Episode 31 – Richard Morris joins Gabor & Raphael for a nutrition nerd safari

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Show notes:

  • Richard’s website is http://2ketodudes.com/ and Twitter is @2ketodudes
  • Richard gives his professional background; after half a maths degree he changed direction to a successful career on Wall Street and as a computer coder, working long hours with little sleep during which he became diabetic and packed on the fat.
  • Richard mentions a few examples of doctors with an engineering background, like Dr.Bernstein and Dr.Naiman, as well as engineers with excellent medical insight such as Ivor Cummins and Dave Feldman.
  • Raphael asks Richard to explain how he deals with the deluge of requests to sell exogenous ketones.
  • Richard explains how the chirality of a molecule, meaning whether it is the left and right-hand version, can affect how our metabolism handles it.
  • Richard gives the notorious thalidomide example, a drug that when initially released was of the wrong chirality and led to serious birth defects. Richard worries that the unresolved question about the appropriate chirality of exogenous ketones may harm the ketogenic diet’s hard won reputation.
  • Richard raises the concern that ‘artificially’ tipping the acetoacetate to beta-hydroxybutyrate ratio by taking exogenous beta-hydroxybutyrate may then lead to unwanted effects on our cellular redox states (the NAD+/NADH ratio).
  • Gabor is not a fan of supplements, in general.
  • However, Gabor does supplement with vitamin D3 during the winter time in Hungary.
  • Raphael explains that he supplements 300mg of Magnesium, 300mg of Potassium and 21mg of Zn daily because he estimates the risk-reward ratio might be favorable given I was chronically inflamed growing up due to my asthma and allergies. People with pulmonary issues are more likely to be Magnesium deficient.
  • Richard emphasizes that our body evolved to handle beta-hydroxybutyrate within a certain context (low insulin, low blood sugar…) and that it is not only a substrate contributing to ATP but also a signaling molecule.
  • Raphael and Richard mention how the FDA approved Precision Xtra® blood glucose and ketone meter only reads the D-beta-hydroxybutyrate (right-handed) isoform of the molecule, yet many lab made ketones are the left-handed L-beta-hydroxybutyrate molecules – asking, can it measure ketone levels accurately when taking left-handed exogenous ketones?
  • Raphael points out that not all exogenous ketones are the same. There are salts, esters and come with other products to make it palatable (amongst other desirable characteristics).
  • Raphael says that Dr.D’Agostino has a very favorable view of (certain) exogenous ketones.
  • Raphael suggests applying the precautionary principle to exogenous ketones.
  • Raphael asks what the contexts are for ‘keto-ish’ being good enough vs a particular blood level of beta-hydroxybutyrate being necessary?
  • Raphael asks what level of blood beta-hydroxybutyrate determines ketosis?
  • Richard and Gabor mentions factors affecting how quickly one gets back into ketosis (sleep, nature of carbs, what carbs are eaten with, metabolic flexibility…)
  • Gabor raises the possibility that carbs + fat may kick you out of ketosis quicker than carbs alone.
  • Raphael brings up Marty Kendall’s questions posed to Dr.Ken Ford after the fantastic STEM-talk podcast episode with Nina Teicholz, regarding exogenous ketones, NAD+/NADH and at what blood level of beta-hydroxybutyrate is one in ketosis.
  • Richard mentions Virta Health’s great results visible in their recently published year-long randomized controlled pilot trial.
