AMYLIN

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.

 

 

As to the mechanism of pramlintide, well, that’s where it gets interesting…

 




 

LEPTIN!

 

Amylin is co-secreted with insulin.  Both hormones exert a net glucose-lowering effect.  In addition to suppressing glucagon, amylin reduces gastric emptying and may induce satiety.  So amylin reduces blood glucose by potentially three distinct mechanisms:

 

  • Inhibits hepatic glucose production
  • Slower absorption of dietary glucose
  • Reduces further glucose consumption (?)

 

In another pioneering study, this one by Jonathan Roth and colleagues in Alain Baron’s lab, the idea of leptin therapy in obesity was raised from the dead (Roth et al., 2008).  Like the Phoenix.

 

phoenix

 

First, they confirmed what we already knew about exogenous leptin therapy.  Administration of leptin alone (500 ug/kg BW) reduced food intake (FI) and BW in lean but not obese rats.  Administration of amylin (100 ug/kg BW) on the other hand, modestly reduced FI and BW in obese rats.  Interestingly, co-administration of leptin and amylin worked synergistically.  That is, the duo reduced FI and BW significantly greater than either agent alone.

 

To further clarify how this was ‘synergistic,’ a clever experiment was designed.  It was previously demonstrated that amylin alone reduced FI, so it was possible that this reduction in FI was responsible for the duo’s superior efficacy.  To determine if reduced FI was the sole mechanism of amylin, leptin-treated animals were pair-fed with amylin-treated animals.

Three groups:

 

  1. leptin alone, who ate and weighed just as much as control animals, simply because leptin alone doesn’t work well in obesity
  2. amylin alone, who ate and weighed less than control animals
  3. leptin-treated animals who were only allowed to eat as much as amylin-treated animals

 

If reduced FI was the sole mechanism for amylin’s effects in leptin-treated animals, then restricting food intake of leptin-treated animals to the level of amylin-treated animals should have completely recapitulated the effects of the leptin/amylin combo.  It didn’t.  The duo still produced greater weight loss meaning that amylin wasn’t simply reducing FI, but rather that amylin was making leptin work better.  In other words, amylin treatment restored leptin’s other effects, eg, regulating energy expenditure.

 




 

amylin improves leptin signaling?

gravitas

 

Importantly, and of most clinical relevance, the weight loss was entirely comprised of fat mass.  Metabolic rate was restored, FI was normalized, and fat got burrrrned.  This has profound implications for the treatment of obesity, and these researchers actually took it to the next level by testing it in obese humans.

Five months of treatment with leptin or amylin alone caused an 8% reduction in BW, whereas patients treated with the combo lost twice as much.  And the combo group was still actively losing weight by the end of the study!

 

Basically, one of the most important findings is the synergistic effect of amylin and leptin co-administration.  And the observation that the increased efficacy attributed to the addition of amylin to leptin therapy is not entirely mediated by the anorexigenic effects of amylin.

However, this is not what was predicted.

 

dramatic-chipmunk

 

A year earlier, Roth did another set of amylin experiments in rats (Roth et al., 2006).  First, they confirmed that amylin treatment (300 ug/kg) reduced FI and BW, albeit with a much higher dose than previously used (100 ug/kg in the other study).  But next they pair-fed a group of control rats to the amylin-treated group and showed that the pair-fed group lost exactly as much weight as amylin-treated rats, suggesting that amylin’s effect on BW is mediated by reduced FI.  This leaves no room for altered leptin signaling, nutrient partitioning, or any other theories.  There was a modest improvement in body comp in amylin-treated rats compared to pair-fed controls, but this may not have been entirely due to the amylin treatment, as pair-feeding is known to negatively impact nutrient partitioning (it’s stressful; recall the mice who got fattier on 5% calorie restriction?).  There were some other minor differences between amylin-treated and pair-fed rats, such as maintenance of metabolic rate after weight loss, however, which may have also accounted for the modestly improved body comp, but this cannot be differentiated from the negative effects of pair-feeding and therefore cannot be definitively attributed to amylin.

 

This was later confirmed with much lower doses of amylin (50 ug/kg) and leptin (125 ug/kg) in a similar study (Trevaskis et al., 2008). The relevance of dosing is of utmost importance because even at these lower doses, they are still quite high for humans; 50 ug/kg for a 300 gram rat may only be 15 ug, but for a 100 kg human is 5 mg, over 300 times higher.  But the authors of this study also measured energy expenditure.  They showed that, as expected, pair-fed rats exhibited a reduced metabolic rate upon weight loss but this was completely prevented by co-administration with amylin and leptin.  Recall that they are eating the same amount of food by design (ie, pair-feeding), so we would expect the pair-fed group to weigh less (same FI + higher metabolic rate = lower BW).  But this is not what happened: BW was statistically similar in the two groups.  Fat mass, on the other hand, was significantly reduced in the treated group suggesting that amylin and leptin co-administration does indeed induce a unique metabolic state whereby fuel utilization is preferentially shifted toward fat oxidation while lean mass is spared.

