Insulin, sympathetic nervous system, and nutrient timing.

Insulin secretion is attenuated by sympathetic nervous system activity; eg, via exercise.  Theoretically, exercising after a meal should blunt insulin secretion and I don’t think this will lessen the benefits of exercise, but rather enhance nutrient partitioning.   And this isn’t about the [mythical?] post-workout “anabolic window.”

Sympathetic innervation of pancreas: norepinephrine –> adrenergic receptor activation = decreased insulin secretion & increased lipolysis (Stich et al., 1999):

Stich insulin

Stich CAS

note how quickly catecholamines are cleared upon exercise cessation

Stich NEFA

To further demonstrate the insulin-suppressive effects of exercise, Heesch and colleagues gave 60 grams of maltodextrin during a 2-hour exercise session; either during the first half, second half, or all along (evenly spaced out) (2013): 

Heesch metabolitesThe 4 conditions:
PP: 250 mL flavored water every 15 minutes for 2 hours (placebo group).
CP: 15 grams maltodextrin every 15 minutes for 1st hour, then water for 2nd hour.
PC: water for first hour, 15 grams maltodextrin every 15 minutes during 2nd hour.
CC: 7.5 g maltodextrin every 15 minutes for 2 hours.

Results and interpretation: if you go into this believing in that the exercise-induced sympathetic nervous system activation suppresses insulin secretion, then the results were relatively predictable.

PP: blood glucose is low and goes lower.  Insulin steadily declines because: 1) glucose is low; and 2) sympathetic nervous system suppresses insulin secretion.

CP: blood glucose increases during first half while the participants are getting maltodextrin, then plummets during second half.  Insulin starts to climb a little in the beginning (due to maltodextrin), then plummets rapidly as soon as the maltodextrin is done.

PC: glucose starts low when during first half, then climbs during maltodextrin treatment.  Insulin levels decline during first half, but don’t increase during the second half when the participants are getting maltodextrin because sympathetic nervous system is fully activated, suppressing insulin secretion.

CC: glucose only increases in the first half, then starts to decline in the second half; the dose of maltodextrin isn’t high enough to overpower exercise-induced insulin suppression and insulin levels just decline throughout the entire trial.

Exercise blunts insulin secretion; meal timing matters (Tipton et al., 2001).

6 grams essential amino acids and 35 grams sucrose either immediately before (PRE) or after (POST) a resistance exercise session consisting of: 10 sets of 8 reps leg press at 80% 1RM, then 8 sets of 8 reps leg extensions at 80% of 1 RM (2 minutes rest between sets, 45 minutes total).


In PRE, insulin increased 3x; in POST, insulin increased almost 6x.  Exercising after the meal nearly cut the insulin spike in half.

In other words, if exercise is performed after the meal, all bets are off; sympathetic nervous system activity is drastically lower… (Costa et al., 2009).  Also, see how quickly catecholamines declined when participants stop exercising in the Stich study (above).

Costa 2009: 86 grams maltodextrin and 29 grams soy protein ingested either immediately after or 1 hour after exercise.  Full insulin response in both cases.Costa

Dietary protein sans exercise can be quite insulinogenic in some contexts (Morifuji et al., 2010)

Morifuji insulin

Morifuji glucose

…which is why you might consider exercising afterword.  But aren’t carbs (and insulin) necessary to fully reap the benefits of exercise?  Magic 8-Ball says: “My sources say no.”  I tend to agree.  So do Staples and colleagues (2011):  25 g protein with or without 50 grams carbs, immediately post-workout.  Calories weren’t controlled (on purpose?).  Modest insulin spike with protein alone, and it doesn’t appear as though the carb-induced insulin is blunted very much (in relative agreement with Tipton and Costa):

Staples insulin

BUT, interestingly, more insulin & calories didn’t translate to more muscle protein synthesis or less degradation in this study:Staples muscle

This is not an isolated finding:

Coingestion of carbohydrate with protein does not further augment postexercise muscle protein synthesis (Koopman et al., 2007)

Addition of carbohydrates or alanine to an essential amino acid mixture does not enhance human skeletal muscle protein anabolism (Glynn et al., 2013)

Even meals primarily comprised of protein-rich foods stimulate insulin secretion.  To attenuate this and facilitate nutrient partitioning, I propose exercising afterword.

calories proper

Further reading: Nutrient timing, Op. 101

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  • Wenchypoo

    Even if you work out second thing in the morning (after shower, dressing, then leaving for work in a fasted state)? I always understood that you ate AFTER your workout if you were fat-adapted.

