Genetics and Type 2 Diabetes

What comes to mind as far as the risk of type 2 diabetes? Usually first up is the mental picture of someone eating donuts and sipping on a Big Gulp. While diet definitely contributes to diabetes risk, not everyone who eats donuts and slurps soft drinks will get diabetes.

Genes and Diabetes:

Not all of your type 2 diabetes risk is from what you eat… Genetics plays a big role in diabetes. Studies on twins show that the genetic component of type 2 diabetes is estimated to be between 46-70%.[ref] Thus, genetic susceptibility plays a big role when combined with incorrect dietary choices.

Diabetes is a term applied when your blood sugar levels are higher than normal or inappropriately respond to foods. Your body regulates blood glucose levels through the release of insulin.

With diabetes, your body can be resistant to the effects of insulin — or — you may not be producing enough insulin.

How can you use this information?

Just as there are multiple ways to have high blood glucose levels, there are multiple genetic variants that cause increased susceptibility to diabetes.

By knowing which genetic variants you carry, you can know which pathways are likely to be causing your high blood glucose levels. This can help you personalize your approach to either managing or reversing your type 2 diabetes.

If you don’t have diabetes, understanding your genetic susceptibility can help you target the right pathways for preventing elevated blood glucose levels. If you know where your genetic weakness lies, you can target that pathway to get the most benefit.

Members perk: Genetic Lifehacks members can easily see their genetic data for all of the genetic variants listed below on the Disease Prevention Topic Summary. Not a member? Learn more.

MTNR1B gene: Timing of Eating

Let’s start with a gene that has nothing to do with what you eat, but rather the diabetic risk is due to when you eat.

The MTNR1B gene codes for the melatonin receptor.  A genetic variant in MTNR1B (rs10830963 – G allele) has been tied to an increased risk of diabetes, but subsequent studies show that the increased risk is mainly for those who eat later at night – when melatonin levels are higher. [ref][ref][ref][ref][ref][ref]

Melatonin is a signaling molecule that rises in the evening  (called dim light melatonin onset) and peaks in the night. Insulin sensitivity is lowest at night, and the melatonin receptors in the pancreatic islets modulate insulin secretion from the beta-cells. [ref]

Check your genetic data for rs10830963 (23andMe 4, v5; AncestryDNA):

  • G/G: upregulation of MT2 receptors, increased fasting glucose levels, increased risk of type 2 diabetes
  • C/G: upregulation of MT2 receptors, increased fasting glucose levels, slightly increased risk of type 2 diabetes
  • C/C: typical

Lifehacks for MTNR1B:

Eat dinner earlier:
A recent randomized, cross-over clinical trial looked at the difference in glucose control from eating dinner early (4 or more hours before bedtime) or eating a late dinner (1 hour before bedtime). The study found that everyone had a better blood glucose response (less of a spike) when eating dinner earlier. The data showed that glucose peaked about 60 minutes after eating, with an average difference of about 20mg/dl decrease in peak glucose levels for eating earlier. But when they broke out the data by rs10830963 genotype, it was clear that those with a G allele had a much greater response to eating dinner early (~30 mg/dl decrease in glucose peak).  The study participants with the C/C genotype actually had very little difference in peak glucose response from early dinner vs late dinner. [ref]

Don’t eat breakfast too early:
Another study found that carriers of the G allele had a longer duration of melatonin production — lasting further into the morning hours (41 minutes). It is possible that getting up early and eating breakfast immediately may not be ideal for this genetic variant. [ref]

Time-restricted eating: 
If you are eating dinner early and then waiting a little bit in the morning for breakfast, you may want to read about all the health benefits of time-restricted eating, since that is essentially what you will be doing. There is a great new book out on the topic called The Circadian Code.


TCF7L2 Gene: Beta Cell Function

The TCF7L2 (transcription factor 7-like 2) gene activates many genes involved in type 2 diabetes including glucagon-like peptide 1 GLP1. Genetic variants are associated with a decreased or impaired beta-cell function. [ref][ref]  Beta-cells are the cells in the pancreas that release insulin.

In people with insulin resistance and impaired glucose tolerance, research shows that they also have decreased TCF7L2. [ref]

Check your genetic data for rs7903146 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of diabetes, decreased beta-cell function, higher nocturnal glucose [ref][ref][ref]
  • C/T: increased risk of diabetes [ref]
  • C/C: typical

Check your genetic data for rs12255372 (23andMe v4, v5 ; AncestryDNA)

  • T/T: increased risk of diabetes[ref][ref][ref]
  • G/T: increased risk of diabetes
  • G/G: typical

Lifehacks for TCF7L2

Glycemic Index Matters:
A study found that those with the TCF7L2 variant had a much higher risk of diabetes (over twice the risk) if they had a diet with a high glycemic index. Here is a chart of the glycemic load of common foods: Glycemic Index Chart.  Keep in mind that everyone is individual when it comes to how their body reacts to foods, so use the glycemic index charts and cookbooks as more of a starting point rather than something that is written in stone for everyone.

