jet

• Neuropathy is not just a blood sugar problem; lowering glucose alone does not fully save the nerve.
• In type 1 diabetes, intensive glycemic control can prevent neuropathy very effectively, but in type 2 diabetes the same glucose-focused move leaves much of the problem untouched.
• The nerve is hit by three forces at once: hyperglycemia, insulin resistance, and glycemic variability.
• Together, those forces make neuropathy a metabolic failure of nerve fuel handling, repair signaling, and oxidative injury.

Peripheral neuropathy basics

• Peripheral neuropathy is damage to nerves outside the brain and spinal cord.
• Motor fibers drive muscle action, sensory fibers carry information from skin, joints, and organs, and autonomic fibers regulate heart rate, blood pressure, gut motility, and sweating.
• The common metabolic pattern is distal symmetric polyneuropathy, a length-dependent process where the longest nerves fail first.
• Symptoms usually begin in toes and feet, move up the legs, and later reach the fingertips.
• Numbness, tingling, burning pain, or loss of vibration sensation comes from small nerve endings that retract and die.
• Skin biopsy can show fewer small nerve endings, and nerve-conduction testing can show slower signals.
• Cardiovascular autonomic neuropathy affects heart and blood-pressure nerves, and small-fiber neuropathy may be an early manifestation.
• Diabetic peripheral neuropathy is very common, drives foot ulcers and non-traumatic lower-limb amputations, and can show up before formal diabetes.

Pillar 1 -- Hyperglycemia

• Peripheral neurons and Schwann cells take up glucose through insulin-independent transporters, so high blood glucose floods the nerve without an effective shutoff.
• Excess intracellular glucose pushes the sorbitol pathway: aldose reductase converts glucose to sorbitol.
• Sorbitol stays inside the cell, pulls in water, creates osmotic stress, and forces the nerve to export useful small molecules.
• Myo-inositol loss weakens sodium-potassium pump function, which slows the electrical signal.
• Aldose reductase consumes NADPH, leaving less NADPH to regenerate active glutathione and defend against free radicals.
• High glucose also glycates proteins and lipids without enzyme control, creating advanced glycation end products over months and years.
• AGEs damage long-lived nerve proteins, myelin, cytoskeleton, and the basement membrane of tiny vessels feeding the nerve.
• AGE binding to RAGE triggers inflammatory signaling in nerve-support tissue and blood vessels.

Pillar 2 -- Insulin resistance

• In type 2 diabetes, hyperglycemia is usually downstream of insulin resistance, and insulin resistance injures nerves partly apart from glucose.
• In type 1 diabetes cohorts, neuropathy risk tracks with modifiable cardiovascular and metabolic-syndrome factors such as triglycerides, BMI, smoking, and hypertension.
• In type 2 diabetes and obesity, human studies connect neuropathy with metabolic syndrome components independent of glycemic status.
• Lifestyle intervention in impaired-glucose-tolerance neuropathy produced measurable cutaneous reinnervation after one year.
• Physiological insulin is a trophic signal for peripheral neurons and Schwann cells.
• Schwann cells make myelin and support axons; insulin and IGF-1 receptor signaling help them make the lipids needed for myelin.
• When insulin and IGF-1 receptors were deleted specifically in mouse Schwann cells, fatty-acid and cholesterol synthesis dropped and sensory neuropathy developed despite normal glucose.
• In insulin resistance, the Schwann cell loses effective insulin signaling while chronic hyperinsulinemia and lipotoxicity promote harmful lipid accumulation.
• The nerve can therefore be deprived of repair, remyelination, and Schwann-cell support even when glucose is normal or only intermittently high.

Pillar 3 -- Glycemic variability

• A1C is a one-dimensional average of a dynamic glucose signal.
• Two people can share an A1C of 7%, while one stays near 100-140 mg/dL and another swings between about 60 and over 200 mg/dL.
• The swings matter because intermittent hyperglycemia can drive more endothelial oxidative stress than a steadier glucose exposure with the same average.
• Each upward excursion is another hit on the NADPH-superoxide system, without enough time for the nerve to adapt.
• CGM studies now make those swings visible.
• In type 2 diabetes with A1C below 7%, higher mean amplitude of glycemic excursions was an independent predictor of diabetic peripheral neuropathy.
• Nerve-conduction work also linked higher MAGE with reduced compound nerve action potential amplitude.
• Long-term HbA1c variability and fasting-plasma-glucose variability were also linked with diabetic peripheral neuropathy and painful diabetic peripheral neuropathy.
• Time in range and time in tight range may matter as much as average glucose for nerve protection.

Why the diabetes types diverge

• In type 1 diabetes, exogenous insulin can address average glucose and modern tools can reduce variability, while underlying insulin resistance is usually absent.
• Intensive glycemic control therefore captures much of the neuropathy benefit in type 1 diabetes.
• In type 2 diabetes, lowering A1C can leave insulin resistance and glycemic variability largely intact.
• Prediabetes and metabolic syndrome can injure small fibers even when A1C is normal because insulin resistance and post-meal excursions are already active.

Practical model

• The burning foot or tingling finger should not be reduced to "your sugar is too high."
• The better model is three simultaneous attacks: hyperglycemia, loss of insulin signaling at Schwann cells, and glucose volatility.
• You cannot out-A1C metabolic neuropathy.
• The solution has to improve all three pillars: carbohydrate control, fasting protocols that stabilize glucose and improve insulin sensitivity, resistance exercise, and better sleep habits.

