One of the biggest players in overall health and longevity is good blood glucose control. High blood glucose levels, whether after a meal or all the time, can increase oxidative stress in the body, leading to long-term chronic health problems.
Genetics plays a big role in your blood glucose regulation. Some people may be able to get by with eating some junk food and not exercising as much, but for others, our genetic susceptibility combines with poor choices to cause elevated blood glucose levels.
Genetics and blood glucose regulation:
Before we get into the genes involved in regulating blood glucose levels, let’s cover the basics of how the body regulates blood sugar. (Skip ahead if you already understand all this.)
Your body regulates the amount of glucose in the blood through a complex system of negative feedback loops.
- When blood sugar rises after you eat, your body regulates it to come back to a normal level.
- Likewise, when blood sugar falls because you haven’t eaten, your body brings it back up to a normal level.
Two main hormones are essential for maintaining glucose levels in a narrow range: insulin and glucagon.
Insulin and glucagon:
Insulin is released by beta cells in the pancreas in response to high glucose levels in the bloodstream. While usually constant, low-level insulin is available, when glucose levels rise, insulin releases in high enough amounts to counteract the higher blood glucose.
In response to insulin, cells in the skeletal muscle, adipose (fat) tissue, and red blood cells increase their absorption of glucose.
In addition to insulin, pancreatic beta cells also release amylin, which slows gastric emptying and tells your brain that you are full. This slowing of digestion keeps blood glucose levels from spiking too quickly after you eat.
The other hormone involved here is glucagon. The alpha cells of the pancreas secrete glucagon. But it acts in the opposite direction from insulin — when blood glucose levels are low, glucagon is secreted.
Glucagon signals to the liver to convert glycogen into glucose and release it into the bloodstream. If needed, glucagon can also stimulate the liver and muscle cells to create glucose from amino acids through a process called gluconeogenesis.
Regulating blood glucose levels:
The normal range for blood glucose is usually defined as between 65 and 100 mg/dl when you haven’t eaten for a while – the fasted state. (This range varies a little bit, depending on who is defining normal). Within two to three hours of a meal, blood glucose levels of under 180 mg/dl are considered OK.
The release of insulin and glucagon is a negative feedback loop: when blood glucose is high, insulin is released inhibiting the release of glucagon. When blood glucose levels drop, glucagon is released and insulin is inhibited.
This system becomes dysregulated in diabetes. People with diabetes may have problems creating enough insulin well as glucagon still causing the liver to release some glucose. Thus blood glucose levels rise.
While the obvious solution to high blood glucose levels is to decrease carbohydrate intake, it isn’t always that simple – nor the right answer for everyone.
Why should you worry about blood glucose levels or insulin sensitivity if you don’t have diabetes?
Glucose is tightly regulated by the body because it is toxic at higher levels. You’ve gotta have it, but don’t want too much. (Yes, you can burn fatty acids for fuel also, but the brain requires some glucose.)
Doctors start talking about diabetes when fasting blood glucose levels are above 125 mg/dL and an oral glucose tolerance test result of above 200 mg/dL.[ref]
If your fasting blood glucose is in the 100-125 mg/dL range for a few tests, then you are likely to be labeled as pre-diabetic.
But what if, once in a while, your blood sugar is high after eating sweets? Or what if your fasting glucose is always around 99 mg/dL, just under the pre-diabetes range? As you can see, there are a lot of gray areas here.
There are three ways that higher blood glucose levels are bad[ref]:
- Damage due to osmosis: High glucose causes dehydration and excessive urination. Glucose causes an osmotic reaction – moving water from one side of a membrane to another. Hyperglycemia (really high blood sugar) can be deadly.
- Increased oxidative stress: Glucose that isn’t used for energy can participate in reactions that cause increased formation of reactive oxygen species (ROS). This increased ROS is what causes long-term damage, such as kidney damage or heart problems, in people with diabetes.[ref]
- Advanced glycation end products: Excess glucose can form a complex with certain other molecules to form advanced glycation end products.
Thus, consistently higher blood glucose levels, even if not in the pre-diabetic/ diabetic range, can increase oxidative stress and the formation of advanced glycation end products.
