The incretin effect – Hormonal Obesity XXII

By Jason Fung, MD

What is the incretin effect?  With the Glycemic Index (GI), we had a physiologic scale for classifying carbohydrates.  Some raise blood sugars more than others.  When researchers looked at carbohydrate containing foods, there is a very close correlation between the GI and the amount of insulin released (Insulin Index – II).

Insulin is the hormone predominantly involved in the regulation of blood sugar.   Carbohydrates raise blood sugar and insulin rises to deal with it. Fats and proteins have a negligible effect on blood glucose.  For years, it was therefore assumed that this meant that it would also have a negligible effect on insulin secretion.  This was not actually true. We had just ignored this rather inconvenient fact.  Since fat and protein do not raise blood sugar, there should be no effect on insulin.  But proteins and their constituent parts – the amino acids can also raise insulin without any effect on the blood sugar.

As far back as 1966, in the Journal of Clinical Investigation the paper “Insulin secretion in response to protein ingestion” showed that oral or intravenous administration of the amino acid leucine would result in stimulation of insulin secretion.  Dr. Nuttall rediscovered this fact in 1991 in his paper “Plasma glucose and insulin response to macronutrients in non diabetic and NIDDM subjects” (Diabetes Care 1991:14:824-38).

So proteins and amino acids are able to stimulate insulin without any change to the blood glucose.  This required an entire change in the way we think about macronutrients.  Around the same time, there was increasing interest in the hormones produced in the stomach (gut hormones), and the so-called incretin effect.
In 1986, Nauck and colleagues noticed something unusual. In humans, the blood sugar response to glucose given through an intravenous or given orally was the same.  That was not really a surprise.  Simple sugars such as glucose are quickly and easily absorbed in the intestines.

However, what was interesting was the insulin secretion.  In response to the same level of blood sugar, there was a huge difference in the insulin response.  Many powerful medicines are given intravenously because there is 100%  bioavailability.  This means that all of the drug is active.  When given by mouth, many medicines are incompletely absorbed or partially deactivated by the liver before getting to the bloodstream.  So intravenous medications tend to be more effective that oral ones.

However, in this case, the oral glucose was far, far better at stimulating insulin than the intravenous.  Furthermore, this mechanism had nothing to do with the blood sugar.  Insulin response is not the same as the blood sugar response.  This had not been seen before.  Eventually, it was discovered that the stomach produces hormones – now called incretin hormones that increase the insulin secretion.  Since the intravenous glucose bypasses the stomach, there is no incretin effect.  This may account for 50-70% of the insulin secretion after oral glucose intake.

So far, two incretin hormones have been described in humans.  These are Glucagon Like Peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).  Both hormones are deactivated by the hormone dipeptidyl peptidase-4 (DPP4).  Inhibition of DPP4 by drugs like saxagliptin causes an increase in the levels of the incretin hormones.  This raises insulin levels and helps to lower blood sugars.

The incretin effect starts within minutes of ingestion of nutrients into the stomach and peaks at roughly 60 minutes.  The incretins have effects other than stimulation of insulin.  They also inhibit glucagon and delay stomach emptying.  This has the effect of slowing down glucose absorption in the body.
The existence of a pathway of insulin secretion entirely independent of blood glucose was new and exciting.  Here was a pathway whereby proteins could stimulate insulin secretion.  Perhaps the amino acids stimulated the incretin pathway as a mechanism of glucose-independent insulin secretion.  Comparing the intake of different proteins, milk and dairy product in particular were potent stimuli of insulin.

This paper “Glycemia and insulinemia in healthy subjects after lactose equivalent meals of milk and other food proteins” published in AJCN in 2004 demonstrates the effects of different proteins.  While milk and cheese stimulate insulin the most, even cod fish has an effect here.

When milk is taken with other foods, it also causes an increase in the insulin response.  In the paper “Milk as a supplement to mixed meals may elevate postprandial insulinaemia“, milk or water was given to test subjects in addition to their spaghetti meal.  It is clear from the diagram that the insulin increases much more with the addition of milk versus the water.

Dairy proteins show a large discrepancy between the blood glucose effect (Glycemic Index) and insulin effect.  Most dairy product score extremely low on the glycemic index, but very high on the Insulin Index.  While lactose is a carbohydrate contained in milk, it does not seem to play much of a role in the insulin response.  Testing the effect of pure lactose, the glycemic index and insulin index parallel each other closely.

As it turns out, it was the dairy proteins that caused the insulin increase.  There are predominantly two type of dairy protein – casein (80%) and whey (20%).  Cheese is composed mostly of casein protein.  The whey portion of the dairy is felt to play the larger role in insulin stimulation, but cheese may also have significant remnants of whey protein left.  The branched chain amino acids found in dairy products may be particularly potent.

Does the incretin effect play a role in insulin secretion in response to whey?

The paper “Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins” sheds some light upon the mechanism of insulin secretion.  They measured glucose and insulin levels after test meals, and then went one step further to test the levels of GLP-1 and GIP.

What they discovered was that the whey protein in dairy product in particular stimulated insulin secretion the most.  While GLP-1 levels were no different between any of the proteins tested (cod, milk, whey and cheese), the whey stimulated GIP to a much larger degree than the others.

This, then at least in part, explains some of the findings we discussed in our last post.  Carbohydrates are not the only stimulator of insulin.  Proteins also cause insulin increase.  Whoa, nelly.  This changes everything.

Continue here to Hormonal Obesity XXIII – Insulin Index
Start here with Calories part I – How Do We Gain Weight?
To see the entire lecture – The Aetiology of Obesity 3/6 – Trial by Diet 

By The Fasting Method

For many health reasons, losing weight is important. It can improve your blood sugars, blood pressure and metabolic health, lowering your risk of heart disease, stroke and cancer. But it’s not easy. That’s where we can help.

Jason Fung, MD

By Jason Fung, MD

Jason Fung, M.D., is a Toronto-based nephrologist (kidney specialist) and a world leading expert in intermittent fasting and low-carb diets.

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