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Nusi-Funded Report Serves Upwardly Disappointment For The Carbohydrate-Insulin Hypothesis Of Obesity

A novel metabolic ward study tests the persuasion that lowering insulin via severe saccharide restriction increases metabolic charge per unit of measurement too accelerates obese loss, independently of calorie intake.  Although saccharide restriction did modestly increment metabolic rate, it genuinely slowed obese loss.  One of the details that sets this study apart from previous studies is that it was funded past times the Nutrition Science Initiative, an organization that was founded specifically to assay out the insulin hypothesis of obesity too related concepts.


Low-carbohydrate diets are widely used for weight loss, too typically, greater saccharide restriction leads to greater weight loss (1, 2, 3, 4).  At the most basic level, in that location are ii primary explanations for the mightiness of low-carbohydrate diets to motility weight loss: either they brand usage swallow fewer calories, or they they brand us flame to a greater extent than calories (or both).

So far, nosotros receive got prove that low-carbohydrate diets brand us swallow fewer calories (5, 6), although much of the effect seems to depend on increasing the proportion of poly peptide inwards the diet rather than restricting saccharide per se (7, 8, 9).  Yet doubt remains over whether or non saccharide restriction every bit good increases the metabolic rate, an effect sometimes called a "metabolic advantage".

Why does this matter?  It matters because it tests a hypothesis that has of import implications for how nosotros should swallow to contend our weight.  This is the carbohydrate-insulin hypothesis of obesity.  In the version championed past times scientific discipline journalist Gary Taubes, researcher David Ludwig, too others, insulin is a key controller of obese storage due to its direct effects on obese cells, too it controls both calorie intake (hunger) too calorie expenditure (metabolic rate).

According to this idea, insulin is the conductor, too calorie intake too expenditure are only passengers, of the fattening process.  It follows that calorie intake is a cherry-red herring, too the solely reasonable strategy for weight management is to restrain carbohydrate, too peculiarly refined carbohydrate.

Unmoved past times a substantial torso of contradictory prove (9B), Taubes too others receive got laid out to encourage novel studies to assay out this hypothesis.  To do so, they founded an organization called the Nutrition Science Initiative (NuSI), which funds question related to the carbohydrate-insulin hypothesis.  I endorsed it (with major reservations) inwards 2012 because it would provide funding to high-quality scientists too ostensibly would non receive got the mightiness to tinker amongst study results (10).

The carbohydrate-insulin hypothesis makes testable predictions that tin live used to evaluate it.  One of these predictions is that exchanging saccharide calories for obese calories, without changing total calorie intake, should increment the metabolic charge per unit of measurement too accelerate obese loss.  This would live consistent amongst the notion that calorie intake too expenditure are passengers, non the conductor, of the fattening process.  Hot off the presses, the start out NuSI-funded study tests this prediction.

Kudos to Taubes too his colleagues for putting their beliefs on the line.  But when you lot do so, you lot opportunity that your beliefs volition live falsified.  Interestingly, sure as shooting outcomes the study are consistent amongst the predictions of the carbohydrate-insulin hypothesis, but the overall painting exhibit is devastating to it.

The study

This study was conducted past times an impressive grouping of obesity researchers, including Kevin Hall, Rudy Leibel, Michael Rosenbaum, too Eric Ravussin (11).

The pattern is quite simple.  17 volunteers amongst overweight or obesity were kept inwards a question facility (metabolic ward) for 8 weeks.  This agency they had no opportunities to swallow non-study foods.  For the start out iv weeks, they were fed the next diet:
  • High-carbohydrate, high-sugar diet (HCD).  50% of total calories from saccharide (338 g/day), too 25% of total calories from sugar.  15% protein.  2,739 Calories per day.
For the instant iv weeks, they were fed the next diet:
  • Very-low-carbohydrate, low-sugar ketogenic diet (KD).  5% of total calories from saccharide (36 g/day), too 2% of total calories from sugar.  15% protein.  2,738 Calories per day.
The volunteers spent ii days a calendar week within metabolic chambers, where their calorie expenditure was measured.  The researchers every bit good used doubly labeled H2O to mensurate the volunteers' average calorie expenditure during the lastly ii weeks of each diet.  

Once every ii weeks, torso composition was measured using dual loose energy X-ray absorptiometry (DXA), which is a gold-standard method too quite sensitive.  They every bit good measured relevant blood markers such every bit insulin, C-peptide, thyroid hormones, urinary nitrogen, too ketone levels.

It's of import to banknote that this study had pre-specified primary too secondary outcomes.  What this agency is that the researchers defined inwards advance which of the study's results volition live the most of import inwards testing the hypothesis, too then that neither they-- nor anyone else-- receive got the mightiness to twist the study's pregnant past times cherry-picking information afterward the fact.