One more important point here – in the wake of the COVID-19 pandemic – is that insulin and insulin sensitivity is essential for T-cells in the immune system to fight off viruses. People who have problems with insulin release (such as in diabetes) or with insulin sensitivity (insulin resistance, prediabetes) do not have as robust of a T-cell response to viruses.[ref]
Let’s dig deeper into the blood glucose regulation system and take a look at some of the genes involved and the solution for those genes.
Which genes are controlling blood glucose levels?
By looking at the genetic variants that significantly impact blood glucose or insulin levels, we can better understand the control mechanisms in place for this complicated feedback loop.
Understanding where exactly your genetic susceptibility to blood sugar problems lies can help you to figure out a targeted plan for keeping glucose levels stable.
I’m going to break this down into sections, but realize that all of this works together:
- regulating insulin release
- taking glucose into cells (insulin resistance)
- glucagon and regulating glucose release from the liver
- digestive system response to food (GIP and GLP-1)
- overnight regulation of insulin (melatonin in the pancreas)
We will take a look at the science first to understand how the genes work, and then you can check your genes in the Genetic Variants section below (with the specific Lifehacks included).
#1 – Regulating insulin release:
KCNJ11 gene: The KCNJ11 gene encodes a potassium channel subunit found in the beta cells of the pancreas. This ATP-sensitive channel opens and closes in response to blood glucose levels. When glucose is present, ATP levels rise (cells using glucose to make more ATP). When ATP rises, the ATP-sensitive potassium channel in the pancreatic beta cells closes, which then triggers the release of insulin.[ref]
Genetic variants in KCNJ11 can decrease the beta cell’s insulin response to blood glucose.
ABCC8 gene: The KCNJ11 gene (above) encodes one subunit of the ATP-sensitive potassium channel. Another subunit, known as SUR1, is encoded by the ABCC8 gene.
The type of diabetes drugs called sulfonylureas bind to SUR1 and thus increase insulin release. Genetic variants in ABCC8 can impact blood glucose levels.
Glucokinase (GCK gene) is important in regulating glucose metabolism in the liver and in beta-cells. In the beta cells, glucose can come in via the GLUT2 receptor (which doesn’t need insulin). Glucokinase in the pancreas can amplify the signal from rising glucose levels, increasing insulin secretion. Genetic variants in the GCK gene are one risk factor for diabetes.
CDKAL1 (Cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1) is part of the signaling pathway that causes insulin release. Genetic variants in this gene can cause decreased insulin release, which then keeps blood glucose levels higher when eating carbs/sugar.[ref][ref]
#2 – Taking up glucose into cells (insulin resistance genes):
Glucose molecules are too big to cross the cell membrane without assistance. Thus, for glucose to get into a cell, it needs to be transported. There are actually several different glucose transport methods, depending on tissue type.
Muscles use a lot of energy and transporting glucose into muscle is a way the body regulates blood glucose levels.
In muscle tissue, GLUT4 (glucose transporter 4) transports glucose into the cells. The GLUT4 transporter is located inside the cells, and it needs to translocate to the cell membrane in order to move in glucose.
Insulin, binding to an insulin receptor on the cell causes a signal to be sent to the GLUT4 receptor, moving it to the cell membrane. This results in glucose being taken up by the cell via the GLUT4 receptor.
There are several genes involved in the insulin receptor and the secondary signals sent to GLUT4. The main insulin receptor gene, INSR, is essential for life, and thus mutations here are rarely compatible with life. But variants in the signals generated by insulin binding to the insulin receptor can change the way that the signal is sent to the GLUT4 receptor.
The IRS1 (insulin receptor substrate 1) gene codes for a key protein in the insulin-stimulated signal pathway. After insulin binds to the insulin receptor, IRS1 is one of the molecules activated to send the message. Variants in IRS1 also have links to an increase in the risk of type-2 diabetes.[ref]
Another gene that interacts with the insulin receptor is ENPP1 (ectoenzyme nucleotide pyrophosphate phosphodiesterase 1). This enzyme downregulates the signal from insulin through interacting with one of the insulin receptor subunits. Genetic variants in this gene are associated with insulin resistance.[ref]
In addition to insulin signaling for GLUT4 to move to the cell membrane, exercise also causes GLUT4 to translocate and take in glucose.[ref]
#3 – Genes involved with glucogen: glucose release from the liver
The other half of the picture with glucose regulation is the signal to the liver to stop turning glycogen into glucose and releasing it into the bloodstream.
