Tag Archives: insulin

A brief explanation of Hall et al., ie, THE LOW CARB WAR

“Examination of acute shifts in energy balance by selectively reducing calorie intake from one macronutrient.”

Intro (1/2): please don’t read this study with the media headlines in your mind.  Don’t even pay any attention to the study’s title, abstract, intro, and discussion.  In no way did this study put low carb proper on the chopping block, regardless of what you’ve seen online or elsewhere.  Mmmkay?

 

Intro (2/2): if you want a lesson (or refresher) in Advanced Nutrition, check out the Supplemental Information: in formulating his mathematical models, Dr. Hall seemingly reviewed every single biochemical pathway and physiological variable ever invented.  Read it, for science.  Really.

 

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Ketosis is a hack: here’s why

There are multiple distinct flavors of diabetes/obesity, as evidenced by the fact that some people have: 1) impaired glucose tolerance (but normal fasting glucose); 2) others have impaired fasting glucose (but normal glucose tolerance); and 3) others have both.  This means there isn’t a linear relationship between these phenomena*.  There are also: 4) obese patients with normal glucose metabolism; and 5) lean patients with type 2 diabetes.

*I think the great Dr. Kraft may have missed some of the nuances here.

There is not 100% overlap among these, suggesting [confirming] distinct diabetes/obesity phenotypes (and probably causes & best treatments).

 

 

midnightsun

 

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Dawn PheNOMNOMNOM

Many pre-diabetic, diabetic, and insulin resistant people have used the low carbohydrate diet to successfully manage their blood glucose levels.  It just plain works.  FACT (P<0.05).

However, a small subset of this population fails to achieve normal fasting glucose.  This is likely due, in part, to a type of circadian mismatch induced by aberrant meal timing and excess exposure to artificial light at night.  For an extensive list of citations supporting the former, see “Afternoon Diabetes;” stay tuned for evidence of the latter.  In brief, a combination of delaying food intake for as long as possible after waking in the morning (“skipping breakfast”) and consuming most calories at night = no bueno.  These behaviors can also promote a circadian mismatch and phase delay.  Hint: eat when the sun is up; sleep when it is down.

 

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Marijuana

Marijuana is a very complex plant: many different strains with differing profiles of psychoactive, non-psychoactive, and peripherally-active compounds that impact metabolism.  Most have THC, which activates endogenous cannabinoid receptors and mimics many of the effects of smoked marijuana (eg, see studies by Hart, Wachtel, and Curran).

Do not underestimate the complexity of this plant.

"LOL"

“LOL”

I’m not ‘anti-pot’ as there are far worse drugs out there… however, some advocates make really bad “pro” arguments, like saying it’s actually healthy (or at least not harmful in any way)…
there are many independent lines of evidence which suggest otherwise, metabolically speaking.

MJ not crack

Rimonabant, the notorious pot-blocker, reduces appetite and is a fairly effective weight loss drug, but has the unfortunate side effect of doing the opposite of marijuana, psychologically speaking.  See any of the RIO studies, eg:

weight loss Rimonabant

All participants lost weight and experienced improved metabolic profiles, insulin sensitivity, etc., by blocking endogenous cannabinoid receptors.

Adverse effects?  Wellll, there’s a drug called Marinol (pure THC) that’s technically an anti-emetic (reduces the urge to vomit); it improves appetite in patients with conditions associated with anorexia or wasting.  It’s a cannabinoid agonist.  Blocking CB1 with Rimonabant induces nausea in some patients: no bueno, but not unexpected given the known effects of Marinol.  Rimonabant is also associated with depression and anxiety (in some patients); also not unexpected.

So, it’s not a good idea to block this receptor pharmacologically (for psychological reasons) or activate it recreationally (for metabolic reasons).  Obesity researchers (and big pharma no doubt) are still looking for a pot-blocker that doesn’t penetrate the brain  to avoid the negative psychological side effects (eg, Klumpers et al., 2013).

Best. Graph. Ever.  The effect of Rimonabant on how stoned participants felt after smoking pot.  Yes, “Stoned” was published in the Journal of the American Medical Association (Huestis et al., 2001).

Stoned

Indeed, Rimonabant effectively treats “cannabis intoxication” (Crippa et al., 2012).  Antagonist versus agonist 101.

Part II: the biological effects of cannabis, THC, marijuana, and antagonists, etc.