 

In yet another study by the same group, weight loss was induced by leptin/amylin and then maintenance of the reduced BW was assessed in rats switched to leptin-only, amylin-only, or both (Trevaskis et al., 2010).  Interestingly, when switched to either leptin or amylin alone, FI and BW returned to normal, but when maintained on the combo treatment, BW plateaued but fat mass continued to decline while lean mass increased.  This is a remarkable feat!  It is an entire body re-compositioning effect.

 

The take-home message: scientists have shown that amylin essentially improves leptin signaling, which produces all of the expected effects: increased fat oxidation and energy expenditure, improved body comp, and reduced appetite.  Leptin appears crucial to this.

 




 

SPECULATION

 

Why do some people lose more fat mass with higher carb diets than they do with lower carb diets?  (and please stop denying that these people exist!)

 

Amylin is co-secreted with insulin — so you naturally get more amylin with carbs.  I’m not proposing a theory to justify those studies on 90% carb diets… which I don’t take too seriously since none of them were properly designed — can you say “control group?”

It just seems likely that in this #context, perhaps the extra amylin is enough to restore leptin signaling to allow for more fat loss without fatigue, hunger, poor metabolic rate, etc.

Maybe this is a reason why carb re-feeds, the Targeted Ketogenic Diet, or just regular low fat diets work better for some people.
maybe

Just a theory, but remember: many of the amylin/leptin studies were successful in humans.  The rodent studies were done to tease out the mechanisms.

 

 

calories proper

 

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  • http://americalaidoff.com/ MichaelGWS

    Alternative Title – The Science Behind 30 Bananas a Day

    This and your earlier post on tissue specific fatty acid oxidations are the Calories Proper Gold Standard. Really a lot of food for thought.

    I have a question – isn’t the lowering of trigs on a LC diet possibly improving leptin signaling to the brain?

    • http://www.caloriesproper.com/ Bill Lagakos

      Thanks!

      “isn’t the lowering of trigs on a LC diet possibly improving leptin signaling to the brain?”

      there are a lot of pre-clinical data supporting this (nothing definitive, but seems like a pretty strong hypothesis, imo)…
      but also, the studies cited in this post suggest amylin may also play a big role, which indirectly implicates more ‘moderate’ levels of carbohydrate, depending on #context, eg, for people w/o T2DM

      maybe

    • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

      30BAD simply doesnt work.
      Freelee and durianrider are naturally slim ppl. Freelee is a bulimic who was never overweight, only in her ED mind was she fat.
      Durianrider is also a spindly wirey type.

      When actual fat people try their diet they usually become massively fat.

      I do think 80/10/10 is probably better for insulin signalling than the higher fat SAD diet but its so totally insane and incompatible with human health, what difference does it make.

      • http://americalaidoff.com/ MichaelGWS

        Hey Woo –

        Why comment was made tongue in cheek 😉

        Freelee & Durianride are absolute nut jobs.

  • Gerard Pinzone

    This is a huge discovery! Woo know about this? I wonder if any endos treating people with leptin know about this? (Probably not many are since leptin injections don’t work.)

    • http://www.caloriesproper.com/ Bill Lagakos

      currently, the only indication for metreleptin is lipodystrophy, and it works in this context.

      it also works in the weight-reduced (this is where pramlintide comes in –> “synergy”)

  • http://www.caloriesproper.com/ Bill Lagakos

    My current thinking for an obese patient:
    1) lose ~10% body weight (diet/exercise/whatever);
    2) and THEN, when leptin signaling is in the garbage, initiate metreleptin/pramlintide therapy.

    • Gerard Pinzone

      How would you determine whether or not there’s an issue with leptin signaling? Lots of people plateau for (probably) lots of reasons.

      • http://www.caloriesproper.com/ Bill Lagakos

        1) you could just measure leptin levels, because in this context (ie, weight-reduced), the impaired leptin signaling may simply be due to leptin-deficiency (as opposed to obesity, when leptin is abundant)

        2) I’d say it’s probably safe to assume leptin is in the can if you were long-term obese and then lost >10% body weight…

        This is where I think metreleptin/pramlintide may be most effective — the human studies strongly hinted at not only successful weight maintenance, but also continued weight loss.