  • Raphael mentions (@ascarbs) Andrew Scarborough’s case where exogenous ketones seemingly help with various aspects of his (now past!) brain tumor.
  • Richard mentions that aspects of ketone metabolism are being considered for future astronauts traveling to Mars. Who but Dr.D’Agostino would be involved in such a cool thing!
  • Raphael mentions how radiation can deplete NAD+ and ketone metabolism may help replenish NAD+.
  • Raphael brings up The Protein Question (discussed in episode #30)
  • Richard notes that (the rare instance) of protein poisoning can happen – unlike fat or carbohydrate poisoning – due to ammonia buildup. *This is known to happen in hypocaloric scenarios called ‘rabbit starvation’ where only lean meats like rabbit are available. In fed, isocaloric, scenarios it’s difficult to know what the upper limits are protein intake are.
  • Richard mentions how unfortunate it is that some people pushing ‘high-protein’ diets not only want to feel vindicated eating that way but want others to eat that way too.
  • The point is made that in an isocaloric scenario it’s not generally feasible to consume much about 35% of calories from protein, which in grams is approximately 200-300g/day on a 2,000-2,700kcal/day diet [assuming 4kcal per gram of protein and 9kcal per gram of fat].
  • Riched posits crossover trials looking at high levels of protein consumption may be confounded by the fact that the washout period between crossovers enables to properly buffer the buildup of ammonia, possibly giving a false sense of security about the very high end of protein intake in weight stable scenarios.
  • Raphael asks Gabor what he think about the effect to ‘up the protein’ to achieve caloric restriction when people are stalling in their fat-loss efforts.
  • Gabor considers this a plausible approach given the thermic effect of protein and more of a ‘biohack’ than a long-term solution.
  • Gabor lists other such possible hacks, such as using MCTs that have a high energy cost when being processed by the liver, or acute bouts of cold thermogenesis.
  • Gabor consider the notion of a ‘fat as a lever’ to simply be a restatement of the CICO (calories in calories out) truism.
  • Raphael questions the validity of defaulting to ‘upping protein’ as the go to advice for fat-loss stalls rather than, say, optimizing sleep or circadian entrainment.
  • Gabor proposes we focus on ‘sleeping to satiety’
  • Raphael goes over the design and results of a Perry et al. 2017 study called “Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes
    • Design: a rat model of poorly controlled type 2 diabetes where both groups ate ad lib for 3 weeks, one a high-fat diet (59% fat, 26% carbohydrate, 15% protein) and another a control Chow diet (18% fat, 58% carbohydrate, 24% protein). After diabetes was induced by streptozotocin injection, some rats were calorically restricted for 3 days eating 5g total (kcals unknown) and the others continued to eat their respective diet ad lib.
    • Results: (1) there was “reductions of hepatic DAG content resulting in decreased PKCε activation and improved hepatic insulin sensitivity”. We care because uncontrolled chronic activation of PKCε results in severe diseases such as malignant tumors and diabetes. (2) There were “reductions in rates of net hepatic glycogenolysis” and (3) “reductions in hepatic acetyl-CoA content leading to decreased hepatic gluconeogenesis due to decreased hepatic VPC [pyruvate carboxylase] flux”. We care about the latter because pyruvate carboxylase catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate. Oxaloacetate is a key to gluconeogenesis (see our post) given how acetyl-CoA can allosteric activator of pyruvate carboxylase.

