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.
For most people, type 2 diabetes is due to a combination of lifestyle and genetic risk factors.
Why this matters: Knowing your root cause can help you to prioritize your solutions to:
Genetic factors interact with environmental factors, such as:
You can prioritize these environmental factors based on your genetic variants.
Adding up the genetic risk:
Researchers link diabetes risk to genetic variants in a number of different genes. A genetic risk score can be calculated based on the number of different diabetes-related variants a person carries. 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). Instead of worrying about an individual variant, 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 carried a number of genetic risk variants. The Western dietary pattern did not matter much for diabetes risk in people without the risk variants. [ref]
Below are some of the most well-researched genetic variants linked to diabetes, but there are other genes, including obesity-related genes, that add tangentially to the risk for diabetes.
|Gene||RS ID||Risk Allele||YOU||Notes about the Risk Allele:|
|MTNR1B||rs10830963||G||—||Increased risk of diabetes, increased fasting glucose levels|
|SLC30A8||rs13266634||C||—||Increased risk of T2D, zinc related|
|IRS1||rs2943641||C||—||Slightly higher risk for diabetes|
|HHEX||rs7923837||G||—||Increases risk of impaired glucose-stimulated insulin response|
|KCNJ11||rs5219||T||—||Decreased insulin response to glucose|
|KCNQ1||rs2237892||T||—||Decreased risk of diabetes (good!)|
|PPARG||rs1801282||G||—||Increased risk of metabolic syndrome and insulin resistance|
|PCSK9||rs11591147||T||—||Decreased LDL cholesterol, but an increased risk of diabetes|
|CDKAL1||rs7754840||C||—||Increased risk of diabetes|
|CDKAL1||rs7756992||G||—||Increased risk of diabetes|
|CDKAL1||rs10811661||C||—||TT: Decreased risk of diabetes (good!)|
|CDKAL1||rs564398||C||—||CC: Decreased risk of diabetes (good!)|
|TCF7L2||rs7903146||T||—||Increased risk of diabetes, decreased beta-cell function.|
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]
Check your genetic data for rs10830963 (23andMe 4, v5; AncestryDNA):
Members: Your genotype for rs10830963 is —.
Lifehacks for MTNR1B:
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]
Check your genetic data for rs13266634 (23andMe results v4,v5)
Members: Your genotype for rs13266634 is —.
Lifehacks for SLC30A1:
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)
Members: Your genotype for rs2943641 is —.
Lifehacks for IRS1:
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. Variants in the HHEX gene are linked to impaired glucose-stimulated insulin response. [ref][ref][ref]
Check your genetic data for rs7923837 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs7923837 is —.
Check your genetic data for rs1111875 (23andMe v4; AncestryDNA):
Members: Your genotype for rs1111875 is —.
Lifehacks for HHEX:
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]
Check your genetic data for rs5219 (23andMe v4 )
Members: Your genotype for rs5219 is —.
Lifehacks for KCNJ11:
Check your genetic data for rs2237892 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs2237892 is —.
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):
Members: Your genotype for rs1801282 is —.
Lifehacks for PPARG:
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]
Check your genetic data for rs11591147 R46L(23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs11591147 is —.
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.
Check your genetic data for rs7754840 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs7754840 is —.
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]
Check your genetic data for rs7756992 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs7756992 is —.
Lifehacks for CKDAL1variants:
Additionally, there are variants in the CKDAL1 gene that decrease the risk of type 2 diabetes.
Check your genetic data for rs10811661 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs10811661 is —.
Check your genetic data for rs564398 (23andMe v4; AncestryDNA):
Members: Your genotype for rs564398 is —.
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]
Check your genetic data for rs7903146 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs7903146 is —.
Check your genetic data for rs12255372 (23andMe v4, v5 ; AncestryDNA)
Members: Your genotype for rs12255372 is —.
Lifehacks for TCF7L2:
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.
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]
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]
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.
One thing that weight loss does is 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 for 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]
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 seems 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]
Going keto while on a diabetes medication can cause diabetic ketoacidosis for some people. [case study][case study][case study][case study] If you are going to try a big dietary change, talk with your doctor and know what the warning signs are for negative side effects.
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.