Why I think protein is particularly important in type 2 diabetes

(Amino-acid stimulated insulin secretion)

There’s always a lot of debate and controversy about the importance of the macronutrients (protein, carbohydrate and fat) in nutrition. Much of this is overblown - either there is no consistent data either way, or the effect size (the magnitude of the increase/decrease of an outcome) is so small as to be of little clinical relevance. However, there are definitely cases where there is clear or promising evidence that the amount of protein in the diet can have a real impact. One of these is in type 2 diabetes (T2D).

People talk a lot about insulin resistance in T2D, but it’s important to remember that defective insulin secretion is the primary distinguishing feature: about 60-65% of the population have insulin resistance, yet only about 6-10% (depends on the population) have T2D. (If we add in prediabetes this might be another 20-30% depending on how we define it). The difference is that the latter groups have defective insulin secretion; in the former, their beta-cells (the cells in the pancreas that produce insulin) are able to release enough insulin to keep glucose within normal levels.

Insulin secretion is much harder to study than insulin resistance, but basically what we know is this: as people develop T2D, their beta-cells get less sensitive to changes in glucose concentration. In healthy people, glucose sensor[s] on the beta-cell are able to detect a rise in glucose, and can quickly respond by sending instructions to release insulin (we call this stimulus-secretion coupling). Imagine you eat a few slices of bread for breakfast - if you are healthy, your beta-cells will recognise the rise in glucose within seconds, and you’ll get a pronounced insulin response like this:

In contrast, look at what happens in type 2 diabetes:

In fact, it’s worth mentioning that we see this reduction in beta-cell response to glucose very early on, and defective insulin secretion has even been observed in young offspring of people with T2D.

Why does it matter that your beta-cells are able to launch a robust insulin response a rise in blood glucose? It turns out a pronounced “insulin spike” is pretty essential for controlling post-prandial blood glucose via a variety of mechanisms including 1) shutting down hepatic glucose output after a meal and 2) promoting uptake of glucose into peripheral tissues. In the DiRECT trial (a large RCT which tested the effect of marked weight loss with meal replacements on remission of T2D), getting the insulin spike back was the primary determinant of who got remission or not. If people got the insulin spike back, they got remission. If they didn’t get that insulin spike back (even if they lost loads of weight, had improved insulin sensitivity etc), their glucose remained in the diabetic range. So it looks like a robust insulin response is essential for optimal glucose control in T2D*.

[Glucose is released from the liver throughout the night to keep you alive. But if your liver continues to release its endogenous glucose into the bloodstream, at the same time as your bloodstream is receiving exogenous glucose from your breakfast, the result is hyperglycaemia]

So what does all this stuff about insulin secretion have to do with protein? Well everything I have described so far has been about glucose. And to be honest, our approach to T2D has been gluco-centric for a long-time. We generally test the health of the beta-cells in pre-clinical and clinical trials by exposing them to a lot of glucose, and seeing how much insulin they produce and how quickly**. So when people talk about “defective insulin secretion”, implicitly what they mean is “glucose-stimulated insulin secretion”. But, remember how I talked about stimulus-secretion coupling above? Well, amino acids are also a stimulus for insulin secretion.

It’s important to note that amino acids on their own at physiological concentrations do not promote insulin secretion. But mixtures of amino acids do. And most importantly, the addition of amino acids/protein to a glucose stimulus results in a MASSIVE release of insulin compared to glucose alone. In other words, the addition of protein to a carbohydrate meal will cause a much greater rise in insulin. And finally, the most exciting thing (and I think this observation is really under-appreciated in the nutrition/endo world) is that while glucose-stimulated insulin secretion declines in T2D, amino-acid stimulated insulin secretion seems to remain more or less intact in dysglycaemia.

To be clear, a greater rise in insulin after a high-protein meal is probably of no meaningful clinical significance in healthy people (I’m not aware of any good data on this anyway). However, in people with T2D who have a defective insulin response to a rise in blood glucose, the boost of prandial insulin from the addition of protein to a meal is probably very useful at getting post-prandial glucose under control.

There are a number of trials in the literature that have tested this (curiously they all have 30%kcal from protein, with 15%kcal in the control groups). Obviously if you add protein, you will be adding calories unless you also decrease carbohydrate or fat, so these trials vary in the background macro content. And because the control group did not match the carb content, these individual trials in and of themselves are not solid “proof” that high protein (30%kcal) per se lowers glucose in T2D. From trials which have used 20%, 30%, and 40%kcal from carb, it looks like the real sweet-spot might be at 20/30%kcal from carbohydrate (two separate groups have replicated these findings which is pretty rare in nutrition lol). So maybe the reduced carb plus addition of protein have synergistic effects. However, we still see glucose lowering with added protein even at 40%kcal carbohydrate, and protein lowers glucose in a dose-dependent fashion in people without diabetes.

Why do I think it’s [mostly] the protein that has the glucose-lowering effect in these trials? I am not convinced that moderate reduction in carb (without increasing protein or decreasing calories) lowers glucose in T2D. In fact, my hunch is that the reason ostensibly low-carb diets seem to do so well in some “low-carb” interventions, is because they HAVE MORE PROTEIN. I acknowledge we still don’t have data (that I know of) that modifying protein while keeping carb constant changes glucose concentrations in T2D but I am working on this, and I am pretty confident it does (laugh at me in 12 months if my own data proves me wrong).

In fact, if I could summarise why I think protein is especially useful for T2D, it’s this:

A few disclaimers

We always need to remember the effect of diet on all aspects of health, eg CVD, bone health etc. So in general I follow these principles with my patients:

• Get as much protein from plant-based sources as you can (I will put up some diet sheets soon) : adding lentils instead of rice is a healthful switch.

• Make sure your diet is full of a variety of plant-based whole foods as possible: nuts, seeds, olives, veges, salads, fruit etc.

• Try and get the majority of your fat from unsaturated sources.

Also please note there are lots of ways a person can manage their T2D. Weight loss - regardless of the macronutrient content - can help improve insulin sensitivity and beta-cell function. However, to me the potential value of a high-protein diet in the context of T2D is that it seems to be able to substantially lower post-prandial glucose concentrations even without weight loss. This has been a lot of value in my practice (anecdotes obviously) where my older patients (who don’t want to lose a lot of weight) find that they can get pretty good control of their glucose and even remission by reducing their starch intake and getting more protein.

*It’s possible that people can achieve good glycaemic control without needing a robust insulin response if they follow a ketogenic diet….there is no great data on this but I am open to the idea that the physiological changes (reduced hepatic glucose output) that may occur in people with T2D on a super-low-carb keto diet means that the post-prandial insulin response does not have to be so pronounced to control blood glucose. Also worth nothing that achieving normal glucose levels for even 2 weeks can improve insulin secretion over the long-term, so there’s potentially lots of interesting research to look at here.

**Some clinical tests also use supraphysiological amounts of arginine which is an amino acid but this doesn’t really tell you much about beta-cell response to physiological (normal) amounts of amino acids like you’d get from eating a high protein meal.