THC acts like insulin on adipocytes: increased adipogenesis, fatty acid uptake, and decreased lipolysis (eg, see studies by Teixeira and Cota).   Munchies, anyone?

Cannabinoids and mimetics/agonists induce hunger and repress satiety; cannabinoid blockers induce satiety and weight loss.  However, I actually don’t think marijuana is obesogenic aside from its anti-anorexic effects.  Cannabis use is not always associated with obesity, possibly due to confounding and/or the lack of good crossover studies (you can’t really do a proper study in healthy humans with MJ for ethical reasons).  But most rodent studies agree that cannabinoids, acting via cannabinoid receptors, induce metabolic syndrome-like effects in nearly every single tissue and on the whole-body level.

CB1 cannabinoid receptor deletion in mice leads to leanness, resistance to diet-induced obesity, and enhanced leptin sensitivity (Trillou et al., 2003).  For context, mice lacking CB1 is somewhat analogous to humans not smoking marijuana.

In liver, cannabinoid signaling induces fat accumulation and insulin resistance (Osei-Hyiaman et al., 2008).  This is absent in CB1 and liver-specific CB1 knockout models.   Mice overexpressing this receptor in liver exhibit increased insulin resistance (Liu et al., 2012).

Activating cannabinoid receptor-2 (CB2) causes insulin resistance and adipose tissue inflammation, and this is blunted in mice lacking CB2 (Deveaux et al., 2009).

Stoned

The knockouts & over-expressing rodent models, and pharmacological agonist & antagonist studies are all consistent.  That said, I still don’t think this is the worst recreational drug out there, even among “legal” ones.

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calories proper

Saturated fat, cholesterol, and carbohydrates

“You catch more flies with honey…”

^^^good policy in general, but especially for debating in the realm of nutritional sciences.

 

A short while back, Nina Teicholz discussed low carb ketogenic diets and plant-based diets with John Mackey.  Although I disagree with the dichotomy (keto vs. plant-based), it’s well-worth a watch:

 

 

Three topics that could not be avoided in such a discussion: saturated fat, cholesterol, and carbohydrates.

 

 

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Meal frequency, intermittent fasting, and dietary protein

Dietary protein “requirements” are some of the most context-dependent nutrient levels to decipher, and depend largely on energy balance and even meal frequency.

An objective look at intermittent fasting (Alan Aragon, 2007)

Meal frequency and energy balance (Lyle McDonald, 2008)

New study: “Increased meal frequency attenuates fat-free mass losses and some markers of health status with a portion-controlled weight loss diet” (Alencar et al., 2015)

This wasn’t well-received in social media because bro-science & many low carb advocates say grazing is no longer in vogue — “it’s much better/healthier/whatever to eat once or twice daily, because intermittent fasting and all that jazz” …however, this may be problematic when it comes to meeting overall protein needs, which is particularly important when you’re losing weight.

The study: 2 vs. 6 meals per day, crossover.

Conclusion: “On average, fat-free mass (FFM) decreased by -3.3% following the 2 meals/d condition and, on average, and increased by 1.2% following the 6 meals/d condition (P<.05).

fat-free mass

In other words, 6 meals per day was better for body composition than 2 meals per day.  But context is everything, and this hypothesis has been tested from a variety of different angles, so what does it mean?

The relevant context here: 1) big energy deficit (1200 kcal/d for obese women is a pretty low calorie intake); and 2) “adequateTM” protein intake (75 g/d).

The standard dogma says that in the context of an adequate protein hypocaloric diet, meal frequency matters a LOT, whereas with high protein, it doesn’t matter as much.  Theory being that with an “adequate” (read: too low?) overall protein intake, the fasting periods are simply too long with only two meals per day; you need either: 1) higher protein intake; 2) increased meal frequency; or 3) more calories (ie, smaller energy deficit).

In this study, BOTH diets suppressed insulin and induced weight loss, but the increased protein feeding frequency skewed the weight loss to body fat while preserving fat-free mass.   I actually agree with a lot of the bro-science in this case, and also think that 75 grams of protein is not enough in the context of a big energy deficit (if body composition is a goal).




Historical precedence?

Meal frequency and weight reduction of young women (Finkelstein et al., 1971)

Relevant context:  6 vs. 3 meals per day (3 meals per day may not seem like that many more than 2, but it significantly cuts down on the duration of time spent with no food or protein).