References

• [01:26] The Effect of Intensive Diabetes Therapy on the Development and Progression of Neuropathy — https://doi.org/10.7326/0003-4819-122-8-199504150-00001
• [01:43] Enhanced glucose control for preventing and treating diabetic neuropathy — https://doi.org/10.1002/14651858.CD007543.pub2
• [03:35] Distal Symmetric Polyneuropathy: A Review — https://doi.org/10.1001/jama.2015.13611
• [04:50] Diabetic Neuropathy: A Position Statement by the American Diabetes Association — https://doi.org/10.2337/dc16-2042
• [05:25] Prevalence of peripheral neuropathy in pre-diabetes: a systematic review — https://doi.org/10.1136/bmjdrc-2020-002040
• [06:18] Diabetic neuropathy — https://doi.org/10.1038/s41572-019-0092-1
• [07:10] Aldose Reductase and the Polyol Pathway in Schwann Cells — https://doi.org/10.3390/ijms22031031
• [10:21] The Pathobiology of Diabetic Complications: A Unifying Mechanism — https://doi.org/10.2337/diabetes.54.6.1615
• [11:55] Vascular Risk Factors and Diabetic Neuropathy — https://doi.org/10.1056/NEJMoa032782
• [12:38] The metabolic syndrome and neuropathy: Therapeutic challenges and opportunities — https://doi.org/10.1002/ana.23986
• [12:56] Metabolic Syndrome Components Are Associated With Symptomatic Polyneuropathy Independent of Glycemic Status — https://doi.org/10.2337/dc16-0081
• [13:02] Diabetes and obesity are the main metabolic drivers of peripheral neuropathy — https://doi.org/10.1002/acn3.531
• [13:14] Lifestyle Intervention for Pre-Diabetic Neuropathy — https://doi.org/10.2337/dc06-0224
• [15:08] Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy — https://doi.org/10.1002/glia.23755
• [17:38] Oscillating Glucose Is More Deleterious to Endothelial Function and Oxidative Stress Than Mean Glucose in Normal and Type 2 Diabetic Patients — https://doi.org/10.2337/db08-0063
• [18:08] The relationship between glycemic variability and diabetic peripheral neuropathy in type 2 diabetes with well-controlled HbA1c — https://doi.org/10.1186/1758-5996-6-139
• [19:00] Nerve conduction study of the association between glycemic variability and diabetes neuropathy — https://doi.org/10.1186/s13098-018-0371-0
• [19:19] HbA1c variability and diabetic peripheral neuropathy in type 2 diabetic patients — https://doi.org/10.1186/s12933-018-0693-0
• [19:31] Variability of fasting plasma glucose and the risk of painful diabetic peripheral neuropathy in patients with type 2 diabetes — https://doi.org/10.1016/j.diabet.2018.01.015
• [21:00] Insulin resistance in type 1 diabetes: what is "double diabetes" and what are the risks? — https://doi.org/10.1007/s00125-013-2904-2

• Insulin drives glucose uptake, fat storage, and energy storage.
• Glucagon drives glycogen breakdown, liver fat oxidation, and ketone production.
• The insulin-to-glucagon ratio determines whether metabolism moves toward storage after carbohydrate intake or energy release during fasting and low carbohydrate intake.
• Type 2 diabetes disrupts this system when insulin and glucagon are both high, leaving the liver with a glucose-output signal while tissues are insulin resistant.

The adipose-tissue misconception The textbook idea that glucagon directly pulls fat out of human adipose tissue is incorrect for humans.

• Rodent data made glucagon look like a direct adipose lipolysis hormone through hormone-sensitive lipase activation.
• Human white fat has very low or undetectable glucagon receptor expression in mature adipocytes.
• The 2001 microdialysis work found no local glycerol rise in abdominal fat even with glucagon raised three to fourfold.
• The 2020 human-adipocyte work found low and variable receptor expression and meaningful lipolysis only at superphysiological glucagon levels.
• The 2022 adipocyte-specific receptor knockout mouse work found no change in fasting-induced lipolysis or body composition.
• Human fat loss is not glucagon yanking triglycerides directly out of fat cells.

The liver mechanism Glucagon's fat-burning work occurs in the liver, where glucagon receptors are abundant.

• Glucagon activates adenylate cyclase, raises cyclic AMP, activates PKA, and inactivates acetyl-CoA carboxylase.
• Inactivating acetyl-CoA carboxylase stops new fat synthesis and removes malonyl-CoA inhibition of CPT1.
• CPT1 then moves more fatty acids into mitochondria for oxidation.
• Glucagon also increases CPT1 transcription through CREB, expanding the liver's capacity to burn fat.
• The Yale Nature work connects glucagon to intrahepatic lipolysis through INSP3R1, calcium release, and ATGL.
• The 2024 Cell Metabolism human study shows glucagon infusion raising hepatic mitochondrial oxidation by about 50% in fatty liver disease.

Ketones and the insulin brake Glucagon-driven liver fat oxidation connects to ketone production when insulin is low.

• During fasting, oxaloacetate is diverted toward gluconeogenesis, leaving acetyl-CoA to condense into acetoacetate and beta-hydroxybutyrate.
• Liver-cell work supports glucagon as a driver of fatty acid oxidation and ketogenesis.
• The 2020 mouse work shows ketone production can persist without glucagon signaling during fasting.
• Low insulin is necessary; high insulin can overpower glucagon's fat-burning and ketone-producing effects.

Drug implications and lifestyle implications GLP-1 drugs, dual agonists, and triple agonists show why glucagon biology matters clinically.

• Semaglutide can produce about 15% weight loss over a little more than a year, mainly through appetite suppression, slower gastric emptying, and glucose control.
• A Boehringer Ingelheim dual GLP-1/glucagon agonist at 4.8 mg produced about 14.7% weight loss over 46 weeks and stronger liver-fat effects than GLP-1 alone.
• In MASH/NASH, the same dual-agonist program is tied to 83% biopsy-based steatohepatitis resolution versus 18% on placebo and improved fibrosis scores.
• Retatrutide adds GIP to GLP-1 and glucagon and produced nearly 24% weight loss at 48 weeks at the highest dose.
• These drugs are not routine standalone weight-loss tools; their strongest role is low-dose craving control paired with a smart low-carbohydrate diet.
• Reduced carbohydrate intake and fasting can improve glucagon signaling by shifting the ratio toward fuel release.