        • Wab Mester

          “I’d say it’s probably safe to assume leptin is in the can if you were long-term obese and then lost >10% body weight.”

          Could you elaborate? Are the mechanisms of leptin sensitivity changes known?

          As an aside, it would be great to see a summary of all the various appetite regulatory signals in one place. Know of one?

          • http://www.caloriesproper.com/ Bill Lagakos

            “Could you elaborate?”

            How do you mean?

            “Are the mechanisms of leptin sensitivity changes known?”

            Some mechanisms have been worked out in rodent models, but not 100%.

            “…it would be great to see a summary of all the various appetite regulatory signals in one place. Know of one?”

            yes, the internet :-)

            jk, that would be infinitely complex — for the layperson, I’d recommend picking a hormone or molecule of interest and searching PubMed for review articles — or even more basic, do a Google Image search

          • Wab Mester

            Just curious about your assertion that leptin signaling is trashed after a relatively small weight loss in obese. Still plenty of adipose squirting leptin. Probably improved sensitivity. Not obvious to me how that’d be a trashed state.

            In low-carb, paleo, keto fora, there are many anecdotes of the overweight losing significant weight eating ad lib and effortlessly maintaining at new lower weight. That implies improved leptin sensitivity to me.

          • http://www.caloriesproper.com/ Bill Lagakos

            10% weight loss is not “relatively small!” (see ALL THE STUDIES)

            My problem with the anecdotes is the successes speak up, the failures keep quiet. Anecdotes are problematic, especially when we have a slew of actual studies to go by.

            Don’t get me wrong, LC is great for a lot of people… but it’s not the panacea some people make it out to be — this is what the studies show

          • Wab Mester

            Small relative to remaining leptin-squirting adipose.

            My working hypothesis is that LC success and failure is primarily determined by compliance. So I’m interested in mechanisms of those who have success.

          • http://www.caloriesproper.com/ Bill Lagakos

            success of ANY dietary intervention is primarily determined by compliance :-)

          • Eve

            Ok, this is pretty much the blog entry that’s getting me off low carb. I’ve followed low carb for half a year, exercising (lifting heavy and doing cardio) three to four times a week, and have slowly gained weight despite weighing and tracking macros. I didn’t understand my gain (measurements don’t lie) and was convinced I was doing something wrong. Raised fat, lowered protein. Lowered fat, raised protein. I was lifting before, so it’s not like there were noob GAINZ, plus as a woman, I’m probably not putting on more 0.5lb/month of lean mass. It’s been strangely difficult to try to incorporate obvious carbs because of the compelling evidence in favour of low carb for health. I keep hoping the low carb magic will kick in.

          • http://www.caloriesproper.com/ Bill Lagakos

            “I keep hoping the low carb magic will kick in.”

            unfortunately, I hear this a lot

          • TechnoTriticale

            re: unfortunately, I hear this a lot

            Many usual suspects: gluten-bearing grains not zeroed out, hypothyroid (pandemic), dairy for some, ?6/?3 ratio too high (esp. LA), dysbiosis, cortisol/circadian disrupts, long list of meds and OTC potions.

            There’s a heck of a lot more to optimized diet than just LC, or even LCHF, and it often requires individual tailoring.

          • Eve

            That might be true, but when I did WW Points Plus, I was able to lose a few pounds without trying too hard. I stopped doing it because of several disruptive life transitions, and because of the seeming advantages of low carb (for many). Weight loss isn’t the only story, but I’ll admit that the constant macro tracking and food weighing in the absence of good results has caused me much anxiety.

          • http://americalaidoff.com/ MichaelGWS

            If you’ve been lifting weights all this time maybe you are insulin sensitive and one of that minority who don’t need to bother with lowering carbs.

            What the Internet has taught me is this – body builders and bro’s who lift HATE Gary Taubes and rage on #LCHF way too much;-)

            If you abandon the #LCHF gang – do so in peace. We wish you the best. You can still fit bacon into your 50:20:30 macros.

          • Eve

            Hah, really? BB are totally into cutting carbs for competition prep and “drying out.” :) Sure, their typical diet includes oatmeal and sweet potatoes, but not in huge quantity. I once looked at a sample plan that included six small meals, one of which included 0.5 cup cooked oatmeal and another which included one small sweet potato. The remainder of the meals were lean meat, green veggies, and whey shakes (yuck). That’s not much carb content. They’re pretty careful about consuming enough fat, though.

