Category Archives: Ketosis

“Insulin Dynamics”

This one has a bit for everyone.

 

Relationship of Insulin Dynamics to Body Composition and Resting Energy Expenditure Following Weight Loss (Hron et al., 2015)

 

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.

 

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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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Ketone bodies as signaling metabolites

*non sequiter*

One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.”  It responds to a glucose metabolite and activates transcription of lipogenic genes.  Insulin helps.  Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:

 

ChREBP

 

More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation.  Benefits of fasting sans fasting?  Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.

Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate.  Anti-aging (mostly worm studies, but still).

 

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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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Ketoadaptation and physiological insulin resistance

This is where the magic happens.

Rat pups, fed a flaxseed oil-based ketogenic diet from weaning onward – note the drop-off in ketones after 2 weeks (Likhodii et al., 2002):

flaxseed ketogenic diet

What happened on day 17?

Patient history: these rats have been “low carb” their whole lives.

Side note: flaxseed oil is very ketogenic! (Likhodii et al., 2000):

ketogenic rodent diets

Flaxseed oil-based ketogenic diet produced higher ketones than 48h fasting; the same can’t be said for butter or lard.  PUFAs in general are more ketogenic than saturated fats in humans, too (eg, Fuehrlein et al., 2004):Saturated polyunsaturated ketones

Crisco keto (adult rats) (Rho et al., 1999):

shortening-based ketogenic diet

suspect those two rogue peaks were experiment days…

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Cyclical ketosis, glycogen depletion, and nutrient partitioning

Meal & exercise timing in the contexts of “damage control” and nutrient partitioning are frequent topics on this blog.  I generally opt for a pre-workout meal, but nutrient timing hasn’t panned out very well in the literature.  That’s probably why I’m open to the idea of resistance exercise in the fasted state.  A lot of pseudoscientific arguments can be made for both fed and fasted exercise, and since a few blog posts have already been dedicated to the former, this one will focus on the latter.

The pseudoscience explanation is something like this: since fatty acids are elevated when fasting, exercise in this condition will burn more fat; and chronically doing so will increase mitochondria #.  The lack of dietary carbs might enhance exercise-induced glycogen depletion, which itself would bias more post-workout calories toward glycogen synthesis / supercompensation.  Much of this is actually true, but has really only been validated for endurance training (eg, Stannard 2010, Van Proeyen 2011, & Trabelsi 2012; but not here Paoli 2011)… and the few times it’s been studied in the context of resistance exercise, no effect (eg, Moore 2007 & Trabelsi 2013).  However, there are some pretty interesting tidbits (beyond the pseudoscience) which suggest how/why it might work, in the right context.

Exercising fasted or fed for fat loss?  Influence of food intake on RER and EPOC after a bout of endurance training (Paoli et al., 2011)

John Kiefer, an advocate of resistance exercise in the fasted state, mentioned: “the sympathetic nervous system responds quicker to fasted-exercise. You release adrenaline faster. Your body is more sensitive particularly to the fat burning properties of adrenaline and you get bigger rushes of adrenaline.”

Much of this is spot on.  That is, ketogenic dieting and glycogen depletion increase exercise-induced sympathetic activation and fat oxidation (eg, Jansson 1982, Langfort 1996, & Weltan 1998).

The question is: can this improve nutrient partitioning and physical performance?  Magic 8-Ball says: “Signs point to yes.”  I concur.

Contrary to popular beliefs, glycogen depletion per se doesn’t harm many aspects of physical performance.  A lot of fuel systems are at play; you don’t need a full tank of glycogen.

Effect of low-carbohydrate-ketogenic diet on metabolic and hormonal responses to graded exercise in men (Langfort et al., 1996)

High-intensity exercise performance is not impaired by low intramuscular glycogen (Symons & Jacobs, 1989)

Increased fat oxidation compensates for reduced glycogen at lower exercise intensities (eg, Zderic 2004), and ketoadaptation may do the same at higher intensities.

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More on physical performance and ketoadaptation

The various studies on how low carbohydrate diets impact physical performance are very nuanced.  Here’s what I mean by that.

