-inflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this deadly link."

You are speaking my issues. How can one lower the levels of elevated pro-inflammatory cytokines other than avoiding lactate?

 

[haidut]

You are speaking my issues. How can one lower the levels of elevated pro-inflammatory cytokines other than avoiding lactate?

Avoiding PUFA as much as possible certainly helps. Methylene blue, progesterone, pregnenolone, vitamin D/K also have direct effects on the cytokines but as long as the reductive state remains (high lactate) the issue will probably not be fixed for good.

Methylene Blue Is A Potent Anti-inflammatory, With Possibly The Broadest Spectrum

Some bold statements in this study, which combined both in vitro and in vivo models. The HED for methylene blue (MB) was just 0.15mg/kg, which is in the range of 10mg-15mg doses that showed great effectiveness in treating mental disorders like depression and psychosis. As you can see from the...

raypeatforum.com

 

[Matestube]

A great study, demonstrating that in diabetes (just as in cancer) the so-called Warburg Effect (aerobic glycolysis) is as much a cause of those degenerative conditions as it is an effect of. The study below demonstrated that increased intracellular lactate results in robust increase in systemic release of inflammatory cytokines, resulting in aggravation of systemic insulin resistance. In other words, metabolic effects considered peripheral and unrelated to the core disease (e.g. diabetes type II) are, in fact, major driving factors of that core disease. The study may also explain why not all obese people develop diabetes type II and why some lean people have severe insulin resistance. And, yes, metabolic rate is once again the likely distinguishing factor. Intracellular lactate accumulation, barring cofactor (thiamine, vitamin B2/B3, biotin, etc) deficiencies and/or presence of cancer, is a reliable sign (and also a cause) of low metabolic rate (RMR). Thus, an obese person with higher RMR (per kg of bodyweight) is likely to fare better and be healthier than a leaner person with lower RMR (per kg of bodyweight). On a bit of side note, this discrepancy of RMR (often in favor of the obese/overweight) is the likely explanation of the so-called "Obesity Paradox". In corroboration, up to 60% of hospitalized patients (with any condition) who eventually succumb while in the hospital have lactic acidosis at the time of hospital admission. So, it looks like lactate is no joke and a major factor in both acute (yes, it is involved in COVID-19 mortality as well) and chronic pathologies alike. As such, reducing lipolysis (to limit lactate synthesis due to Randle cycle) and providing a bit extra of the important enzymatic cofactors listed above can go a long way in preventing the chronic, low-grade hyperlactaemia which can apparently wreak havoc on the organism if left unchecked. The more I learn about it, the more lactate starts to sounds like the more evil twin of the already evil endotoxin (LPS). Namely, since endotoxemia in blood is a widely recognized factor in sepsis doctors will check for it and try to address it, while high intracellular lactate is very hard to diagnose (short of a biopsy, which is usually only done for cancers) and will likely go unaddressed as it won't be suspected as a cause of the increased blood levels of the inflammatory cytokines.

Now, while the study does not say it, I'd also venture a guess that lactate is also a promoter/driver of the obesity often seen in type II diabetics. If lactate is a robust promoter of inflammation, as a consequence cortisol would also be elevated (and indeed it is, when measured in such patients). Cortisol is a confirmed obesogen, and the increase in fatty tissue it causes will also result in synthesizing more estrogen (another obesogen). So, the humble lactate that really does not get on anybody's (medical) radar may turn out to be one of the most fundamental driver's of chronic conditions related to inflammation...which is basically all of them. PUFA called and wants its "evil mastermind" title back

Lactate is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue

"...Numerous evidences indicate that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, what triggers obesity-induced inflammation is poorly understood. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of pro-inflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of pro-inflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this deadly link."

There's is somewhat of a paradox in my bloodwork results:
C reactive protein is incredibly low, but my lactate is above the top of the range.

Which one is the true marker for inflammation?

 

[haidut]

There's is somewhat of a paradox in my bloodwork results:
C reactive protein is incredibly low, but my lactate is above the top of the range.

Which one is the true marker for inflammation?

The study is about lactate inside the cell, not in the blood. The former is probably not being measured on blood tests.

 

[freyasam]

Avoiding PUFA as much as possible certainly helps. Methylene blue, progesterone, pregnenolone, vitamin D/K also have direct effects on the cytokines but as long as the reductive state remains (high lactate) the issue will probably not be fixed for good.

If someone has been avoiding pufa for 8 years, should lactate be low? I think lactic acid is an issue for me, and probably lactate.