    Straighten me out here–this may drastically change up Hubby’s morning routine for the better.

    I’m sending this on to Hubby at work, so he can read this for himself.

    • William Lagakos

      If you’re fat-adapted, I don’t think this will make a *huge* difference; just might give you a little more bang for the buck…

      I’ve never been a fan of exercising in a fully fasted state; and pre-workout nutrition makes more sense (to me) than the “post-workout anabolic window.”

      Precision Nutrition just posted an article about this:

      • Jason Hoy

        Interesting about the timing. I have always preferred going for my run in the fasted state but it certainly makes sense to have some amino acids laying around to avoid muscle a catabolism.

        I usually just do 5-10g of Amino Acid tablets as I don’t like running/lifting with anything in my stomach.

        Are you saying in your article that if I am going to have a 40g whey protein/coconut oil shake I should have the whole thing pre-exercise and nothing post for better body composition ?

        Having trouble putting on any more lean body mass (at a plateau with squats,etc) being ketogenic. The conventional wisdom seems to say carbs are necessary for more anabolic growth. What say you ? :)

        • William Lagakos

          Regarding the whey/coconut shake, I think pre-workout might offer a slight advantage over post-workout.

          Check out the studies by Staples, Koopman, and Glynn. Dietary protein and resistance exercise are two fairly potent anabolic / anti-catabolic stimuli.

          • Jason Hoy

            Thanks a lot, more reading to do. One would think something like this would be figured out by now in regards to carbs/muscle growth :)

          • johnnyv

            Carbs seem not needed, just sufficient protein, excess energy, adequate stimulus and adequate rest.
            Unless of course the level of carbs required is so low that almost any diet will have enough. Similar to insulin where only T1 diabetics don’t produce enough for hypertrophy.

    • Jane Plain (Woo)

      In my experience, working out after eating is way better for wt control. Insulin still reacts to postprandial nutrients, whether 500 cal of fat or 500 cal of carb, insulin happens and exercise will reduce it by amping up catecholamines, SNS, and fat oxidation.

      A lazier way to do this is to take nicotine gum and vinegar after / with meals, as these supplements also increase fat oxidation and inhibit insulin action on adipocytes .

      Remember, low carb diets really don’t increase energy oxidation or basal metabolic rate, often times they may reduce it by superior inhibition of leptin/insulin (thus T3). 1000 cal of insulin free buttarz I quite assure you contributes an insulinogenic burden unless 1000 calories of insulin free buttarz is at or below your basal metabolic rate. Assuming, of course, you are or were a fat lard bag. If thin, then 1000 cal of anything either weakly promotes insulin or alternatively you are resistant to fat gain .
      I am “fat adapted” and my exercise is vastly more efficient when I’ve eaten, and pathetic if I am fasting. This is to be expected as my body poorly tolerates fasting and even on a ketotic diet, will never allow for high / rapid use of body fat. Energy conservation inducts quickly w/o food. This is expected given I am obese.

      BTW, leptin replacement changes that and fasting is easy.

      I tend to think regardless of diet exercise would be most effecient (metabolic energy wasting / insulin suppressing) and less inducing of stress responses in a nourished state.

      I predict exercising fasting = HPA mayhem, with greater insulinemia postprandial as a result of that, relative to fasting, eating, and then exercising.

      • Jane Plain (Woo)

        Here is what I mean by my body resists high/rapid use of body fat for energy.

        Lifting heavy boxes for hours, minimal food intake other than a little bit of macadamia nuts and cream, my ketones were measured in a fasting state the next day at … 1.4

        1.4 for me is probably like 3 for a normal person, lol.

  • Jack Kruse

    Again for the sake of clarity and persistence, Cold increases sympathetic tone and activate beta 3 agonist receptors that turn FFA from adipocytes into heat. In this way, you can see cold mimics exercise because insulin is also blunted by cold too.

    • William Lagakos

      love seeing all the connections.

      Also, the beta3’s are pretty interesting:
      Stimulation of the beta3-Adrenoceptor as a novel treatment strategy for anxiety and depressive disorders.

      Confirmation of antidepressant potential of the selective beta3 adrenoceptor agonist amibegron in an animal model of depression.

      • Sam Knox

        Is this the same as “?-cell ?-adrenergic receptor activation” mentioned here?

        • William Lagakos

          “alpha” adrenergic receptors in the pancreas vs. “beta” adrenergic receptors in adipose.

          Beta3’s are present in brown fat, but given the anxiety/depression stuff, they’re probably also in the CNS.