Exhibit A. Phinney 1980

Phinney 1980

In this [pioneering] study, obese patients were subjected to a variety of performance assessments in a baseline period, then after 1 and 6 weeks of weight loss via protein-sparing modified fast (1.2 g/kg ideal body weight from lean meat, fish, or fowl; probably around 80 grams of protein/d, 500-750 kcal/d). They lost a lot of weight, 23 pounds on average, two-thirds of which was body fat. There was no exercise intervention, just the performance assessments.

During the ‘exercise to exhaustion’ treadmill exercise, RQ steadily declined from baseline to week 1 to week 6, indicating progressively more reliance on fat oxidation.  This was confirmed via muscle glycogen levels pre- and post-exercise: during the baseline testing, they declined by 15%; after 6 weeks of ketoadaptation, however, they only declined by 2%, while ‘time to exhaustion’ increased by 55%.  After only 1 week of the diet, time to exhaustion plummeted, as expected, by 20%.

This was, as mentioned above, a pioneering study in the field of ketoadaptation. It also challenges one of the prevailing theories of ‘fatigue’ …while carb-adapted, the subjects fatigued after 168 minutes, with muscle glycogen levels of 1.29 (reduced by 15%); while ketoadapted, they fatigued after 249 minutes with muscle glycogen levels of 1.02 (reduced by 2%).  In other words, they had less glycogen to begin with, used less glycogen during exercise, and performed significantly better (running on fat & ketones).

Exhibit B. Vogt 2003

Highly trained endurance athletes followed a high fat (53% fat, 32% carbs) or high carb (17% fat, 68% carbs) diet for 5 weeks in a randomized crossover study. In contrast to Phinney’s study, these participants were: 1) highly trained; and 2) exercised throughout the study.

Maximal power output and VO2max during a similar ‘time to exhaustion’ test was similar after both diet periods.  Same for total work output during a 20 minute ‘all-out’ cycling time trial and half-marathon running time.  Muscle glycogen was modestly, albeit statistically non-significantly lower after ketoadaption; however, ketoadapted athletes relied on a higher proportion of fat oxidation to fuel performance as indicated by lower RQ at every level of exercise intensity:

Vogt RQ

Again, this is the essence of ketoadaptation. Physical performance as good as or better using fat and fat-derived fuels.

One reason Phinney’s glycogen-depeleted ketoadapted subjects may have done so well is their reliance on ketones (probable) and intramyocellular lipids (IMCL) (possible).  In Vogt’s study, IMCL increased from 0.69 to 1.54% after ketoadaptation…

Also, food intake and body fat declined, and training volume increased in the low fat group; whereas food intake increased, and body fat and training volume declined in the high fat group.  Reminiscent of anything?

High fat, low carb -> eat more, exercise less, STILL LOSE BODY FAT.

Vogt data

Sorcery?  No.  Diet impacts more than just mood and body composition – resting energy expenditure increased in the ketogenic dieters.  This isn’t an isolated finding.

Exhibit C. Fleming 2003 

This was another study in non-trained athletes, consuming high fat (61% fat) or control (25% fat) diets for 6 weeks.  The tests were the 30-second Wingate, to examine supramaximal performance, and a 45-minute timed ride, to examine submaximal performance.

This study differed from the previous two in several significant ways.  For starters, peak power output declined in both groups, slightly more so in the high fat group (-10% vs. -8%).  Furthermore, RQ didn’t wasn’t significantly lower during this test in the high fat group, which possibly suggests they weren’t properly ketoadapted.  In Phinney’s study, the large energy deficit ensured ketoadaptation; this study lacked that aspect, somewhat more similar to Vogt’s, although unlike Vogt’s, these participants weren’t athletes which presumably makes ketoadaptation more difficult.

There are many factors at play… I wasn’t kidding when I said these studies are very nuanced!

Exhibit D. the infamous, Paoli 2012 

These were ‘elite artistic gymnasts,’ who could likely beat you in a race running backwards.  The ketogenic phase consisted of 55% fat and much more protein than the control phase (39% fat; protein: 41% vs. 15%). The significantly higher protein content was modestly offset by slightly more calories in the control phase, which reduces the amount of protein required to maintain nitrogen balance.

