Physiological Insulin Resistance in Circadia

If you haven’t read Petro Dobromylskyj’s posts about Physiological Insulin Resistance, then just go do it.  Highly recommended.
I’ve written about it as well, albeit in a slightly different context:
What is our proper “natural” diet?
40 years ago a group of researchers turned ketosis into poetry.

But now on to more pressing matters.  In the food deprived state, Physiological Insulin Resistance develops, in part, to spare muscle (yea yea yeah and glucose for the brain).  But how much of this is due to ‘food deprivation’ per se as opposed to something else… like circadian rhythms.

Exhibit A. Hat tip to Dr Kruse for writing about this TED talk.  In it, Jessa describes a crab that lives on the beach; scurries up the beach when the tide comes in and back down when it goes out.  Scientists captured a few, flew them halfway around the world and put them in little tilted cages.  The crabs still scurried up & down, in time with the tides.

Exhibit B. Evidence that the lunar cycle affects human sleep.  People tend to sleep a little less during the full moon.  Subjects were recruited to a windowless sleep lab and had no exposure to sun/moon/anything outside – they maintained this circadian rhythm for 3 days  (Cajochen et al., 2013).  Different from the crabs, but similar (in a way).

Exhibit C. Circadian Disruption Leads to Insulin Resistance and Obesity (Shi et al., 2013)

There are times when Physiological Insulin Resistance is relevant, important, and even vital.  this isn’t one of them.  I had no intention of writing about this study but it literally took hours to figure out how the researchers teased apart the effects of feeding, or when the mice last dined, from the circadian rhythm’s impact on insulin resistance… but I think they did.  Like this:  protocol

There were four conditions (mice normally sleep during the day and eat at night):

divide and conquer

13h CT1 = for 13 hours after their last “light’s on (sleepy)” phase, the mice lived in red dim light.  The experiment took place in next 1st theoretical daylight hour, when the mice are usually just crawling into bed.

19h CT7: 19 hours of red dim light, the experiment began in the 7th  theoretical daylight hour, when the mice would’ve been deep asleep.

25h CT13: 25 hours of red dim light; experiment began in the 13th hour after theoretical lights on, which is equivalent to the 1st hour of lights off (12 hour light-dark cycle), when the mice would’ve normally just started eating.  This circadian period is directly opposite from 13h CT1.

31h CT19: 31 hours of red dim light, experiment began in the 19th hour after theoretical lights on, which is equivalent to the 7th hour of lights off (19-12=7), when the mice would’ve been actively eating.  This circadian period is directly opposite from 19h CT7.

As the time in red dim light progressed, we can only assume that their strict 12 hour feeding regimen slowly shifted into a more grazing-like pattern.  But they were all deprived of food for 5 hours prior to insulin sensitivity testing; only difference was [presumably] a shift in their circadian rhythm.  The researchers could’ve done another group, 37h CT25, but this would’ve put the mice back into the 1st theoretical daylight hour (sleepy time).  Had the results been that 31h CT19 mice were the most insulin resistant, we could’ve said some critical threshold was reached after 25 hours in red dim light.  But that didn’t happen.  The mice showed [Physiological] Insulin Resistance at 19h CT7; when they would’ve normally been sleeping – highly inactive, and their ‘natural’ fasting period.  They were just as ‘fasted’ as the other groups, but were the only ones showing signs of [Physiological] Insulin Resistance that appears to have been programmed by an innate ‘free-running’ circadian rhythm devoid of light cues.  Then, when they were back in normal feeding time (25h CT13), insulin sensitivity was restored, presumably to prepare for the onslaught of CIAB.GIR

Tangent: those glucose infusion rates are a little lower than expected for healthy mice with Lean Metabolisms, likely due to the low insulin infusion rate (2 mU/kg*min).  The use of a lower insulin infusion rate allows for the assessment of liver and skeletal muscle insulin sensitivity, because hepatic glucose production is almost completely shut down by higher insulin infusion rates, meaning any differences in the glucose infusion rate are more likely due to skeletal muscle insulin sensitivity.  I only ever clamped at 8 mU/kg*min because 2 mU isn’t very effective in obese insulin resistant mice.  Neither infusion rate (2 or 8 mU/kg*min) is very good at assessing adipose insulin sensitivity because lipolysis is inhibited at very low levels of insulin.  Their clamping technique was pretty good because they sampled arterial blood (as opposed to repeated tail nicking), and their mice were free-living (as opposed to enclosed in a restrainer which essentially completely immobilizes them [stressful]).  Notably, this wasn’t lost on the authors :/Clamp technique

Back to the data: in agreement with the presence of Physiological Insulin Resistance, glucose levels were higher at 19h CT7… and they went back down 6 hours later.  All of this was seemingly pre-programmed by a “free-running circadian rhythm” devoid of light cues.fasting glucose

“Light” is an important input into the circadian system, but I couldn’t find anything peculiar with their circadian disruption protocol to account for the appearance of Physiological Insulin Resistance exactly when we would’ve expected it had the mice been eating normally.  Pretty cool.

calories proper

Update: Tim Noakes & Bryan Davis tweeted a bunch of quotes & opinions about The poor, misunderstood calorie; some of which are hashtagged #TPMC.  Check ’em out!

