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Peter Attia MD312 - A masterclass in lactate: metabolic fuel, implications for diseases, and therapeutic potential
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CHAPTERS
- 0:02 – 12:32
Lactate vs. lactic acid and Meyerhof's frog experiment
Peter Attia and George Brooks open by clarifying that the body makes lactate, not lactic acid. They walk through Meyerhof's century-old half-frog experiment and how it tied lactate, acidosis, and oxygen lack together.
- •Brooks says the body does not make lactic acid and calls the naming a hundred-year mistake
- •Meyerhof's setup used a frog muscle in a jar with no oxygen or blood flow, quantifying glycogen used and lactate produced
- •The experiment led to the ideas of lactic acidosis, anaerobic threshold, and oxygen debt
- •Brooks thinks the muscle stopped because ATP and creatine phosphate were depleted
- •Attia describes how tightly physiology holds pH near 7.4, citing trauma patients
- 12:32 – 15:02
Warburg, the Nobel history, and lactate versus pH in the ICU
The discussion moves to Meyerhof and Hill's Nobel Prize and to Warburg's observation in cancer cells. Brooks explains that the last glycolytic step is alkalizing, so lactate and acid should be distinguished, which matters for how clinicians read lactate in sepsis.
- •Meyerhof shared the Nobel Prize with A.V. Hill
- •Warburg was Meyerhof's professor; cancer cells turn glucose to lactate even under ample oxygen
- •The final step of glycolysis does not make acid; other intermediates can
- •Clinicians measuring lactate in sepsis are really using it as a surrogate for pH concerns
- 15:02 – 26:40
How glucose becomes ATP: transporters, glycolysis, and glycogen
Attia asks for a walk through glucose metabolism. Brooks covers glucose transporters, the splitting of glucose into two three-carbon molecules, the role of stored glycogen in working muscle, and why the body protects blood glucose for the brain.
- •Glucose must cross the membrane via transporters such as GLUT4, moved by insulin or muscle contraction
- •Glycolysis splits a six-carbon glucose into two three-carbon molecules and ends in lactate
- •About 80% of carbon flow in working muscle comes from stored glycogen
- •Muscle is kept from draining blood glucose needed by the brain
- 26:40 – 33:49
Lactate as mitochondrial fuel and the Cori cycle
Brooks says lactate enters the mitochondria and is a major fuel, contradicting textbook teaching that only pyruvate does. They discuss the Cori cycle, the mitochondrial lactate oxidation complex, and what controls the path of carbon.
- •Brooks says most oxidative chemical energy arrives as lactate in the mitochondrial reticulum
- •Attia contrasts this with the textbook story of pyruvate to Krebs cycle and lactate to the liver
- •The Coris first described the lactate shuttle, supplying blood glucose during exercise
- •The ADP to ATP ratio drives glycolysis, and lactate activates mitochondrial lactate dehydrogenase
- 33:49 – 40:13
Lactate preferred over fat, and implications for type 2 diabetes
Brooks explains that lactate's breakdown to acetyl-CoA blocks CPT-mediated fatty acid entry, which fits a fight-or-flight logic. They apply this to elevated resting lactate in type 2 diabetes and the heart after MI, and discuss isotope tracers and the lactate clamp.
- •Lactate blocks CPT1 and CPT2, shutting the door on fatty acid oxidation
- •Fats are saved for recovery while glycogen and glucose fuel fight or flight
- •Brooks now frames elevated lactate in diabetes as strain, a way to bypass impaired glucose uptake
- •Isotope tracers and the lactate clamp measure flux and show glucose uptake is suppressed
- 40:13 – 53:51
Lactate infusion for traumatic brain injury and brain fuel competition
They discuss the PET image showing infused lactate halting glucose uptake in a TBI patient, the astrocyte-neuron lactate shuttle, and competition among glucose, lactate, and ketones. Brooks says lactate would likely dominate in an injured brain, and they cover trials, tracer ideas, and safety limits of sodium lactate.
- •The injured brain takes up about half its usual glucose and is in metabolic crisis
- •Lactate transporters are highly expressed in the brain, and ketones share the MCT transporter but lactate is preferred
- •In an injured brain, lactate would suppress BHB uptake
- •A Stage 2 trial began at UCLA and a Swiss group gives hypertonic lactate
- •Half-molar sodium lactate is near the upper safe limit, and kidney function and sodium load are concerns
- 53:51 – 56:42
Exercise lactate, acidosis, and appetite suppression
Attia describes the discomfort of very high lactate after hard exercise, and Brooks says the discomfort comes from acidosis rather than lactate. Brooks adds that lactate acts on the hypothalamus and suppresses ghrelin, so moderately raised lactate can curb appetite.
- •Attia's highest measured lactate was about 18 millimole after intense exercise
- •Brooks says lactate is a protective strain response and the discomfort reflects severe acidosis
- •Lactate crosses the blood-brain barrier, acts in the hypothalamus, and suppresses ghrelin
- •Three to four millimolar lactate could help satiate people
- 56:42 – 1:04:32
Athletes versus insulin-resistant individuals: mitochondria and lactate clearance
Attia asks how a highly trained aerobic athlete differs metabolically from an insulin-resistant person. Brooks stresses mitochondria as disposal sinks, the limits of liver perfusion at high intensity, and training-driven increases in mitochondrial mass.