Smaller energy deficit: 1700 kcal/d in overweight patients is less of a deficit than 1200 kcal/d in obese patients.

Higher protein intake: 106 – 115g/d.

Result: nitrogen balance (a surrogate for the maintenance of muscle mass) and fat loss were similar in both groups.  This study fixed two problems in the abovementioned study: 1) 3 meals is better than 2 in the context of an energy deficit; and 2) protein intake was higher.

And again here, with 3 vs. 6 meals per day (Cameron et al., 2010), just to make the point that 3 meals per day is better than 2 for preserving lean mass in the context of an energy deficit.

The effect of meal frequency and protein concentration on the composition of the weight lost by obese subjects (Garrow et al., 1981)

This study tested the opposite extremes: super-low calorie intake (800 kcal/d), much lower protein intakes (20g – 30g/d), and 1 vs. 5 meals per day.

Result: “a diet with a high-protein concentration, fed as frequent small meals, is associated with better preservation of lean tissue than an isoenergetic diet with lower-protein concentration fed as fewer meals.”

It basically confirmed all of the above.

Protein feeding pattern does not affect protein retention in young women (Arnal et al., 2000)

1 vs. 4 meals per day; and 70 grams of protein but no energy deficit (~2000 kcal/d isn’t very hypocaloric for lean young women).  In this study, no effect of meal frequency was seen, likely because 70 grams of protein isn’t inadequate when energy intake isn’t restricted.

1. PROTEIN “NEEDS” ARE HIGHLY CONTEXT-DEPENDENT

2. NEED =/= OPTIMIZATION

3. MEAL FREQUENCY & meal timing and peripheral circadian clocks > “MACRONUTRIENTS”

If you’re losing weight (ie, in an energy deficit), then intermittent fasting is cool if protein intake is high (above “adequateTM“)… the bigger the energy deficit, the more protein is necessary to optimize changes in body composition.

How much is ‘enough?’  Sorry, can’t give you a gram or even gram per pound of body weight answer… but if you’re losing weight and seeing no discernible effect on body composition (muscle vs. fat mass), then it may be prudent to consider eating more protein-rich foods… and paying more attention to sleep quality (which also greatly impacts nutrient partitioning).

No amount of protein will help you if circadian rhythms aren’t intact!!!

further reading:

Yes, it’s a high protein diet (Tom Naughton, 2015)

Protein requirements, carbs, and nutrient partitioning

Dietary protein, ketosis, and appetite control 

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calories proper

Good calories

Nuts are good calories.

I’m not a big fan of the omega-6 fatty acid linoleate, but that’s largely in the context of processed foods and confectioneries, where it’s more than likely no longer in it’s native form (Dc9,1218:2n6)… but in the context of unprocessed whole foods (eg, nuts), a little n6 is fine imo.

What are good calories?  They’re nutrient-dense and don’t generally lead to overeating… like the opposite of soda and junk food.  Nuts are low carb and many are highly ketogenic (eg, Brazils, macadamias, and pecans are ~90%fat).  Mr. Ramsey may even approve of macadamias because they have virtually zero PUFAs.

BONUS: magnesium, copper, selenium, many trace minerals and micronutrients, etc., etc.

I’m not saying you should crack open a can of Deluxe Mixed Nuts and sit down with nothing to do other than NOM NOM NOM ALL THE NUTZ.  I’m talking about a few nuts with a meal.  Possibly earlier in the day (coinciding with LIGHT); nuts are tryptophan-rich and this may improve melatonin onset -> good for circadian rhythms:

nuts and melatonin

Appetitive, dietary, and health effects of almonds consumed with meals or as snacks: a randomized controlled trial (Tan and Mattes, 2013)

In this study, the participants were instructed to eat a serving of almonds (~43g, ~245 kcal) daily for four weeks, at different times of the day (with breakfast, midmorning snack, lunch, or afternoon snack).

Regardless of when the almonds were consumed, the calories were practically completely compensated for.  The participants unwittingly ate less other stuff.  And in 3 out of 4 of the conditions, the almonds were so satiating that the participants actually ended up eating fewer overall calories.

That, in a nutshell, is what I call “good calories,” and I don’t think it’s too far from Taubes’ original definition… especially because it was accompanied with [modest] reductions in body fat (NS).  To be clear, they were instructed to eat more (in the form of almonds), but ended up eating less, BECAUSE ALMONDS.  This wasn’t a cross-sectional study, so no healthy user bias or other obvious confounders.