References

• [04:09] Glucagon and the Insulin:Glucagon Ratio in Diabetes and Other Catabolic Illnesses — https://doi.org/10.2337/diab.20.12.834
• [08:02] Physiological Levels of Glucagon Do Not Influence Lipolysis in Abdominal Adipose Tissue as Assessed by Microdialysis — https://doi.org/10.1210/jcem.86.5.7460
• [08:32] Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes — https://doi.org/10.1016/j.mce.2019.110696
• [09:06] Glucagon receptor signaling at white adipose tissue does not regulate lipolysis — https://doi.org/10.1152/ajpendo.00078.2022
• [11:50] Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis — https://doi.org/10.1038/s41586-020-2074-6
• [12:26] Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease — https://doi.org/10.1016/j.cmet.2024.07.023
• [14:59] The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition — https://doi.org/10.2337/db19-1216
• [16:25] Once-Weekly Semaglutide in Adults with Overweight or Obesity — https://doi.org/10.1056/NEJMoa2032183
• [17:27] Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial — https://doi.org/10.1016/S2213-8587(23)00356-X
• [17:51] A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis — https://doi.org/10.1056/NEJMoa2401755
• [18:50] Triple-Hormone-Receptor Agonist Retatrutide for Obesity — https://doi.org/10.1056/NEJMoa2301972

• Ben Bikman is a biomedical scientist focused on metabolic disorders, and the talk covers GLP-1 drugs, their consequences, and their use.
• The worldwide rise in overweight, obesity, and insulin resistance is the metabolic problem that makes GLP-1 drugs relevant.
• Insulin resistance affects more than half of adults worldwide and contributes to many plagues of prosperity.

Fat-cell biology and weight loss

• Fat mass expands through larger fat cells, more fat cells, or both; the usual human pattern is hypertrophy.
• Hypertrophic fat cells become insulin resistant because they run out of room to keep storing fat under insulin.
• Large fat cells also become hypoxic, pro-inflammatory, and leaky with free fatty acids, which drives whole-body insulin resistance.
• Metabolic weight loss means shrinking fat cells by reducing energy and reducing insulin.
• Carbohydrate control and structured fasting lower insulin and help shrink fat cells, while simple calorie cutting plus exercise increases hunger.

Why GLP-1 became a drug target

• The gut is a major endocrine organ, and incretins are gut hormones tied to blood-glucose control.
• Gastric bypass data make GLP-1 central because diabetes markers can improve within about one week before major fat loss.
• GLP-1 slows intestinal movement, signals the brain to reduce hunger, stimulates fat-cell lipolysis, supports ketogenesis, and suppresses glucagon.
• GLP-1-based glutide drugs began as anti-diabetic medications because glucagon suppression lowers blood glucose; weight loss was initially a modest side effect.

High-dose consequences

• The weight-loss versions are higher-dose versions of diabetes drugs, so the intestines can be slowed too much.
• Excess gut slowing can reach intestinal paralysis, and body-weight loss can include substantial lean mass along with fat mass.
• After stopping a GLP-1 drug, weight often returns, while lost lean mass may not return as readily, leaving a higher body-fat percentage.
• Real-world persistence is poor: US and UK type 2 diabetes data show roughly two-thirds to 70% discontinuation by 24 months.

Insulin, fat-cell number, and receptor pressure

• The idea that GLP-1 drugs disprove insulin control of fat storage is inaccurate; whole-body studies show insulin secretion can fall during GLP-1 exposure after meals.
• GLP-1 agonists may also move preadipocytes toward differentiation, which can mean smaller fat cells during active weight loss but more capacity for later fat regain.
• Chronic GLP-1 receptor agonism can make receptors less responsive and may lower endogenous GLP-1 production.

Drug combinations and food-based GLP-1 release

• The next wave of obesity drugs pairs GLP-1 action with other appetite signals such as amylin, while muscle-preservation drugs are being tested for lean-mass loss.
• Endogenous GLP-1 can be increased with soluble fiber, yerba mate, allulose, protein, and natural fats.
• Saturated and monounsaturated natural fats produced much stronger GLP-1 responses than refined seed oil in the fat-comparison data, and recent low-carbohydrate meal data showed about triple the GLP-1 response of a low-fat meal.

Practical stance

• Lower-dose GLP-1 drugs were more favorable, but higher-dose use makes dose the key issue.
• The best use is the lowest effective dose under clinician guidance, especially where severe carbohydrate addiction blocks dietary control.
• Any GLP-1 use belongs with structured resistance exercise and nutrient priority: essential amino acids and essential fats come first, while essential carbohydrates do not exist.
• When appetite is low, focus on fats and prioritize protein.

References [11:29] Remission of type 2 diabetes after gastric bypass and banding: mechanisms and 2 year outcomes — https://doi.org/10.1097/SLA.0b013e3181efc49a [13:49] Incretin Levels and Effect Are Markedly Enhanced 1 Month After Roux-en-Y Gastric Bypass Surgery in Obese Patients With Type 2 Diabetes — https://doi.org/10.2337/dc06-1549 [17:49] Impact of Semaglutide on Body Composition in Adults With Overweight or Obesity: Exploratory Analysis of the STEP 1 Study — https://doi.org/10.1210/jendso/bvab048.030 [18:37] Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension — https://doi.org/10.1111/dom.14725 [19:48] Real-World Adherence and Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists Therapy in Type 2 Diabetes Mellitus Patients in the United States — https://doi.org/10.2147/PPA.S277676 [19:48] Real-world weight change, adherence, and discontinuation among patients with type 2 diabetes initiating glucagon-like peptide-1 receptor agonists in the UK — https://doi.org/10.1136/bmjdrc-2021-002517 [22:30] Normalization of Glucose Concentrations and Deceleration of Gastric Emptying after Solid Meals during Intravenous Glucagon-Like Peptide 1 in Patients with Type 2 Diabetes — https://doi.org/10.1210/jc.2003-030049 [25:03] GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis — https://doi.org/10.1159/000478872 [27:22] Chronic Exposure to GLP-1R Agonists Promotes Homologous GLP-1 Receptor Desensitization In Vitro but Does Not Attenuate GLP-1R-Dependent Glucose Homeostasis In Vivo — https://doi.org/10.2337/diabetes.53.suppl_3.S205 [27:49] Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial — https://doi.org/10.1111/dom.14242 [28:47] Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a randomised, controlled, phase 1b trial — https://doi.org/10.1016/S0140-6736(21)00845-X [30:33] Nutritional modulation of endogenous glucagon-like peptide-1 secretion: a review — https://doi.org/10.1186/s12986-016-0153-3 [30:37] Mate tea (Ilex paraguariensis) promotes satiety and body weight lowering in mice: involvement of glucagon-like peptide-1 — https://doi.org/10.1248/bpb.34.1849 [30:46] GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose — https://doi.org/10.1038/s41467-017-02488-y [32:40] The Effect on Glucagon, Glucagon-Like Peptide-1, Total and Acyl-Ghrelin of Dietary Fats Ingested with and without Potato — https://doi.org/10.1210/jc.2009-2559