Here are the key outcomes they listed:
  • Primary outcomes: changes inwards total calorie expenditure, changes inwards sleeping calorie expenditure, too respiratory quotient, every bit measured past times the metabolic sleeping accommodation (not every bit measured past times doubly labeled water).  
  • Secondary outcomes: torso composition changes, every bit measured past times DXA.
The results

Although the diets were supposed to render plenty calories to proceed the volunteers' weights stable, they like shooting fish in a barrel lost weight during the HCD, amounting to a loss of 1.1 lbs of torso obese over the lastly ii weeks of the diet (body obese loss during the start out ii weeks was non reported).  This suggests that the calories provided on both diets weren't quite sufficient to keep weight.

Upon starting the KD, the volunteers apace lost weight.  This is expected, since low-carbohydrate diets motility a rapid loss of H2O weight.  Yet despite rapid weight loss, their loss of obese majority genuinely slowed relative to the HCD.  Over the start out ii weeks, they solely lost a total of 0.4 lbs of fat.  Over the lastly ii weeks, this increased to 0.7 lbs, amongst a total of 1.1 lbs over the entire one-month KD period.  On the KD, the volunteers lost the same amount of torso obese inwards i calendar month that they lost inwards ii weeks on the HCD.

I prepared this graph from the study data.  Feel gratuitous to portion it.
Interestingly, the KD did genuinely increment total calorie expenditure, peculiarly presently afterward switching diets.  According to the metabolic sleeping accommodation measurements, volunteers were burning almost 100 extra Calories per hateful solar daytime for the start out x days or so.  Yet this effect waned over time, too past times the destination of the four-week KD period, total calorie expenditure had dropped exactly about dorsum to baseline ( xl extra kcal/day; non statistically significant).  Averaged over all metabolic sleeping accommodation measurements, they burned 57 extra Calories per hateful solar daytime on the KD.  Changes inwards sleeping metabolic charge per unit of measurement followed a similar trend.

The doubly labeled H2O measure indicated a somewhat larger deviation inwards calorie expenditure of 151 kcal/day, favoring the KD.  We don't know how this was changing over time, since this technique gives us i information dot that represents the average of ii weeks of loose energy expenditure.  It's probable that if nosotros had to a greater extent than granular data, nosotros would run across this gap closing over time, since that's what the metabolic sleeping accommodation information suggest.

As expected, insulin secretion declined past times 47% (as measured past times C-peptide) too ketones inwards urine increased almost 11-fold on the KD.  Urinary nitrogen excretion increased for the start out eleven days of the KD, indicating lean majority breakdown, but this was temporary.  Fasting gratuitous obese acid levels increased quite a flake on the KD, but in that location was no alter inwards overall levels of circulating loose energy (glucose addition gratuitous obese acids, ketones, glycerol, too triglycerides).


This study is interesting because some of its results, if considered superficially, are consistent amongst the carbohydrate-insulin hypothesis.  As predicted past times the hypothesis, i of the study's primary outcomes showed that calorie expenditure increased on the KD.  The authors speculate that the increment may receive got been caused past times the metabolic inefficiency of ketogenesis (ketone production) too gluconeogenesis (glucose production), which makes sense*.  These are activated past times falling insulin, too then nosotros tin genuinely say that the increment inwards calorie expenditure was probable caused past times reduced insulin secretion!  Although non the supposed effects of insulin on obese cells.

Yet i time nosotros accept a closer facial expression at the results, they are clearly devastating to the hypothesis.  First, the increment inwards total calorie expenditure was little too transient, too past times the destination of the one-month catamenia it was no longer measurable using the metabolic chamber, which was a pre-specified primary outcome.

Second too most importantly, the extra calories burned during the KD weren't coming out of obese tissue!  The charge per unit of measurement of obese loss genuinely slowed on the KD, peculiarly during the start out ii weeks afterward the diet transition, where volunteers solely lost i 3rd every bit much obese every bit they had lost over the previous ii weeks of HCD.  Over the lastly ii weeks of the KD, obese loss began to rebound, but notwithstanding solely reached ii thirds the charge per unit of measurement of obese loss of the HCD.  In total, the KD caused every bit much obese loss over i calendar month every bit the HCD caused over ii weeks.

This slowed charge per unit of measurement of obese loss on the KD in all likelihood happened for ii reasons.  First, people were burning through their glycogen (carbohydrate) stores inwards the start out few days afterward switching, every bit Hall observed inwards his lastly metabolic ward study (12).  Second, the volunteers were cannibalizing their ain lean tissues for poly peptide over the start out ii weeks of the KD.  Because the KD mobilized stored saccharide too protein, those extra calories presumably displaced obese calories that would otherwise receive got been burned.  In other words, severe saccharide restriction too the resulting driblet inwards insulin motility the torso to flame stored saccharide too poly peptide at the expense of stored fat.  At to the lowest degree initially.

Why did they cannibalize their ain lean tissues for protein?  It's in all likelihood only a resultant of the fact that when in that location isn't much glucose coming inwards from the diet, the torso starts manufacturing it (gluconeogenesis)-- from protein.  This increases the body's poly peptide requirement, too unless the diet is high inwards protein, the torso mines it from lean tissues such every bit muscle.  But inwards the electrical flow study, this effect seemed to live transient, since it tapered off afterward the start out eleven days of the KD.  This may explicate why the charge per unit of measurement of obese loss began to rebound inwards the lastly ii weeks of the KD period.

