Diabetes: Genetic Risk Report

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Is Diabetes Genetic?

For most people, type 2 diabetes is due to a combination of lifestyle and genetic risk factors.

Genetic factors interact with environmental factors, such as:

• diet (sugar and/or fat consumption)
• exposure to light at night
• timing of food consumption
• micronutrient intake

You can prioritize these environmental factors based on your genetic variants.

We often talk about diabetes as though it is one disease, but diabetes can have several different causes or pathways that are impacting glucose regulation. Tailoring your diabetes prevention (or reversal) efforts to fit your genetic susceptibility may be more effective.

Adding up the genetic risk:

Researchers have discovered many different genes that increase the relative risk of diabetes. The genetic variants listed below increase (or decrease) the risk of diabetes in most population groups. These variants are well-studied with many replication studies.

For the most part, genetic variants increase the risk of diabetes a little bit (generally between 10-40% increase in relative risk). Thus, the cumulative effects of multiple risk variants seem to be key. In other words, the risk is generally additive – the more risk alleles you carry, the higher the risk.[ref][ref]

Diet combines with Genetic Risk Score:
Research shows that a ‘Western Diet’ is associated with an increased risk of diabetes only in people who carry a number of genetic risk variants. The Western dietary pattern did not have much of an impact on the risk of diabetes in people without the risk variants.[ref]

Genetic Variants Linked to Diabetes:

Below are some of the most well-researched genetic variants linked to diabetes.

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Details on the genetic variants:

Eating late at night (MTNR1B gene):

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]

The MTNR1B gene codes for the melatonin receptor.  A genetic variant in MTNR1B (rs10830963 G) initially was identified as a general risk factor for diabetes, but subsequent studies show that the increased risk is mainly for those who eat later at night.ref][ref][ref][ref][ref][ref][ref]

Lifehacks for MTNR1B:

• Eat dinner earlier: Simply shifting your dinner to be earlier and not snacking at night has been shown in studies to mitigate the risk from this variant.
• 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]

 

Zinc and beta-cell function (SLC30A8):

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] The pancreatic beta-cells have the highest levels of zinc of any tissue.[ref]

Lifehacks for SLC30A8:

• Increase your zinc  -if it is low: Research shows 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 for rs13266634 had a greater decrease than those who carried the C allele (risk genotype). The majority of studies show that carriers of the rs13266634 C allele are at an increased risk of diabetes, but this may not be true for all population groups. The risk may depend on the normal dietary intake of zinc in the populations that are studied.[ref][ref][ref][ref]
• Food sources of zinc include oysters, beef, crab, pork, beans (soaked first), pumpkin seeds, and chicken.[ref]

 

Insulin Resistance and higher insulin production (IRS1 Gene:)

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]

Lifehacks for IRS1:

• Vitamin D: Vitamin D increases insulin sensitivity for the insulin receptor and stimulates insulin release. Carriers of the rs2943641 T/T genotype had an even greater reduction in the risk of diabetes with higher levels of vitamin D.[ref][ref] The only way to know what your vitamin D level is to get a blood test done. If you are on the low end,  either expose your skin to the sunshine between the hours of 10:00 – 2:00 or consider supplementing with vitamin D to raise your levels to the healthy range.
• Weight loss diet: If you need to lose weight, one clinical 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]

 

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 the embryonic development of the liver, thyroid, and pancreas. Variants in the HHEX gene are linked to impaired glucose-stimulated insulin response. [ref][ref][ref]

Lifehacks for HHEX:

• Low glycemic index diet: 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:

The KCNJ11 gene codes a protein involved in insulin release.  Sugar (glucose) activates this protein, which releases insulin from the pancreas. The rs5219 T allele gives a decreased insulin response to glucose.[ref][ref]

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.
• Decrease alcohol consumption: Research shows that chronic alcohol consumption combines with the KCNJ11 variant to increase the risk of type-2 diabetes.[ref]

 

KCNQ1 gene:

The KCNQ1 gene codes for a potassium voltage-gated channel KQT-like subfamily, member 1. This protein is important in the pancreatic islet cells and the regulation of insulin secretion.[ref][ref]

 

Metabolic syndrome and insulin resistance (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]

Lifehacks for PPARG:

• Exercise works for increasing glucose tolerance: People carrying the G allele for rs1801282 had a greater benefit from exercise for increasing glucose tolerance. Multiple studies show that carriers of the G allele are more responsive to ‘beneficial health effects of lifestyle interventions.’[ref][ref]

 

Low LDL Cholesterol Genes:

Several genetic variants are solidly linked to life-long lower LDL cholesterol levels, which generally cuts the risk of heart disease by about 50% (a good thing). But the flip side is that these variants are also linked with an increased risk of type 2 diabetes. This may also link in with statins, a type of cholesterol-lowering medication, also being associated with an increased risk of type 2 diabetes.[ref]

PCSK9 gene:

Decreased insulin release (CDKAL1 gene):

The CDKAL1 gene codes for cyclin-dependent kinase 5, which is a protein expressed in the pancreatic islet cells.[ref] The genetic variants in the gene are important in the release of insulin in response to glucose. Not enough insulin released leads to higher blood glucose levels.