- •At the same relative effort a trained athlete produces lactate but burns it and sends it to the Cori cycle
- •At very high intensity blood is shunted away from liver and kidneys, lowering lactate disposal
- •Training can roughly double mitochondrial mass, and the whole network of enzymes rises proportionally
- •Mitochondria form a reticulum Brooks calls the cellular energy power grid
- 1:04:32 – 1:16:22
MCT transporters and the cell-to-cell lactate shuttle between fiber types
The conversation turns to monocarboxylate transporters, their discovery, and their presence in mitochondria. Brooks explains how fast glycolytic fibers export lactate that neighboring red fibers oxidize, and why the field has been slow to accept this.
- •MCTs were identified around 2000, and Brooks's group found them on mitochondria around 1995
- •Training increases MCT abundance
- •Fast glycolytic fibers export lactate to adjacent oxidative fibers in a cell-cell shuttle
- •Rat measurements showed lactate about 10-12 in fast fibers, 4 in arterial blood, and 3 in red fibers
- •Brooks says there has been a stonewall silence in the field and textbooks are being revised
- 1:16:22 – 1:24:48
What makes an elite cyclist: carbon flux and lactate clearance
Attia compares a top amateur cyclist friend to himself. Brooks attributes the friend's endurance to type one fibers, a dense mitochondrial reticulum, and high carbon flux with strong lactate disposal.
- •The friend sustains about 430 watts for an hour yet cannot match Attia's leg-press weight
- •Brooks guesses he is mostly type one fibers with a highly expressed mitochondrial reticulum
- •His power is limited by the carbon flow he can sustain
- •Brooks says the best performers likely clear lactate more efficiently
- 1:24:48 – 1:33:39
Measuring lactate: venous versus arterial levels, oxidation, and arms versus legs
They discuss where lactate is sampled and how venous effluent from working muscle can be far higher than arterial or fingertip values. Brooks cites oxidation of about 75 to 80% and explains why arm-dominant efforts generate more lactate.
- •Femoral venous lactate may be 10-12 while arterial drops to about 4 within one circulation
- •Lungs and red blood cells convert lactate, and the liver dilutes it
- •Brooks says oxidation accounts for about 75-80% of lactate disposal in their studies
- •Arms are more glycolytic than legs, so upper-body effort produces more lactate and clearance problems
- 1:33:39 – 1:43:07
Lactate, cancer, and the importance of flux over concentration
Attia raises the Warburg effect and building-block theories of cancer metabolism. Brooks describes cancer as unrestrained glycolysis in which lactate stimulates untoward processes, and argues that exercise raises clearance capacity, so the issue is flux rather than concentration.
- •Brooks says cancer cells have mitochondria and can oxidize lactate
- •Work with Inigo San Millán suggests lactate stimulates glycolytic enzymes across cancer stages
- •Brooks changed his view: exercise increases lactate clearance and may lessen carcinogenesis
- •Attia compares lactate flux to intramyocellular fat, a flowing river versus a stagnant pond
- 1:43:07 – 1:50:17
Brain health, sepsis, and D-lactate
They discuss other disease roles for lactate, including exercise, neurogenesis, and dementia. Brooks then turns to sepsis, raising Bellomo's challenge about hypoxia and suggesting gut microbes produce D-lactate that standard assays miss.
- •Physical exercise may protect the brain, and lactate may stimulate neurogenesis in the dentate gyrus
- •Bellomo challenges clinicians to show where hypoxia is in septic patients
- •Brooks suspects lactate in sepsis may come from the gut
- •Standard analyzers measure only L-lactate, while D-lactate is neurotoxic and pro-inflammatory
- 1:50:17 – 2:04:09
Enteric glycolysis, the oral glucose tolerance test, and metformin
Brooks describes his latest finding that lactate appears in arterial blood within minutes of oral glucose, indicating gut glycolysis. They discuss the liver's role in sequestering glucose, the cost of definitive experiments, and Brooks's colleague's idea that metformin raises lactate via enterocytes.
- •Lactate peaks within about 15 minutes of oral glucose, before glucose rises
- •The liver sequesters about 80% of the glucose load and releases it later
- •Lactate and glucose have an indirect pathway through muscle
- •A colleague suggests metformin may encourage enterocytes to make lactate
- •An R01 of about two and a half million dollars could start these studies
- 2:04:09 – 2:09:24
Does high lactate mean acidosis? Clinical caution and pH
Attia returns to conventional teaching about metformin and lactic acidosis. Brooks says caution is still warranted, but infused lactate clamps showed slight alkalosis, and he would be inclined not to act on high lactate when pH is unchanged.
- •Conventional teaching warns metformin raises lactic acidosis risk
- •Brooks says it is unknown whether metformin raises production or blocks disposal
- •Lactate clamped at four millimolar slightly raised pH to about 7.4
- •Brooks would do little if lactate is high without a pH change
- 2:09:24 – 2:20:55
Lactylation, signaling, and exogenous versus endogenous lactate
Brooks describes lactate as a redox-changing signaling molecule that can modify histones through lactylation. They discuss why endogenous lactate during exercise may drive mitochondrial biogenesis differently than infusions, speculate about study designs, and close with thanks.
- •Lactate is more reduced than pyruvate and changes cell redox
- •Lactylation of histones is an emerging area, and lactate added to muscle cells activated about 500 genes
- •Results from lactate clamps on mitochondrial protein expression are mixed, and Brooks says endogenous lactate seems to stimulate biogenesis more
- •Brooks cites a study where cognitive scores rose with exercise lactate and another where infused lactate raised BDNF
- •Attia calls for funding of modest but fundamental flux experiments
