The Subcellular Processes That Belie All Chronic Disease. The Hateful (or Grateful) Eight #lustig

A 10-day controlled feeding study of 43 children from UCSF's obesity program with metabolic syndrome and fatty liver showed that reducing dietary sugar from 28% to 10% of calories while maintaining total caloric intake (replacing sugar with starch) improved every aspect of metabolic health: liver fat decreased 22%, de novo lipogenesis decreased 46%, VLDL decreased 49%, visceral fat decreased 7%, and insulin kinetics normalized—without any change in weight

“we took 43 children from our obesity program at UCSF all with metabolic syndrome all with fatty liver and all high sugar consumers and we studied them on their Baseline diet...we put them on a diet for the next 10 days we catered their meals no added sugar we took their percent calories as sugar from 28 percent pre-study down to 10 percent on study...we wanted them to stay the same weight so we had to give them back the 350 to 400 calories that we were taking out as something else we took the sugar out we had to put something else back in that was calorically equivalent we gave him extra starch we did a starch for sugar exchange ISO caloric...and we studied them again at the end of 10 days every aspect of their metabolic Health got better their liver fat went down 22 percent the novel lipogenesis rate went down 46 percent their vldl in their blood went down 49 their visceral fat went down seven percent and most importantly their insulin kinetics came back to normal”

Of the 42.4% of the U.S. adult population that is obese (BMI > 30), 80% are metabolically sick (sick because they're obese), but 20% are metabolically healthy obese (MHO) and will live a normal lifespan without costing taxpayers money; conversely, 60% of the normal-weight population (BMI < 30) have the exact same metabolic diseases as obese individuals, demonstrating that obesity is a risk factor but not a cause of metabolic disease

“42.4 percent obese BMI over 30. 57.6 normal weight BMI under 30. okay so two mutually exclusive circles every one of you is in one of the two circles and you know who you are okay here's what the doctors and the nutritionists and the Institute of medicine and the National Institutes of Health and the Surgeon General and the White House and Congress and the food industry all say they say 80 percent of those 42.4 percent obese these 86 million people here they're sick they're fat and they're sick and they're sick because they're fat...it is true that 86 million people are obese and uh and sick that's true okay but that means and that's 80 of the total that means 20 are not they are metabolically healthy we have a name for them m-h-o metabolically healthy obese they will live a completely normal life diet a completely normal age not cost the taxpayer a dime”

Glucose activates two mitochondrial enzymes (AMP kinase and HADH) that increase mitochondrial beta-oxidation and fuel burning, and AMP kinase is a primary signal for generating new mitochondria; fructose inhibits three mitochondrial enzymes (AMP kinase, ACAD-L, and CPT-1A), blocking fatty acid beta-oxidation and mitochondrial biogenesis

“glucose activated two count them two enzymes that improved and increased mitochondrial beta oxidation it increased ampicinase the fuel gauge on the liver cell and amp kinase actually is one of the signals one of the primary signals to generate new mitochondria...also it increased this enzyme here called hadh hydroxyacyl COA dehydrogenase which is necessary for fatty acid beta oxidation so the ultimate goal of glucose is to increase mitochondrial beta oxidation thus the Green Arrow upwards here now take fructose notice fructose is in red that's not in red because it's not green it's red because it's a stop okay because in fact fructose inhibits three mitochondrial enzymes it inhibits amp kinase...it also inhibits this enzyme down here called acad L acyl COA dehydrogenase long chain...and lastly because of it's the increase in uric acid associated with sugar consumption the uric acid inhibits this enzyme here called cpt-1a carnitine Palmetto transferase 1A”

TOFI (thin on the outside, fat on the inside) individuals with equal trunk fat but different fat distribution—visceral/intra-abdominal fat versus subcutaneous fat—demonstrate dramatically different metabolic health outcomes; visceral fat is dangerous while subcutaneous fat is protective, making the location and type of body fat more predictive of health than total weight

“here are two equally weighted people CT scans through the abdomen of two equally weighted people notice trunk fat 12.8 12.8 one's healthy one's sick which one's sick b b is sick a metabolically healthy obese he's got big love handles subcutaneous fat not dangerous in fact might be protective in many cases protective this guy's got fat all around his organs intra-abdominal fat okay and we have a name for this it's called tofi t-o-f-i thin on the outside fat on the inside real medical term 1500 Medline citations coined by Dr Jimmy Bell at University College of London”

