What is insulin resistance?

Everything suggests that nature developed some level of insulin resistance as a protective mechanism against food shortages, but what evolution could not foresee, are the excesses.

In other words, pathological insulin resistance appears to be basically a consequence of the continued activation of the Growing Mode.

In Recycling Mode (fasting or exercise) or even on a very low carbohydrate diet, adipocytes (fat cells) increase lipolysis (fat burning) to release fatty acids and glycerol to be used for fuel and to aid in gluconeogenesis, which is the synthesis of sugar in the liver.

In this state the body will have the tendency to save as much glucose as possible for the central nervous system, that is, the cells reject glucose to prioritize the brain. Therefore, in this scenario we are faced with a mild insulin resistance without high levels of insulin, something completely natural and reversible.

As we have seen, when we eat a food that has an impact on blood sugar, the beta cells of the pancreas secrete insulin.

In a healthy individual, the presence of this hormone causes the cells to capture glucose to be used or stored (glycogen or fat) and the mobilization of energy is slowed down. In other words, the liver slows down gluconeogenesis and fat cells, the lipolysis. But when there is pathological insulin resistance, this changes in a significant way.

Pathological insulin resistance is very complex and not easy to define, so let’s go by parts.

Insulin resistance in muscles:

Insulin resistance in muscle cells appears to be the beginning of the downward spiral (1).

Thanks to Drs Gerald Shulman (2), Kitt Petersen, and colleagues, whose contribution to science in this field over the past three decades is outstanding to say the least, we have a better idea of the onset and progression of this disease.

Rather than using static concentrations such as cholesterol or blood glucose, these researchers used nuclear magnetic resonance imaging to receive very specific information in humans, such as ectopic fat, glucose-6-phosphate levels, enzyme activities, or how much glucose is accumulated as glycogen.

Based on experimentation (3), we can see how the accumulation of lipids within muscle cells (ectopic fat) alter insulin signaling and decrease glycogen synthesis, suggesting that this is the first step that leads to resistance to insulin in the rest of the body.

At this step (1), we are still many years away from this being reflected in blood sugar, as at this stage (as well as later stages) beta cells are working extensively to maintain homeostasis. Or in other words, the pancreas generates large amounts of insulin to maintain normal blood glucose despite the resistance of muscle cells to the signal of this hormone.

Insulin resistance in the liver:

This appears to be the next stage, as muscle cell resistance eventually ends up affecting the liver.

When young, lean, and insulin-resistant subjects were compared with insulin-sensitive control subjects after two high carbohydrate intakes (1), it was observed that net muscle glycogen synthesis was reduced by approximately 60% in subjects with insulin resistance.

Insulin resistance in the muscles generated a deviation of glucose towards the liver, increasing hepatic de novo lipogenesis (fat synthesis).

Although de novo lipogenesis does not appear to be significant in healthy individuals (4), this apparently changes when insulin resistance begins in muscle cells (1,5). Since when this happens, an increased hepatic lipogenesis has been observed with the consequent export of VLDL, so that plasma triglycerides rise and HDL fall. Which has the potential to change the lipid profile dangerously (a topic that does not need to be understood now as we will develop it later in future blogs).

Insulin resistance in fat cells:

With regard to adipocytes (fat cells) I’m inclined to two hypotheses.

On the one hand, we have the research of Dr Shulman and colleagues that suggests that there is also insulin resistance in adipocytes and on the other (with a completely opposite idea), the hypothesis put forward by the brilliant veterinarian Peter Dobromylskyj in his blog “Hyperlipid” (6), which raises the possibility that systemic insulin resistance is due to pathologically insulin-sensitive adipocytes.

1 – Dr. Shulman’s hypothesis (2):

Under normal conditions, the presence of insulin slows lipolysis in the periphery, but according to Dr. Shulman, insulin resistance in adipocytes does not allow this suppression and lipolysis is further increased by localized inflammation in these cells. In addition, since there are more fatty acids and glycerol reaching the liver, gluconeogenesis increases significantly both due to the direct influence of glycerol, as well as due to the excess of acetyl coenzyme A.

Since gluconeogenesis increases hyperglycemia further, this closes the vicious circle that leads to type 2 diabetes.

2 – The hypothesis of Peter Dobromylskyj (6):

Peter Dobromylskyj’s hypothesis is as brilliant as it is complex to explain, as it goes deep into the function of the electron transport chain. So to those of you unfamiliar with mitochondrial function, we suggest reading on as it will all make sense eventually.

In very simple words, NADH and FADH2 (coenzymes) are “vehicles” that transport electrons generated in glycolysis and the Krebs cycle to the electron transport chain.

Long-chain saturated fatty acids produce the highest amount of FADH2 relative to NADH, and since these carriers deliver electrons to different mitochondrial complexes, this difference in the ratio NADH / FADH2 causes many electrons to go “backwards”, resulting in the production of reactive oxygen species.

These reactive oxygen species in turn generate insulin resistance in the adipocyte, something that in this case appears to be positive, since it results in less hypertrophy (growth) of fat cells.

Instead, an excess of polyunsaturated fatty acids keeps fat cells pathologically sensitive to insulin, causing them to continually grow.

As adipocytes grow, so does basal lipolysis, leading to a continuous release of fatty acids into the blood.

(Note: Currently, the vast majority of polyunsaturated fatty acids do not come from unprocessed natural foods, but are consumed in exaggerated amounts in vegetable oils from seeds (linoleic acid), a topic that we will develop in the future blogs on lipids)

This is where the hypotheses of Dr Shulman and that of Peter Dobromylskyj coincide, since in both models, the release of fatty acids in the context of pathological insulin resistance, is what leads to the onset and development of type two diabetes.

Although hyperinsulinemia initially tries to compensate for these dysregulated processes, in some cases beta cells can reduce insulin production (2), leading to even higher sugar levels and perpetuating the downward spiral.

(TakeAway: In Recycling Mode, free fatty acids and gluconeogenesis are the result of an adaptation so that the body continues to have energy substrates at its disposal, even in the face of nutrient deprivation.

In contrast, in pathological insulin resistance, this is a consequence of an exaggerated Growing Mode activity that leads to a gradual increase in unused blood sugar and fatty acids, leading to dangerously high levels of glucose and a lipid imbalance that leads to fatty liver with the consequent export of VLDL, lowering HDL and raising triglycerides, which is an independent marker of coronary heart disease.

The research suggests that pathological insulin resistance begins in the muscles, eventually leading to de novo lipogenesis, which in turn leads to hepatic insulin resistance, fatty liver and hyperinsulinemia that closes the loop leading to diabetes and if this is sustained, in some cases what follows is the deterioration of beta cells that decrease insulin production, going from hyperinsulinemia to insulin deficiency, closing the circle with greater hyperglycemia)

So, how can we maintain stable insulin levels?

While hyperinsulinemia appears to be a consequence of several factors that we’ll develop in future blogs, maintaining stable insulin levels through the type of carbohydrates consumed seems like a smart move as well, especially if we are looking to reverse a pathology.

As we have seen, independently of what causes insulin resistance or sensitivity, carbohydrates take center stage in the insulin response, and their quality, determines the speed and quantity that is secreted.

We obtain carbohydrates from our diet through sugars, starches, and fibers found in fruits, grains, vegetables, and dairy products.

Carbohydrates are classified as simple or complex and the difference between the two forms is the chemical structure, which is what determines how quickly they are absorbed.

In the next blog we are going to put carbohydrates in order according to the impact they have on the insulin response.