Next time someone says VLC/keto is harmful or at least not helpful for fat loss because of a new rodent study, they’ll probably be wrong.
BOOKMARK THIS ONE GUYS.
Rodent studies on ketogenic diets or exogenous ketones are valuable and interesting in a variety of #contexts, although I’d argue that regulation of fat mass isn’t really one of ’em.
For starters, rodents aren’t particularly ketogenic – it’s rare to see ketones >1 after an overnight fast even in long-term ketoadapted mice. Also, many rodents gain weight until they die, whereas humans plateau and stay relatively weight-stable for their entire lives (at least historically, and I’m not talking about yo-yo dieting).
Skeletal muscle, on the other hand, seems more similarly regulated: keto isn’t muscle-sparing in either specie… most people, perhaps unwittingly, increase protein intake on keto, and THIS spares muscle (N.B. this is simply to spare muscle, whereas in non-keto dieters, it’s not uncommon to see increased muscle in the #context of high protein). That’s because carbs are more anabolic than fat. QED.
There’s just a fundamental difference in the way fat mass and appetite is regulated between the species. There are many similarities, which is why these studies are still valuable, but fat mass isn’t one of ‘em.
Weight loss on low-fat vs. low-carbohydrate diets by insulin resistance status among overweight and obese adults: a randomized pilot trial (Gardner et al., 2015)
Low carb diet: participants went from 230 grams/d to less than 50 for the first 3 months, then creeped up to ~80 over the next 3 months.
Will the critics say “the carbz weren’t low enough!”? REALLY?
Brief background reading: amylin (according to Wikipedia)
In a study by Hollander on type II diabetics, the synthetic amylin analog pramlintide was tested (Hollander et al., 2003). In this year-long RCT, over 600 patients were treated with placebo or up to 120 ug pramlintide BID (twice per day). On average, these subjects were obese (BMI 34), diabetic for ~12 years, and had an HbA1c of 9.1%. After one year, HbA1c declined 0.62% and they lost about 1.4 kg… not very impressive.
But it’s not all bad news; after viewing those relatively negative results (3 lb weight loss over the course of 1 year), another group of researchers led by Louis Aronne and Christian Weyer believed amylin had yet to be tested proper. So they designed a better study; it was shorter, used higher doses of pramlintide, and they enrolled obese yet non-diabetic patients (Aronne et al., 2007). They opted for higher doses of pramlintide (240 ug TID [three times per day]) because in dose-escalation studies, the incidence and severity of adverse drug reactions was consistently low at all doses tested.
They chose to study obese-er subjects (BMI 38, compared to 34 in the Hollander study) because obese subjects lose fat more readily than lean people, so if the study is designed to measure fat loss, then it is better to select a population of subjects where more fat loss is predicted. They selected non-diabetic subjects for a similar reason; diabetics must regularly inject insulin which promotes the accumulation of fat mass — this could counteract any fat reducing effects of pramlintide.
In other words, it was a more powerful and better designed study.
After 16 weeks, pramlintide-treated subjects lost an average of 3.6 kg (~8 lbs), or about half a pound per week. 30% of patients lost over 15 pounds (1 lb/wk)! Importantly, the weight loss didn’t appear to have reached a plateau by week 16, so it would have most likely continued along a similar trajectory had the study been longer. There were no side effects, and a battery of psychological evaluations showed that the patients receiving pramlintide felt it was easier to control their appetite and BW, they didn’t mind the daily injections, and overall well-being increased. At the very least, these evaluations meant the subjects weren’t losing weight because of nausea or malaise. In fact, it was quite the opposite.
I’m totally cool with keto, honestly! but still don’t really like seeing stuff like the above graphic and people interpreting it to mean “KETO IS MUSCLE-SPARING.”
“please stop asking gurus how many carbs you need to optimize health”
An interesting paper came out recently by Zeevi et al. (2015), showing, in part, that we’re all unique snowflakes (in some contexts).
#context
Mini-rant: this study is in line with a lot of my beliefs about individuality in human biology. We don’t know all the mechanisms, but we do know that some people respond better to some interventions than others. We learn a lot from studies on diet, light, sleep, physical activity, etc., but the findings rarely/never apply equally to everyone (and some people experience completely opposite effects; eg, see studies where individual data are reported). LIGHT exposure can improve sleep quality in some but cause agitation in others. Low carb diets can help weight loss in some people but low fat is better for others. Dairy, wheat, protein, the ‘biome, and fibre/resistant starch all fall into this category. Sleep ‘requirements’ vary by person, season, geography, etc., etc… there’s no QED answers in many of these contexts.
anecdote: some people say they’ve never had better blood glucose than when they were having a few servings of beans/legumes per week; others just report bloating & farts (no bueno).