In this study, performance was, for the most part, ‘maintained,’ with relative increases in a few of the tests; eg, the “legs closed barrier.”  Changes in body composition were more robust: significantly reduced body fat and increased lean body mass after 30 days of ketogenic dieting (with their normal exercise routine).

Paoli data

The major confounder in this study was the use of an herbal cocktail only in the ketogenic diet group; despite this, the results are largely in line with the other studies.  For more on this study, see here.

Exhibit E. the most dramatic one to date: Sawyer 2013 

Please see here for the details, but in brief, strength-trained athletes showed improvements in high intensity exercise performance after only 7 days of carbohydrate restriction.  The nuances of this particular study are discussed more here.

barbell

Collectively, these studies show that physical performance in both endurance and high intensity realms does not always suffer, can be maintained, and in some cases is improved by ketogenic dieting.  Important factors are duration (to ensure adequate ketoadaptation), energy balance, and regular physical activity (athletes and regular exercisers can adapt to burning fat much quicker than sedentary folks).

 

calories proper

Diet study: American Diabetes Association vs. Low Carb Ketogenic

A randomized pilot trial of a moderate carbohydrate diet compared to a very low carbohydrate diet in overweight or obese individuals with type 2 diabetes mellitus or prediabetes (Saslow et al., 2014)

Disclaimer: this study was not ground-breaking; it was confirmation of a phenomenon that is starting to become well-known, and soon to be the status quo. That is, advising an obese diabetic patient to reduce their carb intake consistently produces better results than advising them to follow a low fat, calorie restricted diet.

The two diets:

Moderate carbohydrate diet: 45-50% carbs; 45 grams per meal + three 15 gram snacks = 165 grams per day; low fat, calorie restricted (500 Calorie deficit).  Otherwise known as a “low fat diet (LFD).”

In their words: “Active Comparator: American Diabetes Association Diet.  Participants in the American Diabetes Association (ADA) diet group will receive standard ADA advice. The diet includes high-fiber foods (such as vegetables, fruits, whole grains, and legumes), low-fat dairy products, fresh fish, and foods low in saturated fat.

Very low carbohydrate diet: Ketogenic; <50 grams of carb per day, no calorie restriction, just a goal of blood ketones 0.5 – 3 mM.

In their words: “Experimental: Low Carbohydrate Diet.  Participants will be instructed to follow a low carbohydrate diet: carbohydrate intake 10-50 grams a day not including fiber. Foods permitted include: meats, poultry, fish, eggs, cheese, cream, some nuts and seeds, green leafy vegetables, and most other non-starchy vegetables. Because most individuals self-limit caloric intake, no calorie restriction will be recommended.

Both groups were advised to maintain their usual protein intake.

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On resistant starch and blood glucose control

For overall health and well-being, fermented foods like sauerkraut and kefir are great.  Especially when following a low carbohydrate diet which is generally low in the types of foods which feed the gut microbiome.

For those with gastrointestinal problems, the gut microbiota is probably involved.  Whether it is bacterial overgrowth or dysbiosis, gut bugs are usually the culprit.  Treatment options vary widely, ranging from global extermination with vinegar & a low fibre diet (as per Jane Plain), or remodeling the microbiome with a prebiotic like galactooligosaccharides.   Probiotics like bifidobacteria can help, too, if they’re administered with either prebiotics or fermented foods (they need something to nourish them in transit).  Dark chocolate is also an excellent vessel.  Resistant starch is another option, although the question remains as to whether or not this is compatible with a low carbohydrate diet.

Resistant starch has been around for a while, and when I was in school it received about 10 minutes of attention during the fibre lecture.  But Jimmy Moore and Richard Nikolay have been talking about it a lot lately so I decided to freshen up on the topic.  In brief, it can be therapeutic for GI issues, but some studies have shown mixed effects on glucose & insulin metabolism.  The former is virtually unarguable, but I found the latter interesting.  And the impact of resistant starch on ketosis is included as well.

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