• Ken Berry brings Anthony Chaffee on for a "state of carnivore" update and for correction of myths after recent controversy.
• Berry sees carnivore as a powerful 90-day intervention for chronic issues such as type 2 diabetes, prediabetes, acne, PCOS, menstrual problems, perimenopause, and fatty liver.
• Chaffee is an American physician in Western Australia using carnivore, ketogenic diets, and lifestyle to improve metabolic health and reduce medication reliance.

Recent carnivore reversals

• Berry sees the new "add carbs back" wave as recycled high-carbohydrate, low-fat advice, not a discovery.
• The old food-pyramid pattern is the diet Berry grew up with and the diet he links to his mother's diabetes after decades.
• Berry and Chaffee connect some reversals to views, business incentives, and fear around cortisol, thyroid, or long-term carnivore anecdotes.
• Chaffee says long-term ketogenic trials and meta-analyses do not show persistent hypercortisolism; early cortisol rises remain normal and later settle.
• Berry suspects some hidden hypercortisol syndromes surface because keto/carnivore patients and doctors check more labs.
• Berry and Chaffee reject rice, fruit, or starch as magic fixes for metabolic dysfunction; short-term feeling better does not prove long-term health benefit.

Dairy

• Chaffee says adults probably need no dairy for optimal nutrition because mammals are normally weaned onto the adult diet.
• Dairy contains valuable fats, minerals, and fat-soluble vitamins, including odd-chain fatty acids, but it also contains lactose, insulin signals, and caseomorphins.
• Berry and Chaffee see dairy as useful where it prevents malnutrition, but unnecessary and often counterproductive when meat and animal fat already supply nutrients.
• Berry thinks fermented dairy such as yogurt or kefir may be less inflammatory than milk because fermentation reduces lactose and alters proteins, but it still is not a daily adult requirement.

Plants and fermentation

• Chaffee explains "plants are trying to kill you" through plant defense chemistry, not literal intent.
• He learned this from a cancer-biology professor who taught that edible plants can still contain carcinogenic or harmful natural toxins.
• The speakers name lectins, oxalates, tannins, phytates, saponins, cyanogenic glycosides, goitrogens, and other plant compounds as possible chronic irritants.
• Beans, almonds, and kale serve as examples of plant foods whose toxic load can require soaking, boiling, fermentation, crossbreeding, or restriction.
• Berry adds that domestication, cooking, soaking, sprouting, roasting, and fermentation reduce phytotoxins but do not remove all of them.
• Fermented vegetables and dairy are less toxic versions of plant or dairy foods, not essential foods.

Microbiome and oral health

• Berry and Chaffee think microbiome science is still too immature for confident probiotic testing, supplement targeting, or species manipulation.
• Chaffee thinks a carnivore diet can change the oral microbiome and that saliva may help seed the gut microbiome during meals.
• They connect carbohydrate-fed oral bacteria with cavities, gingivitis, plaques, and glioblastoma-related findings.
• Berry says gingivitis and periodontitis often go into remission after 90 days of carnivore in the people he has seen.
• They use oral health as a proxy for overall health: a natural diet should not rot teeth.

Meat choices and daily eating

• Chaffee says all meat is beneficial, and people should eat the meat they enjoy, tolerate, and can afford.
• Ruminant meat may work better for autoimmunity, but pork, chicken, fish, and other meats are acceptable when enough fat is included.
• Chaffee usually eats beef, eggs, and fatty steaks once daily, adding a second meal when training raises appetite.
• Berry's baseline is also beef and eggs daily, with occasional pork, chicken, fish, cod liver, or sardines.

Labs, lipids, and A1C

• Berry asks about Robert Sikes's concern that some carnivores develop high triglycerides, high glucose, low HDL, inflammation, rising A1C, and cortisol issues.
• Berry sees mild A1C elevation on carnivore as often false or misleading when fructosamine is normal, possibly because red blood cells live longer.
• Chaffee has rarely seen high triglycerides, low HDL, and pattern-B LDL in strict patients, and in his examples stress and poor sleep were the shared factor.
• The speakers do not chase lab numbers alone; they focus on the patient, symptoms, context, sleep, stress, exercise, and diet creep.
• Chaffee says daily hard training can raise glucose transiently and move A1C upward without meaning pathology.

Fruit, honey, fructose, and fatty liver

• Berry worries about high-fruit and high-honey animal-based diets because A1C and fructosamine measure glucose glycation, not fructose glycation.
• Research in the exchange indicates fructose is much more glycating than glucose and may create long-term vascular damage even without high A1C.
• Chaffee warns that adding fruit and honey can slide into broader carb intake and weight regain for some people.
• Berry and Chaffee connect fructose to fatty liver through hepatic metabolism and cite Lustig's child fructose-restriction work.
• Foie gras serves as a practical example that carbohydrate overfeeding can fatten the liver rapidly.
• Berry and Chaffee reject the idea that eating fat causes fatty liver because dietary fat enters lymphatics before the bloodstream, not direct liver loading.

Protein, gluconeogenesis, creatine, and vitamin C

• Chaffee says protein does not force harmful gluconeogenesis; glucose production is demand-driven and often comes from glycerol during fat breakdown.
• Berry and Chaffee reject the fear that ketogenic or carnivore eating causes muscle loss, using old-school steak-and-eggs bodybuilding as a counterexample.
• Berry gets about 6 g creatine daily from meat and questions whether carnivore eaters need creatine powder.
• Chaffee thinks meat supplies enough creatine for ordinary muscle and brain needs, while high-dose creatine may have a role after concussion or TBI.
• Chaffee says carbohydrate intake raises vitamin C need and competes with vitamin C handling, while meat supplies hydroxyproline and hydroxylysine for collagen.
• Berry says low measured vitamin C on near-zero-carb carnivore does not necessarily equal functional scurvy when wound healing is rapid.