Dietary fiber:
Several studies have found that higher dietary fiber (higher whole-grain carbs) intake reduced the risk of diabetes for those carrying the risk alleles. One theory is that the fiber stimulates GLP1, and the TCF7L2 variants cause impaired GLP1. [ref][ref]  Caveat: I don’t think it is totally clear if the benefit comes from adding fiber vs. swapping out the refined carbs for unrefined carbs. So just adding a fiber supplement may not do anything for you here. Instead, if you eat refined carbs, switch to more unrefined options.

Curcumin:
An animal study showed that curcumin stimulates TCF7L2. [ref]  Curcumin is found in the spice, turmeric, and as a supplement.

Medication choices:
One study found that people carrying a TCF7L2 variant did not respond as well to the class of diabetes medications known as sulfonylureas. This may be something to discuss with your doctor if you are on a diabetes medication that isn’t working well for you.  The study did note that metformin response was not impacted by TCF7L2 variants. [ref]


SLC30A8 gene: Zinc Transport in Beta Cells

The SLC30A8 gene codes for the zinc transporter ZnT-8. This zinc transporter is found in pancreatic beta-cells and transports the zinc from the cytoplasm into insulin secretory vesicles where it stabilizes it and prevents degradation. [ref]

Check your genetic data for rs13266634 (23andMe results v4,v5)

  • C/C: (most common variant in most populations) increased  risk of type 2 diabetes [ref]
  • C/T: somewhat increased risk of type-2 diabetes
  • T/T: typical risk of type 2 diabetes

Lifehacks for SLC30A1

Increase your zinc if it is low?
Studies are a bit contradictory on whether increasing zinc reduces the risk for those with the risk alleles listed above. One study in India did not show that SLC30A1 was a risk factor in that population. Another study showed that increasing zinc levels by 10 ug/dl decreased the odds of type-2 diabetes for everyone by a little bit, but those with the T/T genotype had a greater decrease than those who carried the C allele (risk genotype). But the majority of studies show that carriers of the rs13266634 C allele are at an increased risk of diabetes. The differences in these studies may be due to the normal dietary intake of zinc in the populations that are studied. [ref][ref][ref]

So how can you increase your zinc levels? Food sources of zinc include oysters (really great source!), beef, crab, pork, beans (soaked first), and chicken. [ref] Cronometer.com is a free app for recording the foods that you eat. It includes the nutrient values for foods, so you can easily see how much zinc you get each day.

Zinc supplements can easily be purchased at health food stores or from online sources, but note that higher doses of zinc can cause an upset stomach for some people. More information on zinc supplements.

Vitamin A from vegetables:
A large study looked at the interaction between nutrient markers in diabetics and healthy controls. The strongest correlation that they found was that higher levels of trans-β-carotene and cis-β-carotene were protective against diabetes (about half the risk!) only for those with the rs13266634 C/C or C/T genotype.  There was no correlation for those with the T/T genotype.  The study wasn’t able to determine if the correlation was due specifically to vitamin A or β-carotene — or if the correlation was due to eating a healthy diet with a high intake of fruits and vegetables. [ref]  My guess… the best bet here is to increase vegetable and fruit intake. β-carotene is found in orange vegetables and fruits, so carrots, pumpkin, and sweet potatoes are good sources. Spinach and collard greens are also good sources. Not everyone is good at converting β-carotene to vitamin A (check your conversion genes), so also including sources of true vitamin A may be important as well. [ref]

 


IRS1 Gene: Insulin Resistance and higher insulin production

IRS1 (insulin receptor substrate 1) variants have also been linked to an increased risk of type-2 diabetes.  The IRS1 gene codes for a key protein in the insulin-stimulated signal pathway. [ref] The genetic variants of this gene are associated with insulin resistance and hyperinsulinemia, rather than impaired beta-cell function. [ref]

Check your genetic data for rs2943641 (23andMe v4, v5; AncestryDNA)

  • C/C: typical risk for diabetes  [ref] lower fasting glucose levels in people without diabetes [ref]
  • C/T: slightly increased risk for type 2 diabetes [ref]
  • T/T: lower risk of type 2 diabetes in people with high vitamin D levels. [ref]

Note that for this gene, studies refer to the C allele as increasing the risk for type 2 diabetes. Since it is the most prevalent allele, you could also look at it as the T/T genotype being protective.

Lifehacks for IRS1

Get enough vitamin D:
Carriers of the T/T allele had an even greater reduction in the risk of diabetes with higher levels of vitamin D.[ref] Sunshine is your best bet for vitamin D.
A lab test can tell you if you are low in vitamin D.  UltaLab Tests Vitamin D.  If you decide to supplement with vitamin D, be sure to choose one that includes a good type of oil (as opposed to a cheap vitamin D with soybean oil).  I personally like Sports Research with coconut oil, K2 and vitamin D. (In general, it is good to combine vitamin K2 and D3 but be aware of interactions if you are on a blood-thinning medication.)

