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…
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.
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.
- leptin alone, who ate and weighed just as much as control animals, simply because leptin alone doesn’t work well in obesity
- amylin alone, who ate and weighed less than control animals
- 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?
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.
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.
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.
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.
— Bill Lagakos (@CaloriesProper) March 16, 2016
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