Do blood glucose "spikes" contribute to insulin resistance, or is prolonged elevation required?

Question

There's increasing public discussion about the health risks of chronic insulin resistance* (IR). In many cases there's a focus on high glycemic index foods that "spike" your blood sugar, which implies that a rapid increase in blood glucose is by itself sufficient to contribute to IR.

On the other hand, I've heard the claim that if a person is 1) moderately active, 2) not in caloric surplus, and 3) not already insulin resistant, then they will will quickly clear excess blood glucose by replenishing glycogen or through general energy expenditure. This is claimed to have no effect on IR, even though the individual was temporarily exposed to elevated glucose / insulin.

This leads me to two questions:

1) Is it true that high blood glucose is normalized substantially more rapidly in people who have depleted their glycogen, or who have higher energy needs?

2) Does repeated exposure to high levels of blood glucose contribute to IR by itself, or are high and prolonged levels of blood glucose required?

This has public health implications -- If the "spikes" theory is inaccurate, then glycemic index may not be very important to sufficiently active people**, and low glycemic index meals may not be as helpful as expected for people at risk of developing IR if total glucose exposure is high.

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*"chronic insulin resistance" would exclude gestational diabetes and the reversible insulin resistance seen on ketogenic diets.

**For this discussion, let's ignore effects of blood sugar swings on hunger, mood, behavior, etc, since my interest is in the specific physiological triggers for IR.

Answer 1

Great Question.

The biggest problem is persistent insulin signaling from prolonged excessive high blood glucose over time. The reason being that it is this kind of signaling that results in insulin insensitivity due to down-regulation of the insulin receptors.

Any bolus of carbohydrates > ~ 25grams in a sitting is going to bump up blood sugar at a fast enough rate to warrant the release of insulin to help lower blood sugar levels. This can be mitigated by an excessive amount of fat along with the carbohydrates, thus slowing down the spike.

Your question: 1) Is it true that high blood glucose is normalized substantially more rapidly in people who have depleted their glycogen, or who have higher energy needs?

So this is a little confounded by several variables. The thought process is that people that have less glycogen or higher energy needs, don't have insulin insensitivity; thus the same amount of insulin would do a better job of shuttling glucose into cells. We know that consistent exercise increases insulin sensitivity, as does lack of persistent insulin signaling (such as comes from being in a glycogen depleted state). So the answer to your question is generally YES for these reasons.

2) Does repeated exposure to high levels of blood glucose contribute to IR by itself, or are high and prolonged levels of blood glucose required?

What we know from epi studies suggests that it isn't insulin spikes. It is prolonged insulin signaling that causes insulin insensitivity through down-regulation of insulin receptors.

If you are fuel deprived, or only getting what you need from your food, insulin spikes are normal and transient and don't cause this IR.

Persistent insulin signaling causes many many side effects. Insulin is mitogenic, has downstream pro-inflammatory cascades, and the insulin insensitivity that results is a major player in non-alchololic fatty liver disease.

Some references for these thoughts and further reading:

1. This one gives evidence of reduced IR activity, not downreglation
2. Insulin signaling and NAFLD
3. Exercise and Insulin Sensitivity