          • http://americalaidoff.com/ MichaelGWS

            This is true – the Bro’s do need to dry out before the douse themselves in suntan lotion to pose down.

          • http://novuelvoaengordar.com Vicente

            Hi Bill,
            I disagree. If that were the case, logical thinking and statistics say there would be already at least one weight loss study where people lose a significant amount of weight and keep the reduced weight in the long term. There is not such a study.

            With your opinion, you are denying the metabolic response to food deprivation.

            This video is illustrative.

            The failure of all CICO-based dietary interventions is primarily determined by the metabolic reaction to food deprivation.

          • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

            is probably case by case bases at what point leptin is in the crapper. But yes it does happen eventually and i would say the barometer is you’re LC, ur not cheating , ur hungry/cold/not losing anymore when initially it worked great.

            I actually took metreleptin and i can say it fixes that completely.

            I was also verified clinically/absolutely deficient of leptin.

  • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

    A+ entry bill, very fascinating.

    I have verified using REAL leptin that my sensitivity to it is more or less dependent upon my diet, as was the case with my native leptin while obese. As expected, the leptin would work significantly better the lower carb intake. While using leptin i had to RAISE my carbs simply to stop losing weight: in other words, i had to purposely induce leptin resistance, so as to avoid becoming emaciated.

    Whichever ppl exit who lose better high carb, they are in the minority I suspect. We like to focus on the 1 or 2 ppl who claim potato starch leads to being thin but i’m not seeing real results. Most people on the “potato diet” are still fat asses, whereas on the other hand, on my keto diet, I’m eating SO MUCH FOOD and a size 0-2. Really makes you think.

    We also hear these anecdotes like “oh, this vegan is emaciated, so clearly carbs dont make you fat” etc. Yes, he was THIN before and hes THINNER now, whats you’re point? Where are the “high carb vegans” who started out fat and actually become lean? You see this occasionally with low carb diets. You RARELY see it with high carb diets. Yes, when lean ppl go keto (e.g. cancer/seizures) they also become shockingly emaciated. Lean ppl on a lower insulin diet become extraordinarily lean. There are a number of real fat ppl who achieve low body weight low carb, but you RARELY see this with a high carb diet. Only lean ppl becoming leaner: so what.

    So, with that aside: yes i agree perhaps there are cases ppl lose better higher carb but this is definitely the rarer event, ESPECIALLY in metabolic disorders/real obesity.

    Regarding the idea that carbs increase leptin signalling through amylin: ironic because enhanced leptin signalling is likely the mechanism of action for the superiority of VLC diets.

    Speaking personally, I am, no doubt, leptin supersensitive while keto/VLC. This is not simply a “hunch” as I have actually used metreleptin for months int he past (FYI wow they give rats tons 100-300mcg/kg? In the study woo was in , starting dose was 80mcg/kg, and if you failed you went up to 120mcg, and if u lost too much weight like woo, you went down to 40mcg and/or were booted!)

    Regarding my experience: my diet completely modified how this leptin worked, just as it modified how my leptin as an obese person worked. I had to eat more carbohydrate to stop losing body fat (not weight, FAT). Read as this: i had to eat carbs, to raise insulin, to induct LEPTIN RESISTANCE/ineffiency, so as to stabilize my weight while taking 0.04mg/kg metreleptin.

    Once i stopped the leptin? I began inhaling food with rapid wt regain. I returned to VLC. Problem solved.

    So my experience, as well as THE MAJORITY of lardasses suggests something about lowering carbs allows your appetite/metabolism/energy to work. My personal experience suggests that thing is surges of insulin rapidly inducts leptin resistance probably by blocking leptin signalling in the brain somehow. Or, some other property of the carb based diet must do this but my money is on insulin as it is well known insulin is antagonistic of leptin signalling in the brain , they have opposite functions on same neuron populations.

    What i may offer however is this: IF PEOPLE are not insulin resistant, perhaps for such ppl insulin is not being super secreted on a “normal” diet, so LC offers no leptin signalling advantage. In contrast, they may lose advantages such as, enhanced T3 levels (also aging, but whatever…) or perhaps, enhanced amylin levels.

    A lot of research supports the idea that normal ppl who are not hyperinsulinemic/IR generally do better on carb diets. I suspect this is rather like saying non parkinsons pts do better w/o sinement or something. Perhaps rather than say non IR ppl do better with carbs its more appropriate to say that IR, hyperinsulinemic ppl are only fat because of an insulin induced leptin resistance, and this can be effectively treated by going lower carb to lower insulin. If insulin is already low/WNL there is no benefit of going low carb, and you only lose the metabolic enhancements / hypermetabolic bells and whistles offered via insulinglucose.