Further, the participants clearly weren’t obesity resistant.  They were overweight, obese, or lean with a strong family history of type 2 diabetes.  Sam Feltham would’ve been excluded.

This is not an isolated finding: another study showed a dose-dependent response to almonds: 28g or 42g consumed in the morning resulted in a compensatory reduction of hunger and total energy intake at lunch and dinner (Hull et al., 2014).  This wouldn’t happen with soda or junk food.

Another study tested ~350 kcal almonds daily for 10 weeks and concluded: “Ten weeks of daily almond consumption did not cause a change in body weight. This was predominantly due to compensation for the energy contained in the almonds through reduced food intake from other sources” (Hollis and Mattes, 2007).

Almonds vs. complex carbs? Almonds, FTW.

1 Brazil nut daily: “After 6 months, improvements in verbal fluency and constructional praxis (two measures of cognitive performance) were significantly greater on the supplemented group when compared with the control group.”    ONE FRIGGIN’ NUT!

http://www.dreamstime.com/-image11630100

Walnuts protect against alcohol-induced liver damage (in rats) (Bati et al., 2015) and may improve brain health (in humans) (Poulose et al., 2014).

Pistachios improve metabolic and vascular parameters (Kasliwal et al., 2015).

Meta-analysis (not an intervention study): nut consumption is associated with lower risk of all-cause mortality (Grosso et al., 2015). Yeah yeah yeah, I know, correlation =/= causation.  Whatever.

Nuts are good calories.  That’s all I’m saying.

Tl;dr: buy these and one of these, not this.

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calories proper

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Carbs: Low vs. Lower

 

 

This was met with much backlash from the low carb cavalry, because, well, if low is good then lower must be better

I’m not anti-keto; but I’m not anti-science.  FACT.

 

“…some people are not genetically equipped to thrive in prolonged nutritional ketosis.” –Peter Attia

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LIGHT, Leptin, and Environmental Mismatch

For a long time, the melanocortin system was basically thought to control the color of skin and hair.  It still does, and many redheads are redheaded due to polymorphisms in one of the melanocortin receptors.

Fast forward to 2015: to make a long story short, melanocortins are HUGE players in circadian biology.

 

POMC ACTH a-MSH

 

Brief background (also see figure above):

Fed state -> high leptin -> a-MSH -> MC4R (the receptor for a-MSH) = satiety, energy production, fertility, etc.

Fasted state -> low leptin -> AgRP blocks MC4R = hunger, energy conservation, etc.

MC4R polymorphisms in humans are associated with obesity.  Melanotan II causes skin darkening (marketed as “photoprotection” [no bueno, imo]), enhanced libido, and appetite suppression.

 

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“Afternoon diabetes” and nutrient partitioning

Don’t exacerbate afternoon diabetes with afternoon carbs.

Skeletal Muscle
As discussed previously [at length], insulin sensitivity in skeletal muscle follows a circadian pattern: starts out high in the morning and wanes throughout the day.

Diurnal variation in oral glucose tolerance: blood sugar and plasma insulin levels, morning, afternoon and evening (Jarrett et al., 1972)

impaired circadian glucose tolerance in the morning

Diurnal variation in glucose tolerance and insulin secretion in man (Carroll and Nestel, 1973)

Circadian variation of the blood glucose, plasma insulin and human growth hormone levels in response to an oral glucose load in normal subjects (Aparicio et al., 1974)

Adipose Tissue
And insulin sensitivity of adipose tissue goes in the opposite direction: starts out low, and increases as the day progresses.

Diurnal variations in peripheral insulin resistance and plasma NEFA: a possible link? (Morgan et al., 1999)
The studies were standardized for a period of fasting, pre-test meal, and exercise… Following insulin, NEFA fell more slowly in the morning (149 uM/15 min) than in the evening (491 uM/15 min).

Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non-esterified fatty acids (Zimmet et al., 1974)
Adipose tissue insulin sensitivity is greater in the evening.  FFA are higher, and get shut down more rapidly, after a carb meal in the evening.

Summary: to minimize blood glucose excursions and proclivity for fat storage, eat more calories earlier in the day; this is circadian nutrient timing.  And according to the Alves study, a low-carb protein-rich dinner best preserves lean tissue during weight loss.

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