Deficiencies, thyroid medication, and eggs

• Berry has seen rare thiamine deficiency in narrow beef-only carnivores, resolved by adding pork.
• Chaffee usually sees vitamins and minerals rise, but he checks B12, folate, zinc, magnesium, and malabsorption patterns when progress stalls.
• Chaffee found coffee timing could block thyroid medication absorption in many patients, requiring one to two hours before coffee.
• Chaffee uses low B12 despite meat or liver intake as a clue for MTHFR issues, malabsorption, or pernicious anemia antibodies.
• Berry and Chaffee see egg sensitivity as uncommon and often linked to egg whites; Berry thinks fertilized backyard eggs may be better tolerated.

Carbohydrates, anthropology, and diabetes history

• Dietary carbohydrate is nonessential, and the National Academies/Institute of Medicine language gives zero as the lower limit with adequate protein and fat.
• Chaffee says human insulin fits protein better than carbohydrate spikes because modern rapid insulin had to be engineered for glucose excursions.
• Berry and Chaffee connect agricultural grains, sugar, and starch with dental decay, smaller bodies, smaller brains, and chronic disease after agriculture.
• Chaffee says amylase gene expansion after agriculture means mass starch eating became common only recently in human history.
• Berry and Chaffee say seed oils cannot be the only cause of metabolic disease because diabetes and carbohydrate restriction predate modern seed oils.
• Chaffee cites Osler-era diabetes texts using near-zero carbohydrate, protein, and fat before insulin.

Fasting and cancer metabolism

• Chaffee prefers intuitive feast-and-fast eating over deliberate food withholding when hungry.
• He warns that fasting can backfire when people under-eat on feeding days and suppress metabolism.
• He sees occasional 48-hour fasting as potentially useful for resetting hunger signals.
• For cancer, fasting may lower glucose, raise ketones, reduce GKI, and reduce exogenous glutamine, but the glutamine piece remains unproven.
• For most people, carnivore with hunger-based eating is enough; fasting is optional, not required.

References

• [00:06] Low-carbohydrate diets and men's cortisol and testosterone — https://doi.org/10.1177/02601060221083079
• [00:06] Nutritional Intervention in Cushing’s Disease: The Ketogenic Diet’s Effects on Metabolic Comorbidities and Adrenal Steroids — https://doi.org/10.3390/nu15214647
• [00:12] Nutrition and Physical Degeneration — https://archive.org/details/nutritionphysica0000pric
• [00:39] Formation of Fructose-Mediated Advanced Glycation End Products and Their Roles in Metabolic and Inflammatory Diseases — https://doi.org/10.3945/an.116.013912
• [00:42] Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome — https://doi.org/10.1002/oby.21371
• [00:42] Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity — https://doi.org/10.1053/j.gastro.2017.05.043
• [00:56] Altered Intestinal Absorption of L-Thyroxine Caused by Coffee — https://doi.org/10.1089/thy.2007.0222
• [00:56] Vitamin B12 status and rate of brain volume loss in community-dwelling elderly — https://doi.org/10.1212/01.wnl.0000325581.26991.f2
• [01:04] Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids — https://doi.org/10.17226/10490
• [01:10] Diabetes Research and Care Through the Ages — https://doi.org/10.2337/dci17-0042
• [01:11] Has carbohydrate-restriction been forgotten as a treatment for diabetes mellitus? — https://doi.org/10.1186/1743-7075-5-10
• [01:12] The Principles and Practice of Medicine — https://archive.org/details/principlespracti1892osle

• The body can burn calories without turning them into usable energy.
• Mitochondria normally convert fuel into ATP, and uncoupling lets some fuel energy leak away as heat.
• Insulin makes mitochondria more efficient and helps the body store energy more easily.
• Low insulin with rising ketones makes mitochondria more uncoupled, so more energy leaves as heat and less is stored as fat.
• Calories matter, and hormones help determine what the body does with those calories.

Mitochondrial coupling and uncoupling

• Mitochondria are like a car engine: fuel burning is the RPM, and ATP production is the useful forward motion.
• Coupling means fuel burning is linked to useful work: oxygen use, proton-gradient pressure, and ATP production move together.
• Uncoupling means fuel burning continues while useful ATP output lags; the energy exits as heat.
• Uncoupling is not a failure; it is a built-in way to waste fuel as heat.

Fat tissue and heat

• White fat is the familiar pinchable fat built for storage, with tightly coupled mitochondria that conserve energy.
• Brown fat is packed with mitochondria and uncoupling protein, so its job is heat production.
• Newborns use brown fat for warmth because they cannot shiver enough with muscle.
• Adults retain brown fat, and cold exposure activates it.
• Adults with more brown fat activity tend to resist weight gain and its metabolic consequences.

Measuring coupling

• The lab measures oxygen consumption as the engine speed and ATP production as the useful output.
• Tight coupling means oxygen use and ATP production rise together.
• Uncoupling means oxygen use stays high or rises while ATP production fails to keep pace.

Historical diabetes clue

• Benedict and Joslin studied severe diabetes before insulin therapy was available.
• The patients had what is now type 1 diabetes without insulin therapy: essentially no endogenous insulin.
• They burned energy about 15% to 20% above the level expected from body size.
• They were losing weight rapidly despite excess calorie intake.
• A 1984 study with better instruments found the same pattern in type 1 diabetes, with measured expenditure around 2,040 kcal/day versus a predicted 1,700 kcal/day.
• Insulin injection lowered energy expenditure within minutes, back toward the predicted level.
• Glucose lost in urine explains some wasted calories but cannot explain a higher measured metabolic rate.
• The missing mechanism points to mitochondria, including mitochondria inside fat tissue.