I have fairly severe ME/CFS (chronic fatigue syndrome) and obesity. This is despite avoiding pufa for 8 years, following Ray's nutritional guidelines including a daily half gallon of milk, OJ, fruit, shellfish, liver, carrot salad, and lately no starch, and taking aspirin, vit D/K, Progest-e & half a pill each of cynomel and cynoplus.

If you had any direction to point me in I would be most grateful! Female, early 40s.

 

[InChristAlone]

Elevated lactate is indicative of thiamine deficiency. Thiamine deficiency can produce lactic acidosis.

This is from the book "Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition"
"From a molecular perspective, hyperglycemia has long been recognized for its role in the glycolytic switch integral to the cancer phenotype. 67 Hyperglycemia deranges mitochondrial morphology, increases ROS production, and promotes mitochondrial DNA mutations. 71 In an effort to compensate and reduce the damage, mitochondrial respiration is reduced (the hypoxic cascades initiated) and mitochondrial dynamics are adjusted (fission/fusion). Concomitantly, we get increased production of lactate, which feeds anaerobic respiration and tumorigenesis, 70 but we also have a notable increase in aerobic glycolysis, suggesting an adaptation to states of both normoxia and hypoxia. 66 All of this occurs in the presence of a microenvironment where hyperglycemia is forced upon the cells and must cause an adaptive response. Tumorigenesis appears to be the mechanism of choice, where the excess sugars can be sequestered and metabolized independently of mitochondrial and normal cellular function."

"Returning to the role of thiamine in mitochondrial oxidative function, it has not yet become clear how cancer cells regulate cellular homeostasis of cofactors adaptively. Putatively, however, we know that thiamine must be involved given its requirement in both cytosolic and mitochondrial glucose metabolism. We also know that thiamine deficiency is common in cancer, as are alterations in thiamine transporter functioning. 73 One review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells. 74 It appears that thiamine supplementation follows an unexpected dose–response curve. Low and moderate doses of thiamine increase tumor activity, whereas supraphysiological doses inhibit or reverse tumor growth. 74 Dr. Lonsdale has long observed that when thiamine deficiency is chronic and/or severe, high doses of the vitamin are required to reengage enzyme activity. Whether this is the case here or not remains to be investigated, but it does present an intriguing possibility and a novel opportunity for treatment."

 

[frannybananny]

You are speaking my issues. How can one lower the levels of elevated pro-inflammatory cytokines other than avoiding lactate?

How do you avoid lactate? Is it related to the lactose in milk? This article was very confusing to me.

 

[Matestube]

Elevated lactate is indicative of thiamine deficiency. Thiamine deficiency can produce lactic acidosis.

This is from the book "Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition"
"From a molecular perspective, hyperglycemia has long been recognized for its role in the glycolytic switch integral to the cancer phenotype. 67 Hyperglycemia deranges mitochondrial morphology, increases ROS production, and promotes mitochondrial DNA mutations. 71 In an effort to compensate and reduce the damage, mitochondrial respiration is reduced (the hypoxic cascades initiated) and mitochondrial dynamics are adjusted (fission/fusion). Concomitantly, we get increased production of lactate, which feeds anaerobic respiration and tumorigenesis, 70 but we also have a notable increase in aerobic glycolysis, suggesting an adaptation to states of both normoxia and hypoxia. 66 All of this occurs in the presence of a microenvironment where hyperglycemia is forced upon the cells and must cause an adaptive response. Tumorigenesis appears to be the mechanism of choice, where the excess sugars can be sequestered and metabolized independently of mitochondrial and normal cellular function."

"Returning to the role of thiamine in mitochondrial oxidative function, it has not yet become clear how cancer cells regulate cellular homeostasis of cofactors adaptively. Putatively, however, we know that thiamine must be involved given its requirement in both cytosolic and mitochondrial glucose metabolism. We also know that thiamine deficiency is common in cancer, as are alterations in thiamine transporter functioning. 73 One review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells. 74 It appears that thiamine supplementation follows an unexpected dose–response curve. Low and moderate doses of thiamine increase tumor activity, whereas supraphysiological doses inhibit or reverse tumor growth. 74 Dr. Lonsdale has long observed that when thiamine deficiency is chronic and/or severe, high doses of the vitamin are required to reengage enzyme activity. Whether this is the case here or not remains to be investigated, but it does present an intriguing possibility and a novel opportunity for treatment."

Even after being on Thorne basic B twice a day for months I still have tons of lactic acid.

 

[InChristAlone]

Even after being on Thorne basic B twice a day for months I still have tons of lactic acid.

Some people don't utilize thiamine hcl if they have been sick for decades. Sometimes it can take injections. And for some it can take using the allithiamine or benfothiamine.

 

[tankasnowgod]

Even after being on Thorne basic B twice a day for months I still have tons of lactic acid.

