Designed By Nature

Research in the past and present has shown us that fat causes insulin resistance. With ketogenic diets becoming increasingly popular, many people fear for a potential negative effect by inducing this insulin resistance.

It is true that insulin resistance does appear on low carb high fat diets such as the ketogenic diet but the context is very different, the mechanism is different and as a consequence the outcome on health is different.

With this post I’ll explain those mechanisms and provide my viewpoints on the cases where it is healthy and where it is detrimental to health.

Pathological Insulin Resistance (unhealthy)

Fructose

When absorbed, fructose is converted into fat in the liver. The type of fat that is created is palmitic acid (PA) and this is the same type of fat when glucose is converted to fat. What the effects are of this PA is explained under glucose but keep in mind that those effects are also applicable to fructose.

“Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027077/

Instead, we’ll focus on other elements.

A first thing to be aware of is that fructose increases the fat accumulation in the liver. Not only by triggering the fat production but also by reducing the liver’s capability to utilize that fat. This has repercussions when we look at diacylglycerol (DAG), a form of stored fat which increases due to this effect.

“Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism.” https://www.ncbi.nlm.nih.gov/pubmed/18924245

The proposed method of action is that the increase in DAG causes a higher activation of PKCe which reduces the expression of insulin receptors 1 and 2 (IR-1 and IR-2).

The accumulation of DAG may result from a disproportionate low level of diacylglycerol acyltransferase (DGAT1) versus the increase in DAG production and potentially further exaggerated by acetyl-coa abundance which also leads to DGAT1 consumption to form TAG.

“Insights into the Hexose Liver Metabolism—Glucose versus Fructose” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622786/#sec7-nutrients-09-01026title

“Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838515/

“The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux” https://www.ncbi.nlm.nih.gov/pubmed/26727229

Glucose

Palmitic acid (PA) is a saturated fat that lowers GLUT2 expression in the pancreas and liver leading to increased glucose levels in circulation as the liver is less responsive in the uptake of glucose and the pancreas is less stimulated to secrete insulin due to a reduced uptake of glucose.

“Dexamethasone Induces Posttranslational Degradation of GLUT2 and Inhibition of Insulin Secretion in Isolated Pancreatic Beta Cells. Comparison With the Effects of Fatty Acids” https://pubmed.ncbi.nlm.nih.gov/9013557/

“Effects of Dietary Fatty Acids in Pancreatic Beta Cell Metabolism, Implications in Homeostasis” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946178/

Glucose is not PA right? Indeed it isn’t but large amounts of glucose stimulate insulin to such levels that de novo lipogenesis takes place. Glucose will be converted to fatty acids. When this happens, the fatty acid that is produced is PA.

We also see that PA has greater potency to induce apoptosis in liver cells. I’m not sure if this contributes to insulin resistance. What is clear is that PA interferes in the signaling cascade of insulin resulting in a deregulated response.

“Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes” https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1746.2008.05733.x

Muscle

GLUT2 and GLUT5 are the only transporters for absorbing fructose. With PA (originating both from glucose and fructose) reducing the GLUT2 in the liver and pancreas, what are the consequences of this circulating fructose?

Some amount of the fructose is converted to glucose. The kidneys secrete part of this glucose. The muscle cells also convert some to glucose but further synthesizes it to glycogen.

“Synthesis of Muscle Glycogen in Man After Glucose and Fructose Infusion” https://www.ncbi.nlm.nih.gov/pubmed/6028956/

Fructose causes a similar accumulation of lipids in the skeletal muscle called intramyocellular lipid (IMCL) synthesis.

“Postexercise repletion of muscle energy stores with fructose or glucose in mixed meals” https://academic.oup.com/ajcn/article/105/3/609/4569698

Fructose does in the muscle cell what it does in the liver. It gets converted into the fatty acid PA, builds up DAG, stimulates PKCe and finally reduces the insulin receptors. The insulin receptor is needed to move GLUT4 into the cell membrane to take up glucose. Unless you do regular exercise, your muscles are now less responsive to insulin. Without the receptor they will not take up insulin from the circulation.

