Monday, November 30, 2015

Does Dietary Protein Impair Insulin Sensitivity?

If you read some diabetes literature you can easily get the sense that everything is bad: protein, fat and insulin cause insulin resistance, while carbohydrates spike blood glucose and insulin levels.  Today I’m going to look at protein and insulin resistance

In many ways there’s a fairly reasonable case for protein impairing insulin sensitivity:

·         Infusion of amino acids impairs insulin sensitivity [1] [2]
·         People with insulin resistance tend to have elevated levels of most amino acids, particularly the branched chain amino acids (leucine, isoleucine and valine) [3] [4] [5] [6], but not glycine [4] [7] [8] [9]
·         Mice fed a high protein low carbohydrate diet developed insulin resistance (the high protein diet was a bit ridiculous at 60% protein, but the ‘moderate’ protein group had at 33% protein had higher insulin levels but similar glucose tolerance to the low protein group at 5% protein) [10]

There’s quite a reasonable mechanism for this.  Amino acids (particularly leucine) activate mTOR.  mTOR forms a complex with Raptor called mTORC1.  mTORC1 activates S6K1.  S6K1 promotes protein and lipid synthesis.  But S6K1 is part of a negative feedback loop as it inhibits the activation of insulin receptor substrate 1 (IRS-1), leading to an impairment in insulin sensitivity [11] [12] [13] [14]

The black circle represents an inhibition

However, whether high protein diets impair insulin sensitivity in clinical trials is fairly mixed

·         A few studies find no difference with a higher protein diet [15] [16] [17] (while the latter of these found an improvement with the high carbohydrate, high fibre diet)
·         Whey protein supplementation improved insulin sensitivity with no change in fasting glucose [18]
·         Unlike the hypocaloric high carbohydrate diet, the hypocaloric high protein diet didn’t result in improvements in fasting glucose, insulin sensitivity and HbA1c [19]
·         The Zone diet (high protein), Akins diet (high fat) and conventional dietary advice (high carbohydrate) all reduced fasting insulin in insulin resistant obese women [20]

t and there are alternative explanations to the observations above

·         Amino acid infusion is hardly a physiological state
·         The higher levels of amino acids seen in people with insulin resistance could be a consequence of insulin resistance rather than a cause of it (see this review paper [21])
·         Higher protein diets (33%) and/or casein (their source of protein + supplemental methionine) are biologically inappropriate for mice 

So I’m not sure whether dietary protein impairs insulin sensitivity.  It’s not a good idea to jump to conclusions based on mechanisms, animal studies and biomarkers.  To answer this question it would be ideal to have a clinical trial to manipulate all three macronutrients because replacing protein with carbohydrate (which is the most common method) only tells you about the effect of protein relative to carbohydrate


  1. Hey Steven,

    Nice commentary on the impact of high protein diets on insulin sensitivity. Could you maybe elaborate as to why high protein diets are biologically inappropriate for mice? I guess, we all know free living mice do not eat milk-derived protein. However, casein-derived diets with supplemental cystine are superior in terms of breeding performance. Of course this begs the question if our research diets are adequately desgined for metabolism research in total.


    1. Hi Thomas, I'm basing this 'alternative explanation' on 2 things.

      1) That 40% fat diets reliably cause obesity, metabolic dysfunction, etc in mice but don't have the same effect in humans (e.g. the Mediterranean diet). It seems that unlike humans, mice may have a narrow range of macronutrient composition that they tolerate well and may not tolerate higher protein and fat since they largely eat plants (and therefore would be more genetically adapted to that).

      2) While I wouldn't like to say definitively how high protein diets affect insulin sensitivity in humans, it seems like high protein diets have a different effect for mice vs. humans, so I need to reconcile these differences