Removing fructose from the diet reduces inflammation in patients with lupus and rheumatoid arthritis, suggesting that dietary sugar directly drives autoimmune disease, and Group A Streptococcus grows better on fructose than glucose, meaning sugar consumption directly facilitates pathogenic bacterial growth

“if we take the fructose out of the diet do does the inflammation get better and the answer is yes it does okay and you can see that in these studies done in patients with lupus and you can see that in patients with rheumatoid arthritis...it turns out that group a strep grows better on fructose than it does on glucose and you can see that here here's two percent fructose against two and two percent sucrose against glucose and you notice that the glucose doesn't cause the bacteria to grow it's only the fructose that causes the bacteria to grow so we are actually making our autoimmune diseases worse by increasing in inflammation in our intestines driving hepatic insulin resistance and chronic metabolic disease”

Ron Khan (researcher at Joslin Diabetes Center) concluded from his own research that high fructose in the diet is bad not because it has more calories but because it has specific metabolic effects that impair liver fat-burning capacity, causing the liver to store more fat, which is bad for the liver and whole-body metabolism

“the sum total of which is that beta oxidation goes down with fructose so the molecule sugar dietary sugar has glucose and fructose what's the net effect the net effect is actually inhibition and this is what Ron Khan himself said about this study the most important takeaway of this study is that high fructose in the diet is bad it's not bad because it's more calories but because it has effects on liver metabolism to make it worse at burning fat as a result adding fructose to the diet makes the liver store more fat and this is bad for the liver and bad for whole body metabolism couldn't agree more”

In individuals with fatty liver, the hazard ratio for developing diabetes is 3.5 times higher because the pancreas and liver are metabolically linked through the portal vein—insulin is released by the pancreas directly to the liver as its primary target, so when the liver is sick, the pancreas becomes sick as well

“if you have fatty liver you are 3.5 times more likely to develop diabetes because of your fatty liver causational and it makes sense because after all when the pancreas releases insulin where's it go es to the liver via the portal vein now the rest of the body you know when a hormone is made it goes into the systemic circulation right but pancreas goes to the liver and the reason is because the liver is the primary target of insulin action and so when your liver's sick guess what so is your pancreas”

Metabolic health and mental health are linked because both depend on mitochondrial function; mitochondria in the brain fail for the same reasons mitochondria in the liver fail, so the same metabolic interventions that fix metabolic syndrome also treat mental illness

“is mental health part of the issue mental health is metabolic health so anything that happened and we're going to talk about mitochondria in a minute okay you got mitochondria in your liver and when they don't work you get fat in your liver you have mitochondria in your brain and when that those mitochondria in your brain don't work you get mental illness and the same things that affect your mitochondria in your liver affect the mitochondria in your brain so in fact metabolic health and mental health go hand in hand and often over not just overlap but are you know due to the same problem”

Fructose is worse than glucose for immune cells because fructose does not convert to lactate like glucose does, and it interferes with the ability of immune cells to respond to glutamine (an immunosuppressant), causing immune cells to become hyperactivated and producing elevated levels of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6)

“when glucose comes in it goes into immune cell goes to lactate no problem when fructose comes in it doesn't go to lactate and it actually interferes with the ability of the cell to respond to glutamine which is actually immune suppressant and so these immune cells get hyped up and you can see that here in terms of tnf alpha whether it's glucose or sucrose Administration tnf Alpha goes up il1 beta goes up il-6 goes up”

U.S. healthcare expenditure and life expectancy diverged from all other OECD countries starting in 1980, with the U.S. falling off the rails while all 37 other developed countries remained relatively stable within their peer group

“if you look at Health Care expenditure per person against life expectancy what you'll notice is all the oecd countries all 37 developed countries you know they're sort of keeping themselves to the you know within the pack here but we fell off the rails here in 1980 and have just been going off ever since”

The increase in processed food consumption and sugar consumption correlates directly with the increase in healthcare expenditure as percentage of GDP beginning around 1980, and similarly correlates with mortality rates across 19 European countries, demonstrating a causal relationship