The carbohydrate-insulin hypothesis relies on the persuasion that insulin suppresses the release of obese acids from obese tissue, reducing overall circulating loose energy levels too creating a state of "internal starvation" that leads to hunger too sluggishness.  If the hypothesis is correct, reducing insulin levels should increment overall circulating levels of loose energy (glucose addition gratuitous obese acids, ketones, glycerol, too triglycerides) too right internal starvation.  Yet reducing saccharide intake from 50% to 5%, too reducing insulin secretion past times nearly half, had no effect on overall circulating loose energy levels.  Evidently, the total quantity of circulating loose energy inwards the blood is regulated tightly plenty that fifty-fifty radical changes inwards diet receive got fiddling demeanor on on it.

It's of import to banknote that inwards many ways, this study was crafted to maximize the apparent effectiveness of the KD.  The KD was really depression inwards saccharide (5%), spell the HCD was high inwards saccharide (50%) too also very high inwards refined saccharify (25%).  If you lot believe the hypothesis that refined saccharify summons Beelzebub to plump upwards your obese tissue regardless of your calorie intake, the comparing should receive got been extremely favorable to the KD.  Yet the effect on obese majority was the contrary of what this hypothesis predicts.

This study confirms that insulin only doesn't travel how Taubes, Ludwig, too other insulin-obesity advocates yell back it does.  As the investigators position it, "it is clear that rule of adipose tissue obese storage is multifaceted too that insulin does non ever play a predominant role".  Despite insulin's well-recognized role inwards regulating dynamic obese acid flux inwards answer to meals, circulating insulin levels are non a dominant controller of obese mass.  Instead, this study suggests to me that obese tissue plays a to a greater extent than passive role inwards loose energy balance: it releases internet calories every bit the torso needs them, regardless of what insulin is doing**.  Insulin is non the conductor of the obese majority train.

The solely remaining explanation for the weight loss produced past times low-carbohydrate diets is that they 1) motility a rapid initial loss of H2O weight, too 2) Pb people to swallow fewer calories, which gradually depletes obese stores.  I do yell back the instant effect is interesting too merits to a greater extent than research.  Why do these diets motility a spontaneous reduction inwards calorie intake, fifty-fifty when people aren't deliberately trying to restrain calories?  Protein is purpose of the explanation, but I'm non sure as shooting it tin fully explicate what happens when the diet is ketogenic (very depression inwards carbohydrate).  I facial expression frontwards to to a greater extent than question on this.

In many ways, this study was state-of-the-art.  It was a truthful metabolic ward study, too then in that location was no diet cheating.  The measure techniques were gilt standard.  Yet it did endure from i puzzling weakness: it lacked a truthful command group.  Therefore, this lawsuit was neither randomized, nor controlled.  I don't know why this determination was made, but it does weaken the result.

This study farther reduces my confidence inwards Ludwig's finding that a very-low-carbohydrate, high-protein diet increases total calorie expenditure past times 300 Calories per hateful solar daytime (13), which Ludwig attributes to the depression saccharide content of the diet, too subsequent reduction of insulin.  This novel study suggests that fifty-fifty severe saccharide restriction, too a substantial driblet inwards insulin levels, has fiddling demeanor on on the metabolic charge per unit of measurement afterward the start out ii weeks when poly peptide intake is controlled.


This metabolic ward study suggests that calorie-for-calorie, a very-low-carbohydrate ketogenic diet substantially reduces insulin secretion, transiently increases metabolic rate, too impairs obese loss.  As such, it i time over again falsifies a pop incarnation of the carbohydrate-insulin hypothesis of obesity.  Perhaps the fact that this study was funded past times NuSI volition aid the message larn through to supporters of the hypothesis.

We tin infer that when people swallow ketogenic diets exterior the lab, they lose obese because they spontaneously cut their calorie intake.  I facial expression frontwards to to a greater extent than question on why this happens.

* Some loose energy is lost inwards the conversion procedure betwixt poly peptide too glucose, too that extra loose energy is released from the torso every bit (mostly useless) heat.  So for example, if you lot start out amongst X number of calories of protein, too you lot convert that into glucose before oxidizing the glucose for loose energy (primarily ATP), you'll destination upwards amongst a smaller quantity of usable loose energy than if you lot had exactly oxidized X calories of glucose directly.  Hence the term "inefficiency".  This term carries a negative connotation, but inwards the context of obesity, metabolic inefficiency tin genuinely live a practiced thing.

** The argue I say this is that glycogen too poly peptide calories seem to receive got displaced obese calories inwards this study, slowing the charge per unit of measurement of obese loss inwards the KD group.  In other words, the charge per unit of measurement of obese acid oxidation was determined past times the loose energy demands of the body, non past times insulin levels.  To qualify my statement, over the longer term obese tissue does play a role inwards regulating appetite too obese mass, but non past times the machinery proposed past times the insulin hypotheis-- it does too then via its release of leptin.


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