In this particular study (video summary below): they continuously monitored the blood glucose responses in 800 people to all of their meals for a week, including a variety of test meals. Main result: many different responses, even to the same foods! An oversimplified example: some people had smaller relative postprandial glucose excursions after 50g carbohydrate from rice compared to 50g carb from potatoes, and other people responded oppositely. And friggin’ tomatoes?!
Translation: need to move beyond recommending #IIFYM.
Some foods were universally well-tolerated [in this population] in the context of mixed meals, like quinoa and salmon; other foods did the opposite, like chocolate chip cookies and sushi. And lastly, some foods like cottage cheese and hummus were good for some people but others.
[participant 445 is winning]
*In general, I don’t believe in labeling foods as categorically good or bad, which is pretty much confirmed by this study, but some patterns emerged wrt postprandial glucose excursions in this population…
I came across a recent study on a mouse model of Angelman Syndrome (an epigenetic disorder), and wasn’t surprised to learn there’s a strong circadian component to it. Epigenetics are one of the main ways circadian rhythms are programmed.
In this case, the circadian connection is more direct.
Angelman Syndrome (AS): you inherit 2 pairs of each gene, one from Mom and one from Dad. In some cases, one of the copies is silenced via epigenetics and you’re basically just hoping the other one is in good shape. In the genetically relevant region in AS, the paternal copy is silenced and the maternal copy does all the heavy lifting, but in AS, the maternal copy is mutated or absent, so none of the genes in this region are expressed.
Interestingly, scientists found that one of the genes, Ube3a (an ubiquitin ligase), is involved in regulating Bmal1, a core circadian gene (Shi et al., 2015) . And mice with a silenced paternal Ube3a and mutant maternal Ube3a exhibit many of the same circadian symptoms of children with AS. They don’t mimic all of the symptoms as there are many other genes in this region. But both show circadian abnormalities.
Prader-Willi Syndrome (PWS) is the epigenetic opposite: same region of DNA, but silenced maternal copy and mutant or absent paternal copy. This disorder is characterized by massive obesity and low muscle mass (among other things).
While reading about this disorder, I was taken aback with how the obesity was explained.
“Insatiable appetite” (Laurance et al., 1981), although from what I can gather, these children would develop massive obesity even if they were fed cardboard. Some studies even showed no change in food intake and/or energy expenditure (eg, Schoeller et al., 1988), which led some researchers to publish entire papers about how these children must be lying and/or stealing food (eg, Page et al., 1983) .
Further, other researchers even explained their obesity was due to an inability to vomit (Butler et al., 2007).
THEY’RE OBESE BECAUSE THEY’RE NOT BULEMIC.
AYFKM?
When these kids gain weight, it’s nearly all fat mass; when they lose weight, it’s nearly all muscle [shoulda been a BIG hint]… this even led some researchers (who detected no change in fat mass after significant weight loss) to conclude that their techniques to assess body composition must not be valid in this population because: surely, they must’ve lost some fat mass like normal people do.
THEY FAILED TO CONSIDER THIS IS AN EXTREME CIRCADIAN MISMATCH DISORDER IN NUTRIENT PARTITIONING
It was actually painful to read: these kids are being accused of stealing food and not vomiting because that’s the only way to explain it.
NO IT’S NOT, SCIENCE.
They can be forced into losing fat while maintaining some muscle with an extreme protein-sparing modified fast (eg, Bistrian et al., 1977)…
A few research groups have considered the possibility it’s a hormonal disorder, and some fairly long-term studies with GH replacement have shown promising results (eg, Carrel et al., 1999).
Prader-Willi Food Pyramid. Wait, wut? O_o
Some have even speculated involvement of leptin (eg, Cento et al., 1999), although this hasn’t been followed-up on.
Disclaimer: I don’t know the cure or best treatment modality for Prader-Willi, although given the strong circadian component in its sister condition, Angelman’s Syndrome, I strongly believe this avenue should be explored (in combination with the seemingly necessary hormonal corrections, which have been the only successful interventions yet). “Diet” doesn’t work; these kids aren’t obese because they’re stealing food or failing to vomit. Interventions strictly targeting CICO have massively failed this population.
Side note: in the Angelman Syndrome mouse model, *unsilencing* the paternal copy worked… maybe the same could work in PWS (and/or other forms of obesity)…?
Evidence supporting potential circadian-related treatment modalities for PWS:
A Prader-Willi locus IncRNA cloud modulates diurnal genes and energy expenditure (Powell et al., 2013)
Magel2, a Prader-Willi syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells (Devos et al., 2011)
Circadian fluctuation of plasma melatonin in Prader-Willi’s syndrome and obesity (Willig et al., 1986)
And the connection with LIGHT:
Artificial light at night: melatonin as a mediator between the environment and the epigenome (Haim and Zubidat, 2015)
Circadian behavior is light re-programmed by plastic DNA methylation (Azzi et al., 2014)
PWS is much worse than just nutrient partitioning (seriously, just spend a few minutes on any Prader-Willi support forum or this; maybe it is an appetite disorder, but given the data on weight gain [mostly fat mass] and weight loss [mostly muscle mass], it seems far more likely a circadian disorder of nutrient partitioning),
but that component jumped out at me; more specifically, despite the only positive results coming from non-dietary interventions, researchers were still all “#CICO.”