DAG is normally further processed into TAG which does not cause the insulin resistance. This is done by DGAT1. There is no clear data available showing why DAG would accumulate but I suspect, like in the liver, it would be the shear volume of DAG production that overwhelms the capacity to convert the DAG to TAG. As seen under fructose, synthesis of fatty acids from acetyl-coa also involves DGAT1. This could be taking place in the muscle as well.

“Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866250/

This study looked at TAG formation using oleic acid and used 2 different concentrations. Despite a double in concentration, it did not lead to a doubling in speed of TAG formation indicating that under high DAG formation there could be a delay in processing leading to the insulin resistance effect described earlier.

“High-content assays for evaluating cellular and hepatic diacylglycerol acyltransferase activity” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975729/

Physiological Insulin Resistance (healthy)

Update 2020-05-16:

My original information led me to believe that a reduction in IRS1 would not take place under a low carb diet but it does seem to be the case. It would be interesting to find out if a reduction in IRS1 can be caused by low basal insulin or if the same mechanism is taking place, a reduction due to increased intracellular fat content (DAG or TAG). On a high fat diet, the lipid droplets in myocytes increases, similar to endurance exercise.

This makes me doubt the information that IRS1 reduction would only be due to DAG or we see an equal DAG production under low carb diets. Either production or absorption from the circulation. It is also possible that DAG is produced, not by de novo lipogenesis but by the breakdown of TAG into NEFA. I’ll need further research to understand this.

I speculate (with a high degree of certainty) we will not see the same IRS1 lowering in the liver as the liver exports its fat content under low insulin. This is also indicated in the paper showing that the hepatic insulin sensitivity index is (non-statistically) even higher for the low carb group. This would make sense given that the high carb group does stimulate insulin to a higher degree. The maintained insulin sensitivity would also indicate that IRS1 doesn’t lower due to lower insulin secretion.

“Reduced Glucose Tolerance and Skeletal Muscle GLUT4 and IRS1 Content in Cyclists Habituated to a Long-Term Low-Carbohydrate, High-Fat Diet.” https://www.ncbi.nlm.nih.gov/pubmed/32109885

Furthering speculation as I understand the mechanism… This effect does entail a level of glucose sparing that is beneficial in a resting state on a LCHF diet as general glucose availability is lowered. This implies that insulin resistance under low insulin can’t be seen as problematic and it is only localized to skeletal muscle tissue. There is not a problem disposing glucose since glucose levels are well maintained and the liver maintains its sensitivity. OGTT will be worse though since less can be absorbed by the skeletal muscle under resting conditions.

As you will see further down, exercise does move GLUT4 to the cell membrane which overcomes the insulin resistant effect in the skeletal muscle. It would be great to understand how long GLUT4 remains expressed after exercise stops. The reference above noted reduced GLUT4 in a fasted state.

END update 2020-05-16

Low Carb High Fat diet (LCHF)

Reading through the above sections it is understandable for people to be worried about a high fat diet and certainly if it contains saturated fat such as palmitic acid. It is clear that fat causes the insulin resistance.

Let’s have a look at which of the above effects are applicable to our high fat diet.

Fructose & glucose

Those are excluded from the diet apart from small amounts. Certainly sugar is, and fructose may come from fruit which includes fiber, slowing the absorption and the detrimental effects.

This causes the production of lipids to be close to non existing. This prevents the abundance of lipid generation that may overwhelm the TAG production from DAG through DGAT1. This mechanism of IR will thus not take place in the liver, pancreas and muscle.

Dietary Palmitic Acid

But the diet may contain palmitic acid. Certainly when animal fat is consumed. Although that is true, we see that people on a low carb high fat diet have lower circulating levels of PA than high carb low fat diets.

First of all we see this effect in the fat and milk of cows who are grass-fed versus grain-fed. So if you take in fat from animals and you are worried about PA, lower

“A review of fatty acid profiles and antioxidant content in grass-fed and grain-fed beef” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846864/

“Fatty acid composition of cow milk fat produced on low-input mountain farms” https://www.agriculturejournals.cz/publicFiles/13651.pdf

“Effect of Only Pasture on Fatty Acid Composition of Cow Milk and Ciminà Caciocavallo Cheese” https://pdfs.semanticscholar.org/f058/c402b0851e85b4a696552a901cfc2d27fc49.pdf

Can we expect a similar effect in humans? If we eat grass.. no I mean if we keep carbohydrates out of our diet, do we get lower circulating PA fatty acids?