“I've now done is I have overlaid on this Slide the percent of GDP spent on health care for the same period of time and you'll notice that when processed food came in that's when our health care costs started to climb out of control...in Europe okay 19 countries the percentage of ultra processed food consumption correlates with the percentage of obesity okay and also correlates with mortality rates as well for exactly the same reason”

Global diabetes prevalence increased from 151 million in 2000 to 537 million by 2021, at an annualized inflation rate of 6.55% to 10.3% per year—more than double the 3.88% rate that was predicted in 2001, demonstrating that interventions focused on obesity, exercise, and pharmaceutical treatment have made the problem worse, not better

“at that time in the year 2000 there were 151 million diabetics and what was predicted would be that one year decade later in the year 2010 we would be up to 221 million that's a 46 increase or an annualized inflation rate of 3.88 percent this is not what we saw what we actually saw was 285 million that's an annualized inflation rate of 6.55 percent doubling over what was anticipated by 2014 up to 422 million that's an annualized inflation rate of 10.3 percent of tripling over what was anticipated so as we've learned about the Obesity epidemic as we've been you know throwing obesity drugs and you know various other diabetic agents and gym memberships and you know everything else Under the Sun at the problem it has only gotten worse by the year 2019 we were up to 463 million 2021 537 million”

LDL cholesterol correlates with cardiovascular disease at a hazard risk ratio of 1.3, but serum triglyceride correlates at 1.8, making serum triglyceride 50% more informative for predicting heart disease than LDL, yet the entire medical system focuses on lowering LDL

“it is true that LDL levels do correlate with cardiovascular disease that is true the hazard risk ratio is 1.3 you can see it right here at 1.3...and there's your data okay and it's true and it does correlate and I'm not saying it doesn't it does okay but there's something that correlates way better and that's serum triglyceride serum triglyceride correlates with a hazard risk ratio of 1.8 and there's the data right there 1.8 so serum clutch triglyceride is actually 50 percent more informative in terms of heart disease than is LDL”

Statins fail to reduce cardiovascular mortality or events in primary prevention (treating high LDL in people without prior heart disease), and when they do show benefit in secondary prevention, the mean increase in lifespan is only four days, with a number needed to treat of 754 (meaning you must treat 754 people for one to benefit), far exceeding the threshold of cost-effectiveness

“primary prevention you're not self-selecting for people who already have a problem when you do when you look for a primary prevention turns out the rcts do not show any benefit on mortality do you know what the mean increase in lifespan is from treating high LDL with a Statin is four days four days none of these trials reduce cvd events and some of the drugs actually reported harm...How many people do you have to treat with a Statin to actually get it one patient with benefit 754. ridiculous number needed to treat maybe 10 might be cost effective really five might be cost effective 754”

In diabetics on a high-fiber diet (not low-carb diet), glucose excursions are controlled to the same degree as low-carb diet because fiber prevents glucose absorption by acting as a gel that blocks transport of glucose and other sugars from the intestinal lumen into the portal vein

“here's glucose excursions in diabetics on a normal diet and here's glucose excursions in diabetics on a low carb diet much better right that's why everybody's saying low carb diet for diabetes I understand that but here's what happens on a high fiber diet not on a low carb diet but a high fiber diet same thing and the reason is because you're preventing the glycemic excursions because when you consume your food with fiber called real food that those calories those glucose molecules end up not being for you they are for your microbiome they your microbiome chews them up because you have prevented their early absorption because the fiber acts as a gel a lattice work on the inside of your intestine coding the inside of your intestine soluble and insoluble fiber together prevent the transport of glucose fructose sucrose simple starches from the intestine from the Lumen into the portal vein”

Membrane integrity is determined by the composition of the plasma membrane (cholesterol and phosphatidylcholine) and membrane fluidity; omega-3 fatty acids are particularly important in stabilizing membrane fluidity and preventing membrane deterioration, whereas omega-6 fatty acids are pro-inflammatory; fructose impairs membrane fluidity through effects on insulin resistance, which can be ameliorated by omega-3 supplementation, but the modern diet is depleted in omega-3s and high in pro-inflammatory omega-6s.