Insulin in fat mitochondria

• The lab raised insulin chronically in rodents for several weeks and examined mitochondria in fat.
• High insulin lowered mitochondrial respiration and shifted mitochondria toward tighter coupling.
• Brown fat became much more tightly coupled, subcutaneous fat became more coupled, and visceral fat shifted little because it was already largely coupled.
• Chronic high insulin lowered whole-body energy expenditure in the animals.
• Insulin is the body’s storage signal: it directs fat cells to take up and hold fuel, and it makes their mitochondria more frugal.
• This mechanism helps explain why insulin therapy often brings weight gain in type 1 diabetes and can make weight gain easier in type 2 diabetes.

Ketones as the opposing signal

• When insulin is low from fasting, carbohydrate restriction, or type 1 diabetes without insulin, the liver turns fat into ketones.
• Beta-hydroxybutyrate is the dominant ketone and works as both fuel and signal.
• The lab tested ketones in cultured fat cells, rodent fat tissue, and human fat biopsies.
• Across all three systems, ketones made fat mitochondria respire faster.
• Cultured fat cells burned roughly 90% more energy; rodent tissue rose even more; human subcutaneous fat from people in ketosis rose 128% higher than non-ketotic comparison tissue.
• ATP did not rise in proportion, creating the signature of uncoupling.
• Gene activity for uncoupling machinery also increased with beta-hydroxybutyrate.

White fat can beige

• White fat is not locked into a permanently frugal identity.
• Under the right signals, especially ketones, subcutaneous white fat can build more mitochondria and take on brown-fat traits.
• This browning or beiging makes storage fat behave partly like heat-producing fat.
• Type 1 diabetes without insulin therapy combines very low insulin with high ketones, so the old 15% to 20% rise in metabolic rate fits the ketone-uncoupling mechanism.

Obesity model

• The calories-only model and the insulin-hormone model are two halves of the same mechanism.
• Calories provide the fuel; hormones determine how efficiently that fuel is stored or wasted as heat.
• High insulin keeps fat-cell mitochondria tightly coupled, so calories are stored efficiently.
• Low insulin with elevated ketones makes the same mitochondria leakier, so more calories leave as heat.
• The fat-cell mitochondrion is where energy balance and hormone signaling meet.

Practical meaning

• A very low-carbohydrate diet can create a metabolic advantage because more total energy is burned at equal calories.
• Controlled human feeding studies have found roughly 200 to 300 kcal/day greater energy expenditure on very low carbohydrate intake in one study.
• That extra calories-out can be comparable to a substantial exercise session.
• Early fasting can raise resting energy expenditure while insulin falls and ketones rise.
• Some fasting-related expenditure comes from the nervous system and epinephrine, but the timing matches the fat-mitochondria pattern.

Closing point

• The type of calories eaten shapes the hormone environment they enter.
• Chronically high insulin makes the body file fuel away with high efficiency.
• Low insulin with ketones shifts fat-cell mitochondria toward the wasteful end of the dial.
• Weight loss becomes easier when carbohydrates are controlled, insulin stays low, and fat mitochondria can be frivolous with energy.

References

• [07:00] Cold-Activated Brown Adipose Tissue in Healthy Men — https://doi.org/10.1056/NEJMoa0808718
• [07:00] Functional Brown Adipose Tissue in Healthy Adults — https://doi.org/10.1056/NEJMoa0808949
• [07:00] Brown Adipose Tissue in Morbidly Obese Subjects — https://doi.org/10.1371/journal.pone.0017247
• [09:00] A Biometric Study of Human Basal Metabolism — https://doi.org/10.1073/pnas.4.12.370
• [09:00] A Study of Metabolism in Severe Diabetes — https://archive.org/details/b32859417
• [10:00] Increased Energy Expenditure in Poorly Controlled Type 1 (Insulin-Dependent) Diabetic Patients — https://doi.org/10.1007/BF00253494
• [13:00] Insulin Selectively Reduces Mitochondrial Uncoupling in Brown Adipose Tissue in Mice — https://doi.org/10.1042/BCJ20170736
• [16:00] Early Decrease in Resting Energy Expenditure with Bedtime Insulin Therapy — https://doi.org/10.1016/j.diabet.2009.04.003
• [18:00] Ketones Elicit Distinct Alterations in Adipose Mitochondrial Bioenergetics — https://doi.org/10.3390/ijms21176255
• [20:00] Mitochondrial Biogenesis and Increased Uncoupling Protein 1 in Brown Adipose Tissue of Mice Fed a Ketone Ester Diet — https://doi.org/10.1096/fj.11-200410
• [24:00] Effects of a Low Carbohydrate Diet on Energy Expenditure During Weight Loss Maintenance: Randomized Trial — https://doi.org/10.1136/bmj.k4583
• [24:00] Energy Expenditure and Body Composition Changes After an Isocaloric Ketogenic Diet in Overweight and Obese Men — https://doi.org/10.3945/ajcn.116.133561
• [25:00] Resting Energy Expenditure in Short-Term Starvation Is Increased as a Result of an Increase in Serum Norepinephrine — https://doi.org/10.1093/ajcn/71.6.1511

TEDx and the lion diet

• Mikhaila Peterson gave a TEDx talk about how the lion diet, an all-meat diet, put her autoimmune disorder into remission after crippling arthritis and two joint replacements.
• Mikhaila Peterson followed TEDx rules carefully because her diet story is anecdotal, and she ended by asking the medical system to study it further.
• TEDx would not post Mikhaila Peterson's talk after four months of back-and-forth, while other vegan disease-cure talks stayed available under guidelines they did not apply to her case.
• Harvard later published a carnivore-diet study about others who had disease remission, so this diet deserves serious medical attention.

Early arthritis and immune suppression

• At age two, Mikhaila Peterson began walking with her feet turned out, and by grade two she had juvenile rheumatoid arthritis active in 37 joints.
• She used methotrexate and naproxen, had cortisone injected into 17 joints, could not sit cross-legged, and used a fat pencil because she could not close her hand.
• In grade four, Enbrel and methotrexate injections put her into a medically induced remission, and she went from nearly wheelchair-bound to playing sports.
• At the same time, her mental health collapsed into OCD symptoms, suicidal thoughts, major depressive disorder, and possible bipolar type 2 with hypomania.