That study has been done looking at the composition of all the different sources of fatty acids in our body and looked at how much of them are made up of PA. They noted:

• 11% reduction of PA in the circulating triglycerides.
• No change in the phospholipids
• 8% reduction of PA in cholesterol

The fatty acid palmitoleic acid is derived from PA. With less PA available, it is reasonable to assume that palmitoleic acid will be affected as well. They noted:

• 32% reduction of palmitoleic acid in the circulating triglycerides
• 35% reduction of palmitoleic acid in phospholipids
• 44% reduction of palmitoleic acid in cholesterol

What is even more impressive is that the intervention was with calorie restriction. Despite the restriction, the high carb group did not notice any change in PA circulation. The high fat group did continue to consume an equal amount of fat as before the intervention yet were affected by the reductions listed above.

“Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation.” https://www.ncbi.nlm.nih.gov/pubmed/18046594

GLUT4

So is there no insulin resistance at all under a high fat low carb diet? It was already mentioned that GLUT4 expression into the cell membrane requires activation via the insulin receptor. Under frequent insulin stimulation, more GLUT4 will be available to take up more glucose from the blood stream.

Under chronic low insulin conditions such as the LCHF diet less GLUT4 is available. This happens in the liver and in the muscle. If you now eat something that is fast and high in carbs then the body will have issues with clearing the glucose because it will take a bit of time before, under stimulation of the insulin, GLUT4 reaches the cell surface and starts taking in glucose.

There are other GLUT transporters active which do not depend on insulin so it is not that glucose absorption completely fails.

What you have to understand is that under a LCHF diet, the liver glycogen buffer is much more reduced so that glucose availability becomes low. In such a situation it makes sense for a mechanism that spares glucose. The brain is the most dependent on glucose while the liver and the muscles are fine with fatty acids to generate energy.

In the following paper we see that after a 58 hour fast, the c-peptide measurement is much higher versus the control (an overnight fast). C-peptide is an indicator of how much insulin is secreted. But when measuring insulin, the level is less increased. What this means is that there is a larger proportion of insulin taken up by the liver under the 58 hour fast. Yet when you look at the increase in glucose, it was higher in the longer fast. It’s a showcase of prolonged low insulin reducing the GLUT4 availability in the liver. When insulin is released, GLUT4 protein will be created and moved to the cell membrane but this doesn’t happen instantaneously.

“Effects of Fasting on Physiologically Pulsatile Insulin Release in Healthy Humans” https://diabetes.diabetesjournals.org/content/51/suppl_1/S255

Exercise

One other way to avoid this lack of GLUT4 expression is by exercising. Contraction of the muscles also moves GLUT4 to the cell membrane. This may not increase expression of GLUT4 in the liver but it keeps the muscles more active in absorbing glucose when blood glucose rises and thus helps to keeps insulin levels lower than without exercise.

“Exercise Causes Muscle GLUT4 Translocation in an Insulin-Independent Manner” https://www.longdom.org/abstract/exercise-causes-muscle-glut4-translocation-in-an-insulinindependent-manner-22388.html

Finally

As you see there are very different reasons and situations that lead to insulin resistance. In the unhealthy state we have a full liver glycogen and reduction in insulin receptor signaling. In the healthy state we have an almost empty liver glycogen and maintain insulin receptor signaling.

In the healthy state, the insulin resistance is easily resolved with a few rounds of triggering insulin as the signaling is not broken and thus will consequently lead to higher GLUT4 expression. In the unhealthy state, you must leave out the carbs from your diet and/or abstain or reduce food intake for a while to resolve the situation where the fat storage in the liver prevents insulin signaling.

I would also like to propose a name change. Because the described insulin resistance under a LCHF diet is more like a function rather than an issue, it would be good to have a name that describes that function. Glucose Sparing Insulin Resistance (GSIR) seems appropriate. And perhaps the pathological insulin resistance can better refer to its cause: Fructose or Glucose Induced Insulin Resistance (FGIIR).

—- END —-