Are You At Risk for Insulin Resistance and Diabetic Complications? (FOXO1)

FOXO1 is a strange, doubled-edged little protein. It is a transcription factor, meaning that it binds to DNA and regulates the activity of other genes. More specifically, it regulates insulin production, DNA repair, cell suicide (apoptosis) and parts of the human body’s antioxidant response [R, R].

High FOXO1 activity can be good or bad, depending on the circumstance. On the bright side, this protein [R, R, R]:

• Protects many cells from oxidative stress
• Suppresses the growth and metastasis of cancer cells
• Promotes DNA repair
• Improves wound healing
• Stimulates cellular recycling (autophagy) to destroy and replace damaged proteins

On the other hand, FOXO1 enhances the inflammatory response and reduces insulin sensitivity. In fact, FOXO1 tends to be highly expressed in atherosclerotic plaques (fatty buildup in blood vessels), and mice with overactive FOXO1 tend to develop diabetes [R, R, R, R, R].

With such a broad and complex role, it’s not surprising that FOXO1 mutations may significantly change a person’s health outcomes and even lifespan.

FOXO1 protects cells from oxidative stress and promotes DNA repair, making it an important cancer suppressor gene. It also stimulates autophagy and improves wound healing, but too much FOXO1 activity may increase risk of diabetes and atherosclerosis.

FOXO1 and diabetes have what you might call a complicated relationship. According to some studies, low FOXO1 activity prevents the body from making enough insulin, thereby creating a diabetes-like state. According to others, low FOXO1 could improve diabetes symptoms like impaired healing [R, R].

So, what’s the truth? What’s going on here?

Type 1 Diabetes and Impaired Healing

In people with type 1 diabetes, wound and fracture healing is often extremely slow; according to rodent studies, FOXO1 may be partially responsible. In mice, blocking or deleting FOXO1 restored the animals’ ability to heal broken bones [R, R].

Thus, high FOXO1 activity may prevent wounds from healing in people with type 1 diabetes, and suppressing FOXO1 may help.

Insulin Resistance and Type 2 Diabetes

At least three SNPs in FOXO1 have been associated with type 2 diabetes risk in humans: rs10507486, rs7986407, and rs4581585 [R, R].

In all cases, the risk allele appears to increase the activity of FOXO1 in the pancreas; according to a series of mouse studies, over-active FOXO1 prevents the pancreas from producing enough insulin and responding appropriately to changes in blood glucose [R, R].

At least two of these variations could interact significantly with obesity; that is, obesity intensifies the risk associated with the bad alleles at these SNPs [R].

On the other hand, in some cell studies, low FOXO1 in fat tissue could also trigger insulin resistance. More research will be needed to untangle the complex relationship between this gene and diabetes [R].

In both type 1 and type 2 diabetes, high FOXO1 activity is associated with complications like poor wound healing and damage to the pancreas.

As we’ve discussed, over-active FOXO1 can damage the pancreas and trigger type 2 diabetes in mice, while under-active FOXO1 causes a diabetes-like state to develop in human fat cells. FOXO1 as expressed in healthy people is beneficial to wound healing; in people with diabetes, it is destructive and may increase lesions, ulcers, and inflammatory complications [R].

Given this apparent contradiction, what can we do to make sure FOXO1 is working well? We’ve got some good news: there’s a pathway in your body that can keep FOXO1 activity from getting too high or too low.

AMPK: The Key to Balancing FOXO1

AMPK is the master energy regulator in your body. It detects available energy in the form of ATP in your cells, and modifies both metabolism and appetite appropriately. When cellular energy is low, AMPK activates and promotes energy production from storage (for example, by burning fat) [R, R].

AMPK can both increase and decrease FOXO1 activity, depending on which is appropriate. It has been shown to induce FOXO1 in healthy animals and to suppress it in animals with diabetes. Furthermore, AMPK increases insulin sensitivity; thus, high AMPK activity may be the key to balancing and optimizing FOXO1 to prevent insulin resistance [R, R].

AMPK, the master energy regulator, can turn FOXO1 activity either up or down. AMPK is likely the key to keeping FOXO1 within its optimal range.

FOXO1 rs10507486

• ‘G’ = Increased FOXO1 activity, increased risk of insulin resistance
• ‘A’ = Decreased FOXO1 activity, decreased risk of insulin resistance
• 70.9% of all people worldwide have the ‘GG’ genotype (highest risk)

FOXO1 rs7986407

• ‘A’ = Increased FOXO1 activity, increased risk of insulin resistance
• ‘G’ = Decreased FOXO1 activity, decreased risk of insulin resistance
• 28.5% of all people worldwide have ‘GG’ genotype (highest risk)

FOXO1 rs4581585

• ‘C’ = Increased FOXO1 activity, increased risk of insulin resistance
• ‘T’ = Decreased FOXO1 activity, decreased risk of insulin resistance
• 24.2% of all people worldwide have the ‘CC’ genotype (highest risk)

Relatively speaking, rs10507486 has less of an impact than either of the other two variants listed here. People with the ‘GG’ genotype at rs10507486 are only about 27% more likely than those with the ‘AA’ genotype to develop insulin resistance. The effect is significant, but small [R].

By contrast, rs7986407 and rs4581585 are much more strongly linked to insulin resistance, each capable of more than doubling your risk. Unfortunately, the research linking these SNPs to diabetes risk is quite recent, only published in 2017. These variants are therefore less likely to be included on a commercial DNA file [R].