Weight loss diet:
If you need to lose weight, one trial of different types of diets found that a low-fat diet (high in non-refined carbs with fiber) worked best for people with the IRS1 rs2943641 C/C genotype, but not for the C/T or T/T genotypes. [ref]  Another (small) study found that a low-fat diet worked best for those with rs2943641 C/T genotype. [ref]


WFS1 gene:

Wolfram syndrome gene variants that impair glucagon-like peptide1 stimulated insulin secretion. [ref]

Check your genetic data for rs10010131 (23andMe v4, v5; AncestryDNA):

  • G/G: typical risk of T2D
  • A/G: protective against type 2 diabetes
  • A/A: Protective against type 2 diabetes [ref]

 


HHEX gene:

HHEX (homeobox) is another gene with polymorphisms that are associated with a higher risk of developing type 2 diabetes.  The HHEX protein interacts with signaling molecules and plays a role in embryonic development of the liver, thyroid, and pancreas.  A European study in 2007 found that rs7923837 was associated with impaired glucose-stimulated insulin response. [ref][ref][ref]

Check your genetic data for rs7923837 (23andMe v4, v5; AncestryDNA):

  • G/G: 3.2x risk for type 2 diabetes
  • A/G: 1.9x risk for type 2 diabetes
  • A/A:  typical risk of type 2 diabetes

Check your genetic data for rs1111875 (23andMe v4; AncestryDNA):

  • G/G: increased risk for type 2 diabetes (OR = 1.36) [ref]
  • A/G: increased risk for type 2 diabetes (OR =1.16)
  • A/A:  typical risk of type 2 diabetes

Lifehacks for HHEX

Lower insulin secretion in people who carry the HHEX genes makes it important to eat a lower glycemic diet. Vegetables and whole foods generally require less insulin to be released after eating them (compared with processed foods). The key for carriers of the HHEX variants may be to figure out which foods spike glucose levels (via frequent testing or a continuous blood glucose monitor) and avoid those foods.


KCNJ11 gene:

One more gene associated with type-2 diabetes is the KCNJ11 gene.  The KCNJ11 gene codes a protein involved in insulin release.  Sugar (glucose) activates this protein which releases insulin from the pancreas.  The T allele gives a decreased insulin response to glucose. It is also associated with plasma leptin levels. [ref][ref]

Check your genetic data for rs5219 (23andMe v4 )

  • T/T: 2.5x increased risk of type 2 diabetes
  • C/T: 1.3x increased risk of type 2 diabetes
  • C/C:  typical risk of type 2 diabetes

Lifehacks for KCNJ11

Cut refined carbs:
Reducing sugar and refined carbs should help people with the KCNJ11 gene variants. Everyone’s insulin response to food is somewhat unique, so a continuous glucose monitor or frequently checking your blood glucose level after eating different foods can give you a better idea of which foods to avoid.


PPARG gene:

The PPARG gene codes for a protein that is important in causing other genes to be expressed. These other genes are involved in fat and energy production. PPARG is needed to regulate the storage of fat and regulate insulin resistance. Rare, loss of function mutations in PPARG  increase the risk of diabetes quite significantly. [ref]

The studies on the rs1801282 variant (found in about 20% of most populations) show conflicting results as to whether the variant increases or decreases the susceptibility to diabetes. Part of this may be due to dietary differences between the population groups studied, and part may be due to exercise. [ref][ref][ref]

Check your genetic data for rs1801282 (23andMe v4, v5; AncestryDNA):

  • C/C: typical genotype,
  • C/G: increased risk of metabolic syndrome and insulin resistance (healthy adults); decreased risk of diabetes in some populations (depending on diet, exercise)
  • G/G: increased risk of metabolic syndrome and insulin resistance (healthy adults)[ref]; decreased risk of diabetes in some populations (depending on diet, exercise)[ref]

Lifehacks for PPARG:

Exercise:
People carrying the G allele for rs1801282 had a greater benefit from exercise for increasing glucose tolerance. The study showed that carriers of the G allele were more responsive to ‘beneficial health effects of lifestyle interventions.’ [ref] Another study came up with similar results. [ref] So if you carry the G allele and have problems with blood glucose levels, exercise may be very beneficial for you.


Conclusion:

There are many different risk factors for type 2 diabetes.  Knowing which genetic variants you carry can help you target a plan for reversing type 2 diabetes.

The list above of genetic variants just covers the most common ones, but there are many other less common genetic mutations that can increase the risk for diabetes. So take this article as a starting point instead of being a complete blueprint for you.

One thing that is not included in any of the Lifehacks above is a ketogenic or very low carb diet.  I didn’t find any studies looking at a ketogenic diet in relation to the specific genetic variants for type 2 diabetes, but I wanted to include it here as an option because a lot of people are having success on it for weight loss and reversing diabetes.

A 2016 study comparing low calorie vs low-carb ketogenic diets found the ketogenic diet more effective for lowering HbA1c and fasting blood glucose levels (although both diets had positive effects!).[ref]

A ketogenic diet isn’t for everyone, but if you have diabetes or pre-diabetes, it is worth considering and talking with your doctor about.


Related Genes and Topics

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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.