 

  • Raphael asks Richard and Gabor what this teaches us?
  • Gabor places his answer in context of his beliefs regarding the origins of metabolic mayhem; first disruptions at the level of the gut occur leading to dysfunctional adipose tissue that feeds forward to aberrant fat deposition (both amount and location such as the liver, pancreas and muscles to various degrees).
  • Gabor warns of the paper’s drug-centric goals versus discussing results with more of a ‘root cause’ lens. The authors appear interested in developing compounds attacking type 2 diabetes in the liver and they have patents pending (not necessarily a bad thing!).
  • Gabor suggests we should be wary of extrapolating the applicability of extreme calorie restriction for such conditions in humans. He prefers fixing the lifestyle and hence root cause issues.
  • Richard brings up the (negative) gestational effects of hyperinsulinemia and high blood sugars.
  • Following Richard’s point about gestational effects, Raphael says it’s not immediately obvious to him if this adaptation (a high insulin producing pancreas) is advantageous or not?
  • If one returns to being a type 2 diabetic when stopping a ketogenic diet, does that imply ketogenic ‘only’ manages the disease? Richard thinks that, either way, people like him are simply too ‘metabolically deranged’ and can no longer return to their previous diet.
  • Returning to the VLCD rat study results, Raphael mentions that the insulin sensitizing effects were confined to liver (as measured by euglycemic-hyperinsulinemic clamp) and that the authors say the nature of the diet was not a factor determining the positive metabolic changes (it was really all about the calorie restriction).
  • Raphael further quotes the authors saying how the 3 days of severe calorie restriction didn’t change the body weight of these rats in a statistically significant manner compared to the ad lib group (!).
  • Raphael suggests better measures, such as metabolic chambers, might zoom in on actual body-weight differences between the groups. After all, Raphael is a fan of the 2nd Law of Thermodynamics (the dissipation law).
  • Nevertheless Raphael is skeptical we’d see no diet effects/interactions in humans. One reason for his skepticism arises from the specific effects of certain fats, such as linoleic acid (LA). LA can increase adipocyte sensitivity and may be part of the obesogenic and diabetic mechanisms (see Petro Dobromylskyj excellent analysis of LA’s effects).
  • Gabor mentions supporting evidence for a large role of calorie restriction in restoring metabolic function in human studies, such as Roy Taylor’s 8-week very low calorie diet trail for diabetics.
  • Gabor highlights that the removal of ectopic fat can happen without a concomitant (significant) reduction in body weight within the first few days.
  • Raphael refers to a discussion he, Gabor and Lucas Tafur had on Facebook where Lucas made the good point about caloric deficits themselves being biological signals. Biological signals from diets do not only arise from qualitative aspects of diets (e.g. macronutrients, micronutrients…).
  • Richard explains that the amount of energy we use on a daily basis is predicated on the amount of energy our body’s sense is available. Mathematically, such a system is represented by chaotic functions.
  • Raphael asks Richard, how should think about the Laws of Thermodynamics when reflecting about nutrition principles? and what did Atwater teach us about calories?
  • Raphael summarizes Richard’s point about the body using ATP to make ATP, saying ‘you gotta spend money to make money’.
  • Raphael says it’s not really feasible to ‘count calories’ accurately (nor with much precision); the substantial error in calorie estimation on food labels [2013 study], the FDA allows for a 20% error up or down. And then there’s Gary Taubes’ simple mathematical example (taken from Eugene Dubois) showing that the 0.8% accuracy required in calculating caloric balance to avoid gaining a mere 2 pounds of fat a year is literally impossible, meaning if this fat gain is avoided it cannot be due to the accuracy with which we can currently assess our daily caloric balance.
  • Understanding the above the solution then becomes obvious, we must focus on solutions controlling homeostatic mechanisms, not DIY energy balance calculations.
  • Raphael points to the common trope whereby it’s said that low-carb diets, when they work for weight-loss, work because avoiding carbs inadvertently leads to negative energy balance (itself a truism). However, the same logic could be applied to calorie restriction – this inadvertently changes multiple qualitative/biological variables that are actually responsible for the weight-loss. Not recognizing the argument goes both ways is a double-standard of sorts.
  • Gabor offers a clever and funny example to expose the absurdity of the calorie-centric view of obesity, pointing out that when we think of what causes a fever, we would never dare suggest it’s fundamentally a disorder of ‘heat balance’. Fevers are in fact evolved responses to pathogens that can be eliminated by subjecting them to higher temperatures.
  • Raphael mentions looking forward to Kevin Hall’s next study given his 2016 study identified a 151 ± 63 kcal/day (p = 0.03) ‘metabolic advantage’ for low-carb/ketogenic diets.
  • Richard and Gabor point out the obvious but not well appreciated fact that 151 fewer kilocalories per day over 1 year results in a big changes in fat-mass (and weight). In fact, Kevin Hall’s 2011 study suggests that eating an excess of 30 kJ/day (or 7-8kcal/day) would be sufficient to explain the average weight-gain.
  • Raphael asks Richard to re-state his drive-by question(s) posed to Prof Feinman (@DrFeinman) at Ketofest 2017
    • Could statins increase (or decrease) ketogenesis? Can HMG-CoA diffuse across the mitochondrial wall or be transported into mitochondria? Given that statins inhibit HMG-CoA reductase, could it then accumulate in the cytosol? Would that then increase HMG-CoA in the mitochondrial matrix and thus increase ketogenesis?
    • Richard’s question stems from observing how his blood ketones dropped about 6 months into his ketogenic diet (which is not strange in and of itself) but occured around the same time he stopped taking the statin. Furthermore, he postulates that it may be relevant that acetoacetate is made from HMG-CoA.
    • Raphael mentions that taking statins reliably associates with worse metabolic endpoints which also suggests there effects on mitochondria is likely negative.
    • Gabor mentions there might be something to Richard’s hypothesis, if only because statins are well known to increase diabetes risk (30 to >40% relative risk)
    • Gabor doesn’t care much for the statin debate, he’s all about adipose tissue dysfunction! He prefers taking care of his guts 🙂

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