I think Baking Soda supplementation has been shown to lower/neutralize lactic acid. It's the bicarbonate part that really does this, so things like magnesium bicarbonate or high bicarb mineral water like Gerolstiner might also work-

Baking soda may treat cancer, metformin may cause it – To Extract Knowledge from Matter

So, if baking soda is therapeutic for cancer then what is the protocol. The study used an oral administration of a human equivalent dosage (HED) of about 250mg/kg daily for a period of 8 weeks. This means that an oral dose of about 20g daily should be enough for most people. The reason I mention the 20g dosage is that it also happens to be the most widely used dosing regimen for enhancing performance among athletes. The performance-enhancing effect is achieved through the same mechanism with which baking soda is therapeutic for cancer – i.e. neutralizing lactic acid (lactic acid promotes muscle fatigue), and increasing CO2 (which improves tissue oxygenation and further depresses lactic acid synthesis).

I know Altitude and Altitude tents have both been shown to increase clearance of lactic acid and/or lactate as well. All of the strategies that increase CO2 may have some potential in this regard, so there are lots of possible things to try, if thiamine in various doses (have you tried a higher dose?) doesn't work, or doesn't appear to be enough on it's own.

 

[Matestube]

I think Baking Soda supplementation has been shown to lower/neutralize lactic acid. It's the bicarbonate part that really does this, so things like magnesium bicarbonate or high bicarb mineral water like Gerolstiner might also work-

Baking soda may treat cancer, metformin may cause it – To Extract Knowledge from Matter

I know Altitude and Altitude tents have both been shown to increase clearance of lactic acid and/or lactate as well. All of the strategies that increase CO2 may have some potential in this regard, so there are lots of possible things to try, if thiamine in various doses (have you tried a higher dose?) doesn't work, or doesn't appear to be enough on it's own.

I'm back to drinking lots of black coffee during the day after quiting completely for 5 years.
Maybe my liver had become sluggish after all this years without coffee and now it will process lactic acid better.

 

[L_C]

How do you avoid lactate? Is it related to the lactose in milk? This article was very confusing to me.

Lactate is basically lactic acid which reduces levels of CO2 in a body and elevates nitric oxide. Even some of the probiotics produce lactic acid.
I'm basically avoiding all the dairy and I avoid everything that says cultured. I don't eat anything fermented either.

 

[DrJ]

I think NAD+ IV infusions might help to reduce lactic acid if nutrition has not been successful by increasing the NAD+ to NADH ratio to steer away from glycolysis and towards oxidative phosphorylation.

 

[Motorneuron]

I think NAD+ IV infusions might help to reduce lactic acid if nutrition has not been successful by increasing the NAD+ to NADH ratio to steer away from glycolysis and towards oxidative phosphorylation.

I agree, this could initially also be achieved with Pyrucet as Pyruvate should partially inhibit glycolysis and promote beta oxidation.

So if you are going to use thiamine HCL in high doses consider that if you take 600mg for example you do not really know how many mg you are absorbing ... that's why in the early stages of recovery the injections may work better and with lower dosages than oral ones.

Remember that you could suffer the refeeding syndrome if the gene / enzyme was dormant for years or otherwise not working for unknown causes ... so support all the pathways with minerals and vitamins otherwise you will create bottlenecks around ... especially on methylation.

In summary: B1 / Pyrucet / Magnesium / Alpha Lipoic Acid / B2 / Calcium / NAD + (all essential cofactors of pyruvate dehydrogenase).

Carbonates for lactic acidosis crises.

I found this...

The Benefits of Lactate - This is Not a Waste Product! — MyBioHack | Unlock Your Genetics

During the 80's, LA was believed to be only a deadend waste product from anaerobic exercise. The idea that lactate is a waste product of the metabolism and a main cause of fatigue, should no longer be considered as an indisputable truth. This molecule, instead, can be shuttled among cells and, ins

mybiohack.com

 

[Motorneuron]

Lactate is basically lactic acid which reduces levels of CO2 in a body and elevates nitric oxide. Even some of the probiotics produce lactic acid.
I'm basically avoiding all the dairy and I avoid everything that says cultured. I don't eat anything fermented either.

Do you think combining targeted breathing with increased CO2 during high-intensity exercise can buffer high lactate?

 

[L_C]

Do you think combining targeted breathing with increased CO2 during high-intensity exercise can buffer high lactate?

In theory I believe that should work but I have never tried.

 

[Elie]

Elevated lactate is indicative of thiamine deficiency. Thiamine deficiency can produce lactic acidosis.