“Lean meat, sugar-free Jello, and skim milk”
FFS
Circadian biology, hormone replacement [where appropriate], and figure out if any specific diets help. PMSF/CR doesn’t work unless “refrigerators and cabinet pantries are locked shut.”
Maybe this applies to other forms of obesity, too.
Maybe.
Check out my Patreon campaign! Join the community of over 300 members for up-to-date information about a variety of topics in the health & optimizing wellness space. At 5 bucks a month, can’t beat it!
Affiliate links: KetoLogic for keto-friendly shakes, creamers, snacks, etc. And get 15% off your ketone measuring supplies HERE.
Still looking for a pair of hot blue blockers? TrueDarkis offering 10% off HERE and Spectra479is offering 15% off HERE. If you have no idea what I’m talking about, read this then this.
If you want the benefits of ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else.
Similar to the glycemic index, which is an estimate of the rise in blood glucose after eating a particular food, the insulin index is an estimate of the rise in insulin after eating a particular food. In general, these indices are obvious: processed carbs have high glycemic and insulin indices, whereas whole foods are lower. Some exceptions are things like dairy and lean meat, which induce more insulin than you’d expect given to their low carbohydrate content…
STORY TIME
When some protein-rich foods were discovered to induce insulin secretion, people thought this information might help type 1 diabetics more accurately calculate their insulin dose. Interesting rationale, worth testing.
Tl;dr: it didn’t work very well.
More of the protein-derived amino acids may have been incorporated into lean tissue, but the extra insulin load ended up causing hypoglycemia more often than not. Hypoglycemia is acutely more harmful than hyperglycemia, and is still quite harmful in the long-term. Some studies on incorporating the insulin index for type 1 diabetics are mixed, ie, increased or no change in risk of hypoglycemia, but no studies show it reduces the risk.
I think study was actually done a few years ago, originally published here (blogged about here), and re-analyzed through the eyes of Chris Gardner. I think. (But it doesn’t really matter as the study design appears to be identical.)
Experiment: give someone an oral glucose tolerance test (75 grams glucose) and measure insulin 30 minutes later. Some people secrete more insulin than others (a marker of insulin resistance); these people also have a lower metabolic rate after weight loss = increased propensity for weight regain. However, if these people follow a low carbohydrate diet, then the reduction in metabolic rate is attenuated. Some people who don’t secrete a lot of insulin after a glucose load may do better in the long-run with a lower fat diet.
Intermittent fasting (IF) is not a universal panacea, regardless of whether you’re not eating anything at all for a few days each week/month or just restricting your feeding window to a few hours per day.
Some protocols, eg, 20h fasting every second day, significantly improve insulin sensitivity in adipose tissue (Halberg et al., 2005). This is expected to make fat gain easier, and while this wasn’t meant to be a study on body composition per se…
After just a few weeks, things weren’t changing in a good way (NS).
Some people say the study design was rigged to favor the Low Fat diet (LF), which is dirty business but not exactly criminal; sometimes, this happens in science.
The claims go something like this: baseline diet was so high in carbs that they were locked into making unreasonable adjustments to formulate isocaloric low fat and low carb diets; eg, fat was too low in the low fat diet and carbs weren’t low enough in the low carb diet.
The biggest finding was “Fat Imbalance,” which favored LF. Here’s why I don’t think the baseline diet mattered very much.
Tl;dr: drastically cutting fat intake (LF diet) is much more effective than upregulating fat oxidation (LC diet) to create a large Fat Imbalance in an acute setting, ie, THE FIRST SIX DAYS.
analog pramlintide was tested (Hollander et al., 2003). In this year-long RCT, over 600 patients were treated with placebo or up to 120 ug pramlintide BID (twice per day). On average, these subjects were obese (BMI 34), diabetic for ~12 years, and had an HbA1c of 9.1%. After one year, HbA1c declined 0.62% and they lost about 1.4 kg… not very impressive.
(an epigenetic disorder), and wasn’t surprised to learn there’s a strong circadian component to it. Epigenetics are one of the main ways circadian rhythms are programmed.
(PWS) is the epigenetic opposite: same region of DNA, but silenced maternal copy and mutant or absent paternal copy. This disorder is characterized by massive obesity and low muscle mass (among other things).
. Some people secrete more insulin than others (a marker of insulin resistance); these people also have a lower metabolic rate after weight loss = increased propensity for weight regain. However, if these people follow a low carbohydrate diet, then the reduction in metabolic rate is attenuated. Some people who don’t secrete a lot of insulin after a glucose load may do better in the long-run with a lower fat diet.