          • discuss

            and in the bladder iirc. who knows what they do there…

    • Chris

      Definitely! cold therapy is also great in mood boosting. I find myself laughing after getting out of a shockingly ice shower!

      • Jane Plain (Woo)

        I think best application for cold therapy is winter atypical depression. Other than wt it really helped with winter blahs. Winter is more or less over now but if I get into torpor mode next year (99% chance I will) I will sit in ice bath.

        Winter depression/fall depression is largely sympathetic mediated anyway so it stands to reason.

        • William Lagakos

          that’s one of the recommendations in “The Hibernation Response.”

          …the authors discuss a relationship between cold intolerance & SAD; and how CT can improve cold tolerance. It’s not a very technical, or mechanistic discussion, but still pretty interesting.

    • Jane Plain (Woo)

      Jack is right about this BTW. Cold does all those things, and thats why it will cause plunging drops in sugar /insulin and increases of fat oxidation even in low leptin, low sympathetic people like wooo.

      However caveat for cold exposure is things that increase SNS short term may be deleterious for wt control long term. Many stressors promote adipogenesis. The human stress response is best described as promoting energy waste/mobilization short term but enhancing thrift in long term. I suspect cold therapy while promoting wt loss short term would make wt gain easier later from adipogenesis, i notice how I store fat seems to have changed after using cold therapy. I seem to store more fat on my back as if new adipose cells have grown there, which I suspect is not unlikely outcome of ovoerexposure to intense stress like cold.

      Another caveat, if your SNS is simply broken like an unmedicated hypothyroid patient, or someone who has adrenal failure, cold therapy will be traumatic and will not help. A lot of paleos resist taking their medicine for some reason, but the body can only work if you are properly treating disease, with medication as need be. There is no paleo advantage to staying persistently low T3 to avoid “evil medicine”.

  • Jane Plain (Woo)

    A+ Bill.

    My favorite aspect of your article is how you acknowledge the role the nervous system plays in controlling the endocrine system. Almost none of the low carb proponents do this. Stall? Advice! CUT OUT THE LAST 5 CARBS U R EATING LAWL. Cuz, u knoa, carbs = teh only relevant factor for teh insulins~

    Most people way better to swill a few caps of tyrosine/EGCG/caffeine to normalize the nervous system more like a non-weight reduced person, actually. Lowering carbs from 5 to 0 is going to do jack and crap other than make it incrementally more likely you induce upon yourself an electrolyte imbalance by not eating avocados anymore in lieu of carb free hot dawg.

    • William Lagakos


      not the biggest fan of George Bray, but fortunately was exposed to the “MONA LISA” hypothesis early on: “Most Obesities kNown Are Low In Sympathetic Activity.”


      • Jane Plain (Woo)

        After study and personal experience I think Bray is correct. The obese either have a global SNS deficit or localized to the adipocytes.

        The former will be your typical big fat 300 pound lady with normal blood sugar normal blood pressure not terrible cholesterol bragging about how healthy she is. In reality she has massive SNS deficit for some reason, acquired brain damage, genetic, micorbial, etc.

        The latter may have full sequellae of metabolic syndrome (very high SNS tone, leading to high blood fats and high blood sugar and high BP) but in particular their adipocytes lack normal adrenergic receptor activity so its like their fat tissue is living in a starvation state.

        Obesity is always worse in females because of E/P vs T and how they affect SNS and fat oxidation.

        Most super fat people fall into one or either of these categories.

        • William Lagakos

          there’s an app for that (i think)! well actually the apps seem more targeted toward athletes, but maybe could be tweaked for obese px… like to see if it’s affected by different foods, for example.

  • Phil Thompson

    So exercise after eating to limit damage from a meal (the traditional “walk off the meal” ) makes sense, however exercising fasted in the morning for better fat oxidation has I believe has been demonstrated in RCTs ? Maybe fasted exercise – breakfast – bit more exercise is the optimum ?

    • William Lagakos

      It’s hard to say. Fat oxidation would be higher during fasting exercise, but then would be lower post-meal (higher insulin secretion due to lower SympNS)…
      so 24 hour fat oxidation?
      As opposed to exercising after a meal, which would [theoretically] result in lower 24 hour insulin AUC.

      • Phil Thompson found higher total fat oxidation for fasted exercise followed by meal. There was a lower average insulin for the meal-exercise but not statistically significant to fasted exercise-meal. Both exercise regimes had much lower insulin than control (no exercise).