This is from the book "Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition"
"From a molecular perspective, hyperglycemia has long been recognized for its role in the glycolytic switch integral to the cancer phenotype. 67 Hyperglycemia deranges mitochondrial morphology, increases ROS production, and promotes mitochondrial DNA mutations. 71 In an effort to compensate and reduce the damage, mitochondrial respiration is reduced (the hypoxic cascades initiated) and mitochondrial dynamics are adjusted (fission/fusion). Concomitantly, we get increased production of lactate, which feeds anaerobic respiration and tumorigenesis, 70 but we also have a notable increase in aerobic glycolysis, suggesting an adaptation to states of both normoxia and hypoxia. 66 All of this occurs in the presence of a microenvironment where hyperglycemia is forced upon the cells and must cause an adaptive response. Tumorigenesis appears to be the mechanism of choice, where the excess sugars can be sequestered and metabolized independently of mitochondrial and normal cellular function."

"Returning to the role of thiamine in mitochondrial oxidative function, it has not yet become clear how cancer cells regulate cellular homeostasis of cofactors adaptively. Putatively, however, we know that thiamine must be involved given its requirement in both cytosolic and mitochondrial glucose metabolism. We also know that thiamine deficiency is common in cancer, as are alterations in thiamine transporter functioning. 73 One review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells. 74 It appears that thiamine supplementation follows an unexpected dose–response curve. Low and moderate doses of thiamine increase tumor activity, whereas supraphysiological doses inhibit or reverse tumor growth. 74 Dr. Lonsdale has long observed that when thiamine deficiency is chronic and/or severe, high doses of the vitamin are required to reengage enzyme activity. Whether this is the case here or not remains to be investigated, but it does present an intriguing possibility and a novel opportunity for treatment."

@sugarbabe this is months after you posted this, however, if you see this, what does the author of this book consider as "high
doses?

 

[Thalgo]

A great study, demonstrating that in diabetes (just as in cancer) the so-called Warburg Effect (aerobic glycolysis) is as much a cause of those degenerative conditions as it is an effect of. The study below demonstrated that increased intracellular lactate results in robust increase in systemic release of inflammatory cytokines, resulting in aggravation of systemic insulin resistance. In other words, metabolic effects considered peripheral and unrelated to the core disease (e.g. diabetes type II) are, in fact, major driving factors of that core disease. The study may also explain why not all obese people develop diabetes type II and why some lean people have severe insulin resistance. And, yes, metabolic rate is once again the likely distinguishing factor. Intracellular lactate accumulation, barring cofactor (thiamine, vitamin B2/B3, biotin, etc) deficiencies and/or presence of cancer, is a reliable sign (and also a cause) of low metabolic rate (RMR). Thus, an obese person with higher RMR (per kg of bodyweight) is likely to fare better and be healthier than a leaner person with lower RMR (per kg of bodyweight). On a bit of side note, this discrepancy of RMR (often in favor of the obese/overweight) is the likely explanation of the so-called "Obesity Paradox". In corroboration, up to 60% of hospitalized patients (with any condition) who eventually succumb while in the hospital have lactic acidosis at the time of hospital admission. So, it looks like lactate is no joke and a major factor in both acute (yes, it is involved in COVID-19 mortality as well) and chronic pathologies alike. As such, reducing lipolysis (to limit lactate synthesis due to Randle cycle) and providing a bit extra of the important enzymatic cofactors listed above can go a long way in preventing the chronic, low-grade hyperlactaemia which can apparently wreak havoc on the organism if left unchecked. The more I learn about it, the more lactate starts to sounds like the more evil twin of the already evil endotoxin (LPS). Namely, since endotoxemia in blood is a widely recognized factor in sepsis doctors will check for it and try to address it, while high intracellular lactate is very hard to diagnose (short of a biopsy, which is usually only done for cancers) and will likely go unaddressed as it won't be suspected as a cause of the increased blood levels of the inflammatory cytokines.

Now, while the study does not say it, I'd also venture a guess that lactate is also a promoter/driver of the obesity often seen in type II diabetics. If lactate is a robust promoter of inflammation, as a consequence cortisol would also be elevated (and indeed it is, when measured in such patients). Cortisol is a confirmed obesogen, and the increase in fatty tissue it causes will also result in synthesizing more estrogen (another obesogen). So, the humble lactate that really does not get on anybody's (medical) radar may turn out to be one of the most fundamental driver's of chronic conditions related to inflammation...which is basically all of them. PUFA called and wants its "evil mastermind" title back

Lactate is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue

"...Numerous evidences indicate that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, what triggers obesity-induced inflammation is poorly understood. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of pro-inflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of pro-inflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this deadly link."

Would beta-alanine help?