Fatigue, pain, and more medication

• By grade eight, she had biting sensations over her body and chronic fatigue so severe that she could not wake up and fell asleep in class.
• By grade eleven, arthritis destroyed the cartilage in her right hip, pain stopped her from sleeping, and she used OxyContin before a hip replacement at 17.
• While she healed from the hip replacement, her body destroyed the cartilage in her left ankle, and she later had that ankle replaced.
• At university, Wellbutrin led to a grand mal seizure, an SNRI made her intensely angry, fatigue made her miss final exams, and she dropped out.

Rash and the search for diet triggers

• After returning home, a rash spread from her back and bum to her face, and dermatologists gave no useful answer.
• She was using Tylenol 3 for shoulder pain, 40 mg of Adderall to wake up, dapsone for skin healing, 40 mg of escitalopram for depression, an inhaler for infections, and a prescription antihistamine for severe allergies.
• She found dermatitis herpetiformis, the skin manifestation of celiac disease, and cut gluten because celiac disease can be triggered by gluten.
• She stopped immune suppressants, monitored symptoms closely, and kept searching because gluten removal was not enough.

Meat, greens, and the first remission

• In September 2015, she reduced her diet to meat, greens, and some root vegetables while removing foods she thought could cause inflammation.
• That month her skin healed for the first time in years, and she lost three pant sizes of bloating she had not known was there.
• Two months in, her fatigue disappeared for the first time since grade eight, and she stopped taking Adderall.
• Three months in, her depression disappeared for the first time in her life, and she stopped escitalopram over two weeks without knowing SSRI withdrawal existed.

Food reactions and withdrawal

• After reintroducing soy, she had a severe autoimmune response: digestive upset, full-body itching, depression worse than ever, mouth ulcers, arthritis, and rash.
• Around the same time, SSRI withdrawal mixed with autoimmune symptoms and food sensitivities, and each food reintroduction caused reactions that lasted 24 days.
• She eventually stopped reintroducing foods, became pregnant, and later returned to meat and greens to control symptoms.
• While breastfeeding, her wrist buckled, arthritis returned, she was itchy everywhere, and the earlier diet no longer worked.

Beef, lamb, salt, and water

• She cut out everything except beef, and after two weeks the itching went away and her joints began to feel better.
• Six weeks into the all-beef diet, her depression lifted and she stopped crying in the morning.
• Five months later, her anxiety lifted, and she felt back in heaven compared with how she had been living.
• The diet became beef, lamb, salt, and water, which she calls the lion diet.

Family results and medical attention

• Her mother used the diet and her osteoarthritis went away; her father used it and lost 70 pounds, and his GERD and psoriasis went away.
• She has heard from thousands of people with autoimmune disorders who tried similar diets and saw similar results.
• She now runs a company, hosts a podcast, raises her child, and shares her experience so people can see what the diet does for her.
• Sick people feel isolated and miserable, and what would be really cool is the medical community taking this seriously and doing case studies.

References

• [00:16] TEDx Content Guidelines — https://storage.ted.com/tedx/manuals/tedxcontentguidelines.pdf
• [00:42] Behavioral Characteristics and Self-Reported Health Status among 2029 Adults Consuming a "Carnivore Diet" — https://doi.org/10.1093/cdn/nzab133

• Ketogenic nutrition entered this work because anorexia nervosa remains severe, deadly, and biologically hard to move with current care.
• Weight restoration is necessary, but it often leaves fears about eating, body shape, and weight intact or worse.
• The unresolved clinical problem is the persistent drive for weight loss after weight normalization and the high relapse risk after intensive care.
• Barbara Scolnick's niece's recovery with ketogenic nutrition and the later five-person pilot made this pathway worth testing.
• The working model is that ketogenic metabolism can affect brain energy, anxiety, and eating-disorder thoughts, not simply body weight.

Trial design and monitoring

• The trial enrolled 22 adults with prior underweight anorexia nervosa who were weight-normalized or mildly underweight at entry, and 18 completed.
• The design used a two-week ketogenic induction followed by 12 weeks of maintained ketosis.
• The diet target was 70% fat, 20% protein, and 10% carbohydrate, with blood ketones around 0.5 or higher.
• Participants met weekly with a dietitian and weekly with Guido Frank to track ketones, labs, symptoms, food logistics, and safety.
• The practical work included restaurants, family dynamics, friends, and the large mental shift from fear of fat to using fat deliberately.

Main results

• The main measures covered eating-disorder symptoms, depression, and related questionnaire scores from study entry through study end.
• Symptoms rose slightly early in weight concern because fat was the macronutrient most feared by many participants.
• Over time, eating-disorder scores and depression scores steadily fell.
• Study completers moved below the eating-disorder questionnaire cutoff, with the global score falling from about 4.1 to about 1.7.
• Compared with partial-hospital data moving from about 4.08 to about 3.09 at discharge, this change was unusually large.
• Seventy-two percent of completers had very large gains, with eating-disorder and depression scores in the normal range by the end.

Weight, safety, and non-response

• Weight was stable across the study, and the BMI graph was essentially flat week by week.
• A few participants entered near BMI 18, briefly dipped under the allowed boundary, added fats, and did not relapse.
• No participant relapsed into anorexia nervosa during the study.
• Five completers did not improve as strongly on eating-disorder thoughts and behaviors; two were flat and three improved modestly.
• Depression still improved in those weaker eating-disorder responders.
• Poor self-esteem emerged as the main hurdle for weaker response, so some patients need direct work on self-esteem and temperament as well.

Clinical experience and mechanism

• Many participants gained liberation from the constant cage of food, fat, shape, and next-meal fear.
• Participants had more mental space, more calm, more energy, and more ability to separate themselves from eating-disorder thoughts.
• The energy idea matters because anxious, perfectionistic patients may feel out of control when stress drains usable brain energy.
• Ketogenic nutrition may give a steadier energy source, reduce anxiety, and reduce the need to regain control through food restriction.
• Caroline Beckwith's earlier experience fit this pattern because the intrusive eating-disorder thoughts and voices went away.
• Some participants said they had their life back, which matters beyond a significant rating-scale change.