“the composition of the plasma membrane creates this thing called membrane fluidity and that is eminently perturbable and when it's perturbed it means cells die especially neurons okay cholesterol and phosphatidylcholine are the prime determinants of membrane fluidity and Omega-3s are particularly important in stabilizing that membrane fluidity”

The diet fit study by Christopher Gardner at Stanford showed identical metabolic outcomes between high-fat and high-carb diets because both groups were fed real food (not processed), indicating that the type of macronutrient (fat vs carb) is less important than the degree of food processing

“the diet fit study that done by Christopher Gardner at Stanford ultimately showed the exact same effect except that all of them all both the high fat and high carb diet he gave was a real food diet so I'm not so concerned about the fat or the carb as I am about the degree of processing because processed food is high in sugar low in fiber high in sugar for palatability low in fiber for shelf life”

Serum triglyceride is a measure of liver function because it represents very low density lipoproteins (VLDL) made by the liver from the conversion of sugar to fat through de novo lipogenesis; therefore, high triglycerides indicate the liver is sick from sugar consumption

“your serum triglyceride is your very low density lipoproteins it is made by the liver and it is made from the conversion of sugar to fat through a process called de novo lipogenesis your triglycerides are your vldl and your chylomicrons but if you're fasting your chylomicrons should be zero so your vldl and your serum triglycerides are the same which means that your serum triglycerides are a measure of liver function and so if your serum triglycerides are high it means your liver is sick if you've got fat in your liver it means your liver is sick”

Autophagy (cellular self-cleaning) declines with age and when impaired leads to cell death, cancer, immunosuppression, cardiomyopathy, neurodegenerative diseases, and infectious disease; increased autophagy is protective and improves health span

“autophagy goes down as you age okay you end up with cell death cancer problems with your immune system cardiomyopathy aging infectious disease fatty liver neurodegenerative diseases Etc so you want more autophagy you want increased autophagy okay because autophagy improves Health span okay it does all of these things all good okay improves immune responses inflammatory responses changes cell death rates reduces cellulose senescence and you avoid oncogenesis okay”

Glycation (non-enzymatic glycation of proteins) occurs through the Maillard reaction when glucose binds to the epsilon amino group of lysine, forming a Schiff base that spontaneously decomposes into an irreversible amidori rearrangement; this is the same browning process that occurs in food at high heat and occurs in the body at 98.6°F over 75 years

“non-enzymatic glycation The Binding of a glucose to an Epsilon amino group of Lysine usually okay so the way to think about this is the following you can roast your meat at 375 degrees for an hour or you can roast your meat at 98.6 degrees for 75 years the answer is the same you are Browning sitting here right now you are Browning you can't stop the only way to stop Browning is to be dead you can control the rate of Browning that's the point okay your mitochondria Brown routinely it's part of them being mitochondria okay...here's glucose you'll notice glucose has an aldehyde group on the position one of the linear form that aldehyde combined to an Epsilon amino group of Lysine...form a shift base which will spontaneously decompose to form this covalent linkage and we call this the amidori rearrangement and you're all familiar with that this is what hemoglobin A1c is right here”

Oxidative stress results from glycation reactions (and other metabolic processes) releasing hydrogen peroxide and oxygen radicals that must be quenched by antioxidants; if not quenched, these reactive oxygen species (ROS) cause lipid peroxidation and protein denaturation, leading to cell damage and death—the same process as rusting in nails, but in cells it involves carbonyl compounds rather than iron oxide.

“number two oxidative stress every time that my art reaction occurs it releases a little hydrogen peroxide a little oxygen radical and that oxygen radical has to be quenched by an antioxidant or it will do damage it will cause lipid peroxidation or protein denaturation it will do something to cause cells to be damaged and die and this is called oxidative stress it's the same thing that happens to Nails Nails rust well we rust too the only difference is that when Nails rust it's iron oxide and when we rust it's these carbonyls instead but it's the same process okay”

AMP kinase is critical for triggering autophagy; when AMP kinase is not working, autophagy stops, and fructose binds to the gamma subunit of AMP kinase causing non-competitive inhibition, thereby shutting down autophagy and leading to cellular dysfunction

“it turns out that amp kinase I told you about okay when it's working you get autophagy when it's not working autophagy stops and what did I tell you about ampicinase and fructose it sits in the gamma subunit and causes non-competitive inhibition so autophagy stops”