    Ok, rambling complete.

    Good entry, as usual :)

    • http://www.caloriesproper.com/ Bill Lagakos

      wow so much awesome, thanks!

      just to clarify one point, so the ketards won’t hate on me more than they already do

      “yes i agree perhaps there are cases ppl lose better higher carb but this
      is definitely the rarer event, ESPECIALLY in metabolic disorders/real
      obesity”

      For the people in this group, I don’t think it’s like, “patient will lose weight on LF but gain weight on LC.”
      I think it’s more like, “patient will lose 10-20% more on LF than LC.”

    • Eve

      Re your comment about obese raw vegans becoming lean: I was once a lurker in a raw vegan group years ago and these people do exist. Not many, but there are some. However, their eating is definitely disordered. The few that I can think of went on months-long juice fasts, and practiced extreme caloric restriction because, you know, sunlight is nourishing and stuff.

      • http://www.caloriesproper.com/ Bill Lagakos
      • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

        well sure if u starve yourself u will lose weight.

        OTOH, i have a history of obesity and i stay lean eating like 2000 calories.

        This doesnt happen on carb diets for genuinely fat people unless they are exercising tons.

        • Eve

          No, but there are a lot of women in the low carb/keto community (XXKeto, Ketogains and 1200IsPlentyKeto on Reddit) who gain if they consume more than 1400, sometimes less.
          The macro calculators tell me that my BMR is 1450, but averaging TDEE 1550 (without exercise) has produced a slow and steady gain in fat tissue–scale and measurements are up–despite meticulous weighing and tracking with MPF. Upping my protein and lowering my fat (no added oils) didn’t seem to help, either.

          • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

            People are awful at measuring body fat and many dieters confuse water with “weight gain”. How many times do i read blogs by neurotic housewives who freak out the scale jumped 2 pounds when they cheated on their diet for the weekend? Its like no part of their brain realizes this is 100% fluid.

            i am NOT AT ALL believing they are ‘gaining” eating 1400 calories. What i think si going on is they are weighing every day foolishly and if they eat more food, the scale goes up because of fluid and food bulk and salt, i.e. being more healthy.

            Especially an obese woman – NO ONE is gaining on 1400 unless you are really a rare metabolic freak , or severely hypothyroid or something.

            In general, when i was younger and looking for advice/inspiration, I found it most therapeutic to IGNORE all the stupid dieters out there. Many of them are mondo f*cked up with food/dieting behaviors, they are crash dieters, they are neurotic and unrealistic entirely about how body fat gain and loss actually works. I found it maddening to read most dieters exploits, so i simply stopped doing so. Nonsense such as “i cheated last night and gained 3 pounds!” or “you have your golden shot to lose weight, then you cant lose weight ever again”, and “if you have 1 bite of carbs, you blow keto” and various other insane , ignorant ED-like quackery is rife. Ignorance / myth stews and festers and becomes viral eventually.

            In short, my advice: take a HUGE grain of salt of what you read on dieter forums. Even if the poster isnt intending to deceive she may be so ignorant / ED / crash diet fubar that she thinks she is being truthful.

          • Eve

            I put on weight averaging 1500 over the course of two months. Scales deceive, but my clothes are tighter, and not from strength training bulk. If I tell people this, they think it’s because I’m not weighing food or tracking macros properly, like the fatty who must be cheating, because otherwise RESULTS!

            In any event, I stopped reading the low carb threads because I couldn’t stand reading the success stories of women permanently dieting on so little. I’d have to drop exercise entirely to function like that and it’s not worth the price. Thanks for confirming the crazy that I’ve seen.

            There’s actually a huge difference in nutritional advice on the low carb women’s threads–plagued by traditional CICO thinking–and the general women’s fitness thread, xxfitness. The latter uses much higher dieting ranges, more in line with your eating, even though you’d expect them to be obsessed with low cal plans.

  • Martin

    Bill, for you these studies might be interesting and prompting you to speculate on the theory of fat loss and hunger control. But you yourself will probably never change the way you eat based on them, nor that you should or have any need for that. Some people will it take it very seriously though. If you visit e.g. Richard Nicoley’s blog you will read about the miracles of the potato-based diet and your post on Amylin might provide them with the theoretical underpinnings. Whether it’s going to work for those folks, time will tell. I’m for one looking forward to hearing how Richard got lean and dropped all the excess weight he couldn’t lose with Paleo and LC.