Controversy, implementation, and next studies

• The main pushback is that restrictive diets are often viewed as unsafe in anorexia nervosa, especially because keto is publicly tied to weight loss.
• Ketogenic nutrition is not automatically a weight-loss diet; in this trial it was weight-maintaining and supervised.
• The "all food is good food" premise should be open to data and not accepted as automatic truth for every person.
• Weight-normalized people with persistent shape, weight, and eating distress are the group with the clearest current fit.
• Underweight patients need a safety-first path with close monitoring, frequent labs, and more data before broad use.
• The next work includes PET brain-glucose studies before and after ketogenic nutrition, underweight recruitment, bulimia nervosa exploration, and randomized controlled trials.

References

• [00:34] Symptom impact and safety of ketogenic therapy in adults with anorexia nervosa: a feasibility trial — https://doi.org/10.1038/s43856-026-01644-0
• [03:44] Remission from Chronic Anorexia Nervosa With Ketogenic Diet and Ketamine: Case Report — https://doi.org/10.3389/fpsyt.2020.00763
• [04:04] Ketogenic diet and ketamine infusion treatment to target chronic persistent eating disorder psychopathology in anorexia nervosa: a pilot study — https://doi.org/10.1007/s40519-022-01455-x
• [04:50] Therapeutic ketogenic diet as treatment for anorexia nervosa — https://doi.org/10.3389/fnut.2024.1392135
• [13:04] Measuring Clinical Efficacy Through the Lens of Audit Data in Different Adult Eating Disorder Treatment Programmes — https://doi.org/10.3389/fpsyt.2020.599945
• [22:59] Ketogenic Diet and Brain Response in Anorexia Nervosa — https://clinicaltrials.ucsd.edu/trial/NCT06540703

• Clair grew up in Canada, entered biology at McGill, and won a full Oxford scholarship to study stem cell biology.
• Clair wanted root-cause biology, so her PhD focused on stem cells that give rise to the human embryo.
• Clair then moved toward clinical use, including infertility models in a dish and later environmental triggers for Alzheimer's disease.
• In infertility work, mTOR, nutrient sensing, autophagy, and DNA remodeling mattered for making sperm and egg in a dish.
• In Alzheimer's work, rats received common pesticides and developed Alzheimer's- or Parkinson's-like disease patterns, with vitamin D and the epigenome in view.

Autophagy, mTOR, and aging biology

• Autophagy is cellular recycling: old proteins, fats, amino acids, mitochondria, and other damaged material can be broken down and reused.
• Autophagy works better in youth, declines with age, and can be adjusted by diet and lifestyle.
• High insulin lowers autophagy; low insulin during carnivore eating can allow more autophagy, while growth signals can still reduce it when needed.
• mTOR senses growth factors such as protein, supports building, and interacts with autophagy.
• AMPK, glucose pathways, mTOR, insulin, and autophagy sit at the center of longevity biology.

From vegan to carnivore

• Clair spent about ten years vegan because the culture, marketing, and university environments made veganism attractive and easy.
• Early benefits did not last; insomnia became the central problem, followed by depression, brain fog, and low energy.
• Psychiatry at Oxford helped, but it did not fix the underlying physical condition.
• Carnivore changed sleep first, moving Clair toward eight to ten hours and reducing anxiety, rumination, depression, and brain fog.
• Better sleep and clearer thinking helped Clair become more productive and learn coding and engineering during biotechnology layoffs.

Longevity work and therapies

• Longevity companies cannot make an FDA-approved drug for longevity itself, so they focus on diseases of aging.
• The current therapeutic strategy targets pathways such as autophagy for Alzheimer's disease, not isolated mutations.
• A secret drug program aims to enhance autophagy in the brain and pair it with keto metabolic therapy.
• Drugs are not Clair's preference for herself, but devastating disease can require intervention when lifestyle alone is too slow.
• Longevity work also targets inflammation, immune function in the body and brain, stem cells, and rejuvenation.

Female hormones and reproductive aging

• Female hormone effects from carnivore are not well defined, but ovarian aging uses mechanisms similar to wider body aging.
• Repair capacity, mTOR, and nutrient sensing matter for ovarian aging.
• Carnivore and ketogenic patients of Ken Berry and Robert Kiltz becoming pregnant later in life point toward reproductive healthspan as a practical target.
• Menopause came up as an evolutionary question, and diet change was linked in practice to fewer hot flushes, less irritability, and more calm.

Epigenome and rejuvenation

• Rejuvenation technology uses the epigenome: DNA organization changes with age, and environmental inputs can shape that organization.
• The genome accounts for about 20% of fate in Clair's explanation, while the environment works through the epigenome for much of the rest.
• The 2012 Nobel Prize discovery showed adult cells can be turned into stem cells, and partial use of those factors aims to make old cells younger without making embryos.
• David Sinclair's vision work and the related clinical direction make partial reprogramming relevant to blindness, hearing loss, arthritis, and other age-related problems.

Community, creativity, observed reality

• Community helped Clair survive depression during vegan years, and the mitochondrial connection remains speculative.
• Carnivore mental clarity helps Clair's creative work as a DJ and artist.
• Academic environments were mostly skeptical of carnivore, but improved productivity and health made the results visible.
• Colleagues who try carnivore often struggle when they eat too little fat, which can damage energy and hormones.
• Animal and insect data are not the same as human use, so clinical observation from doctors and health coaches matters.
• Real people improving kidney function, type 2 diabetes, blood pressure, and arthritis motivates work that helps now while therapies take years.
• Longevity therapy aims to improve standard care by reducing inflammation and increasing autophagy, and carnivore works through overlapping mechanisms.

References

• [00:23] Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors — https://doi.org/10.1016/j.cell.2006.07.024
• [00:23] In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming — https://doi.org/10.1016/j.cell.2016.11.052
• [00:24] Reprogramming to recover youthful epigenetic information and restore vision — https://doi.org/10.1038/s41586-020-2975-4
• [00:24] A Phase 1 Single Dose Study to Evaluate the Safety and Tolerability of ER-100 in Optic Neuropathies [Open Angle Glaucoma (OAG) and Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)] — https://clinicaltrials.gov/study/NCT07290244