        So I’m still thinking an hour of fasted exercise, followed by breakfast, followed by a bit more exercise is probably the optimum for a fatty looking to lose weight. I’m all about the fat oxidation 😉

        • William Lagakos


        • Jane Plain (Woo)

          As I suspected insulin was lower after fed exercise. “Not statistically significant” – in which population?
          Healthy athletes,?
          Fat grandma/grandpa with metaboilc disorders?

          Obese women with terrible SNS tone of adipose?

          People who have lost a lot of fat and are at an artificially reduced fat mass thus supersensitive to wt gain?

          In mildly overweight men, fasting exercise is slightly more insulinogenic than fed exercise. I can only imagine that trend much worse for ppl with worse situations neuroendocrine wise like wooo. I already know how this pans out for me; less energy generation, more energy conservation, relative to eating and exercising.

      • Wenchypoo

        I smell another N=1 experiment coming…time to tell Hubby about it, since he’s going to be the guinea pig. :)

    • William Lagakos

      Also, see Jane Plain’s comment:

      “I predict exercising fasting = HPA mayhem, with greater insulinemia postprandial as a result of that, relative to fasting, eating, and then exercising.”

  • Morris39

    Why do you not provide a legend for the graphs? Without a legend the charts are useless.

    • William Lagakos

      Hi Morris, which graph?! Is there something I can clear up for you?

  • Wenchypoo
    • William Lagakos

      Yup! good article.
      My take: if you already have dietary protein & resistance exercise to stimulate muscle growth/hypertrophy, how much more would carbs add to this? I tend to think: not much.

  • Kindke

    The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the alpha2-adrenergic receptors in beta cells.

    The few times ive tried bromo ( 2.5mg per day ) ive ended up with pretty bad insomnia. Cant say I ever noticed an effect on weight though.

    In the study though they refer to “acute administration” so maybe dose wasnt high enough.

    However the most interesting thing is that they think bromocriptine works for diabetes because it REDUCES insulin secretion. But we still have some people running around proclaiming diabetics need more insulin.

  • Dustin Sikstrom

    Hmm, I guess it’s time to scratch the “leangains” protocol and eat before a workout?

    I’m of the mind that diet controls 95% of bodyweight and I’d really like to n=1 myself down to single digit bodyfat with exercising no more than twice a week, lifting only, no cardio. In what you’ve learned on this matter of nutrient timing, I guess it looks like pre-workout meals reduce bodyfat far more than post workout meals. Or perhaps Phil’s concept ( of exercise before (because I have seen other studies showing fasted exercise to increase fat oxidation) AND after a meal would be optimal for the sole purpose of cutting bodyfat? (Currently at about 12-13% bodyfat, wanting to get to single digits. Eating keto if that wasn’t assumed)

    BTW, I really enjoy your posts and link you like crazy.

    • William Lagakos

      Hi Dustin, thanks!
      At 12-13% BF, I think you may be putting a lot of LBM in jeopardy by doing resistance exercise while fasting. I don’t deny the results of the study Phil posted, but in your context, I think the difference in total fat oxidation will be much smaller than the potential difference in the amount of LBM lost. Perhaps a slow walk in the fasted state, but not heavy lifting.

  • William Lagakos

    Exercising fasting or fed to enhance fat loss? Influence of food intake on respiratory ratio and excess postexercise oxygen consumption after a bout of endurance training.

    Exercise and nutrition are often used in combination to lose body fat and reduce weight. In this respect, exercise programs are as important as correct nutrition. Several issues are still controversial in this field, and among them there are contrasting reports on whether training in a fasting condition can enhance weight loss by stimulating lipolytic activity. The authors’ purpose was to verify differences in fat metabolism during training in fasting or feeding conditions. They compared the effect on oxygen consumption (VO2) and substrate utilization, estimated by the respiratory-exchange ratio (RER), in 8 healthy young men who performed the same moderate-intensity training session (36 min of cardiovascular training on treadmill at 65% maximum heart rate) in the morning in 2 tests in random sequence: FST test (fasting condition) without any food intake or FED test (feeding condition) after breakfast. In both cases, the same total amount and quality of food was assumed in the 24 hr after the training session. The breakfast, per se, increased both VO2 and RER significantly (4.21 vs. 3.74 and 0.96 vs. 0.84, respectively). Twelve hours after the training session, VO2 was still higher in the FED test, whereas RER was significantly lower in the FED test, indicating greater lipid utilization.

    The difference was still significant 24 hr after exercise.

    The authors conclude that when moderate endurance exercise is done to lose body fat, fasting before exercise does not enhance lipid utilization; rather, physical activity after a light meal is advisable.