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  • Michael

    Nice post, Bill!
    Interesting that your book’s getting some traction all of a sudden. Just checked on Amazon and notice that I got it almost one year ago exactly. Can’t remember how I found it, but it was well before I saw your blog. Great book, worthy of its place alongside GCBC on my bookshelf.

    • William Lagakos

      Wow, thanks Michael. I’m really glad you liked TPMC, although I still can’t believe it has been compared to GCBC (by you) and WWGF (by Tim Noakes). Awesome.

  • Michael

    BTW, interesting comment by one Sasquatch (aka S. Guyenet) in that Hyperlipid post you link to. Kinda funny in light of subsequent developments…

    • William Lagakos

      Yeah, from what I can recall, prior to food reward SG was generally in favor of low carb.

  • Nigel Kinbrum

    Hi Bill, I have a couple of questions:-
    1) “The crabs still scurried up & down, in time with the tides.”
    Tides where the crabs came from, or where the lab was?
    2) “The mice showed [Physiological] Insulin Resistance at 19h CT7; when they would’ve normally been sleeping – highly inactive, and their ‘natural’ fasting period.”
    Has anyone measured a mouse’s TEA? I was under the impression that it was negligible, as a mouse weighs ~30g.

    • William Lagakos

      The crabs scurried in time with their home tides – I don’t know how long they were away from home, but seems like a pretty strong “free running circadian rhythm.”

      • Nigel Kinbrum

        Milk + 1 sugar, please 😀 It’s Thermic Effect of Activity (a.k.a. calories burned through exercise).

  • William Lagakos

    Dim light at night exaggerates weight gain & inflammation associated with a HFD in male mice

    The role of adipose tissue circadian clocks in metabolic maintenance

  • Jane Plain (Woo)

    Curious but do the crabs ever entrain their circadian rhythm to the new environment? Perhaps the “code” for their circadian rhythm is something like “x hours after first sunlight, begin scurrying this way to avoid the tide”. Of course in the native environment this would *appear* the crab was synchronized with the tides, when in reality it is the timing of first sunlight that produces the movement… which happens to correlate with tides, adaptively so.

    In other words, I wonder if the movement of the crabs is more of a light-signal or darkness-onset based thing and theoretically can be reprogrammed by moving the crabs and exposing them to a new timing of light and darkness. Of course there would be no more tide to run from, or seek out, but it would demonstrate the circadian patterns can be shifted AS LONG AS light and darkness patterns remain logical.

    An entirely different situation, however, would be trying to make nocturnal animals live during day, and vice versa. I would expect the circadian patterns to remain permanently dysregulated in this case, because the circadian system of all animals is entrained to a logical timing of darkness and light and sleep and waking. IN humans, cortisol secretion begins after sleep, and peaks right before waking; melatonin secretion begins with darkness right before sleep onset, and terminates upon exposure to light. Whether the human is living in new york this month, or living in england next month, the body will eventually adapt to the new rhythm, it will just shift several hours or so.

    The only time adaption fails is when you take a day living animal and try to make it live at night or the converse. Then you will see a permanent, never terminating circadian rhythm disorder… non-terminating jet lag.

    There will always be a peak of daylight right before sleep onset. Darkness maximal during waking. The human can never adapt to this, circadian zeitgeibers remain illogical, and hormone release/timing is always LOL WUT propsition.

    Perhaps in the crabs it seemed the biological rhythm was free-running because being caged and in doors they never were exposed to new sunlight/darkness trends that could reprogram their clocks. Then perhaps we would discover the rhythm is not free running, but timed in accordance with dark/light signals that only happen to adaptively correlate with the tides of the environments the crabs live.

    In nursing homes, geriatric patients with neurodegeneration exhibit illogical sleep / wake patterns, sleeping a few hours at a time, being up most of the night, sleeping some of the day, with behavioral disturbances. While neurodegeneration affects circadian clock keeping and there is certainly an “illness” aspect to this behavior, studies have demonstrated geriatric sleep and behavioral disturbances in such patients can be resolved with exposing them to normal light and darkness patterns vs being caged in a building without any light forever… which produces more aggression and biological dysregulation and sleep/appetite disturbance.

    • Ash Simmonds

      Re: the crab stuff, those circadian rhythm things wouldn’t have anything much to do with sunlight hours, it would be based on remembered/learned lunar position – hence tidal.

      • Jane Plain (Woo)

        Perhaps so, but the larger point is that these processes are entrained to zeitgeibers and might only appear free running, however this will remain hidden unless the animal clock is reset by being exposed to the triggering factor whether it is light or darkness or what have you.

    • William Lagakos

      From the transcript:

      “If you take a horseshoe crab off the beach, and
      you fly it all the way across the continent, and you drop it into a sloped cage, it will scramble up the floor of the cage as the tide is rising on its home shores, and it’ll skitter down again right as the water is receding thousands of miles away. It’ll do this for weeks, until it kind of gradually loses the plot. And it’s incredible to watch, but there’s nothing psychic or paranormal going on; it’s simply that these crabs have internal cycles that correspond, usually, with what’s going on around it.”

      I’d like the next 4 time points (37h CT25, 43h CT31, 49h CT37, & 55h, CT43) to see if insulin resistance reappears at 43h CT31 and vanishes by 49h CT37…

      And then the next 4 time points to see exactly how “permanent” this effect is.

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