Note that rs7754840 is in linkage disequilibrium with rs10946398 and rs471253; thus, most people who inherit a variant in one of these SNPs will inherit the variant in all of the SNPs. Studies link all of the variants to type 2 diabetes risk.[ref]

Lifehacks for CKDAL1variants:

• Link to medications: Sulfonylureas, a type of antidiabetic drugs, have been shown not to work as well for people with the rs7763992 or rs7754840 risk alleles.[ref]
• Low glycemic index diet: Decreased insulin release may mean that a low glycemic-index diet would be most helpful here. One study in women with gestational diabetes found that ‘healthy lifestyle intervention’ was statistically effective for people with the risk allele for this variant.[ref]

 

Additionally, there are variants in the CKDAL1 gene that decrease the risk of type 2 diabetes.

 

Beta Cell Function (TCF7L2 gene):

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/impaired beta-cell function.[ref][ref]  People with insulin resistance and impaired glucose tolerance also have decreased TCF7L2.[ref]

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 – best way to know for yourself is to check your response to different foods with either a continuous blood glucose monitor or a finger prick test.
• Dietary fiber: A large study that divided people by dietary fiber intake found that people who carry the rs12255373 T allele were actually at a higher risk of type 2 diabetes with high fiber intake.  Note that the high fiber intake correlates to high whole-grain carbohydrate intake.[ref]. Other studies show that people without the TCF7L2 risk alleles are likely to benefit from high fiber diets for preventing diabetes, but that those who carry the risk allele do not benefit from a high fiber diet.[ref][ref]
• Curcumin: Animal and human cell studies showed that curcumin stimulates TCF7L2, which theoretically would be helpful for people with the TCF7L2 risk alleles.[ref][ref]
• 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 notes that metformin response was not impacted by TCF7L2 variants.[ref]

 

HNF4A gene:

The HNF4A gene encodes a transcription factor that turns on other gene in the liver and in the pancreas.

Lifehacks for HFN4A: 

Luteolin, a flavonoid found in celery and parsley, decreases  HNF4A and inhibits apoB-containing lipoprotein secretion from the liver.[ref]

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Lifehacks for diabetes:

ADA (Standard) Advice:

The American Diabetes Association recommends eating more non-starchy vegetables, fruits, whole grains. They say to eat ‘less of’ sugary drinks, white bread, cereal, cakes, and cookies. They also recommend getting some exercise. Overall, the American Diabetes Association website has a lot of information about managing diabetes with medications…[article]

Note that the diabetes epidemic in the US doesn’t seem to be improving… which leads to the possibility that the dietary advice of the American Diabetes Association may not be working for everyone.

Exposure to light at night causing impaired glucose tolerance:

Working the night shift and other ways of being exposed to light at night is linked with a higher risk of diabetes.

A recent mouse study was able to elucidate the mechanisms. The study used mice and exposed half of them to light at night and the others had darkness at night. The mice with light at night had impaired glucose tolerance — which returned to normal after they went back to normal darkness at night.[ref]

Quality of Sleep:

Many studies link poor sleep to higher fasting blood glucose levels. Sleep apnea is a big risk factor for type 2 diabetes. If you have been ignoring your sleep apnea, there are some new options on the market that may help- talk with your doctor and make quality sleep a priority.[ref][ref]

A recent (2019) study showed that 4 hours of sleep significantly reduced insulin sensitivity and impaired beta-cell function (compared to 8 hours of sleep). Moreover, if the sleep loss occurred in the early morning hours (e.g. waking up at 3 am and not falling back to sleep), cortisol levels were also impacted.[ref]

Weight loss:

For people who are overweight, most studies show that weight loss helps to decrease blood glucose levels.[ref]

While obesity is a risk factor for diabetes, not everyone with diabetes is overweight. Additionally, not everyone who is overweight will get diabetes. But for people who are both overweight and diabetic, weight loss is likely to help.

Reverse fatty liver disease:

One thing that weight loss does is to reduce the fat content of the liver. Researchers estimate that weight loss, which reduces liver and pancreas fat, can reverse diabetes for a lot of people.[ref][ref]

Some diabetes experts link fatty pancreas to beta-cell dysfunction and fatty liver to insulin resistance – thus tying both of those to the cause of diabetes.[article]  Studies do back up this connection.  Advanced fatty liver disease with fibrosis causes an almost 5-fold increase in the risk of diabetes.[ref]

TUDCA is a taurine conjugated bile acid, available over the counter as a supplement. Animal studies show that it reduces blood glucose levels and increases liver clearance of insulin – in an obesogenic animal model.[ref] Other animal studies indicate that it may help the pancreatic islet cells.[ref][ref][ref][ref]  A small randomized controlled trial (in humans) indicated that TUDCA increases insulin sensitivity in the liver and muscles.[ref]

What about keto?

There are lots of anecdotal reports about people regulating their blood glucose levels using a very low carb, ketogenic diet.  And it makes a lot of sense that reducing carbohydrate intake would reduce the need for insulin.

The studies on this are less clear, though. While the evidence for a low-carb diet causing weight loss is fairly solid, there seem to be individual differences in whether a ketogenic diet is right for everyone.[ref][ref] Other studies give the edge to the keto diet as being a little more effective than a low-fat diet in reducing the need for diabetes medications.[ref]

Caution: Going keto while on a diabetes medication could cause diabetic ketoacidosis. [case study][case study][case study][case study] If you are going to try a big dietary change, talk with your doctor first and know what the warning signs are for negative side effects.

Low-fat diet?

The other diet extreme is to go low-fat (rather than low-carb). This also seems to be beneficial for some people with diabetes.  A recent study found that both a low carb or low-fat diet was effective for reducing body fat and liver fat. But the low-fat diet group had an advantage with some of the parameters tested for cardiovascular disease.[ref]

Talk with your doctor, of course, about any dietary interventions. But common sense dictates that the most effective diet is the one that you can maintain long term.

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