The alpha-cells in the pancreas releases glucagon when blood sugar levels drop. Glucagon signals the liver to turn glycogen into glucose and then release it, which is called glycogenolysis (-lysis = breaking up, so breaking up glycogen).
Lower blood glucose in the alpha-cells causes a decrease in ATP production, which subsequently changes the polarization of certain ion channels. This change in electrical potential then causes calcium to come into the cells, triggering the release of glucagon.[ref]
The KCNH2 gene codes for a potassium-ion channel that has several different roles in the body. It is important in the heart in regulating rhythm and it has recently been discovered to play an important role in the alpha-cells of the pancreas with the release of glucagon.[ref] Genetic variants in KCNH2 have links to a decrease in glucagon production.
#4 – Genetics and GLP-1:
There are a couple of other important hormones that come into play with glucose regulation as well.
GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1) are released by cells at the beginning of the intestines in response to food.
While glucagon increases blood glucose levels via stimulating the liver to release glucose, glucagon-like peptide-1 (GLP-1) has pretty much the opposite effect in that it can decrease blood glucose through stimulating more insulin to be released by the beta-cells in the pancreas.[ref]
GIP (glucose-dependent insulinotropic peptide) not only acts on the GIP receptor (GIPR) in the pancreas, but it also acts upon other tissues such as fat, bone, and endothelial cells lining blood vessels.
GLP-1 has multiple functions as well. Acting on the GLP-1 receptor in various tissues, GLP-1 reduces appetite, stimulates insulin synthesis, and promotes bone formation.
GLP1 levels are impacted by variants in the SLC5A1 gene, which encodes the sodium/glucose cotransporter 1 (SGLT1). SGLT1 is the transporter in the intestinal cells that allows for the uptake of glucose from the foods you’ve eaten.
One of the first genes identified as a risk factor for diabetes was TCF7L2, but initially, researchers weren’t sure why genetic variants in this gene increased the risk of diabetes.
More than a decade of research now shows that TCFL2, a transcription factor regulator, impacts the production of insulin in the pancreas. While there are still many questions about TCF7L2 left unanswered, it has been shown that TCF7L2 is essential to the production of proglucagon via the intestinal cells (not the glucagon produced in the alpha-cells of the pancreas).[ref]
GLP1R (glucagon-like peptide 1 receptor) receives the signal from GLP-1, and variants in GLP1R have associations to altered BMI, weight, and insulin resistance.
#5 – Overnight blood glucose regulation: melatonin genetic variants
Melatonin is a hormone released in large quantities at night by the pineal gland.
Increased melatonin at night decreases insulin secretion.[ref]
This should be the normal way the body works — you aren’t eating at night and thus insulin should be suppressed. Think about it: Your ancestors weren’t raiding the refrigerator for a midnight snack because there wasn’t a fridge to raid or a microwave to heat things up. Insulin levels needed to be low while sleeping so that an individual didn’t become hypoglycemic at night.
Genetics comes into play here. Variants in the melatonin receptor found in the beta-cells of the pancreas are linked to diabetes. The MTNR1B (melatonin receptor) variants increase the risk of diabetes — but only in people who are eating dinner late or snacking heavily at night.[ref][ref][ref][ref][ref]
Genetic variants important in blood glucose regulation
#1 – genetic variants related to insulin release
KCNJ11 gene (pancreas, insulin release):
Check your genetic data for rs5219 (23andMe v4, v5; AncestryDNA ):
- T/T: impaired glucose-induced insulin secretion in obesity; 2.5x increased risk of type 2 diabetes; greater impairment of insulin release[ref][ref]
- C/T: impaired glucose-induced insulin secretion in obesity; 1.3x increased risk of type 2 diabetes
- C/C: typical risk of type 2 diabetes
Members: Your genotype for rs5219 is —.
Lifehacks for KCNJ11: Decrease sugar and alcohol consumption. The rs5219 T allele gives a decreased insulin response to glucose.[ref][ref] Alcohol consumption also affects beta-cell function. Carriers of the rs5219 T allele have significantly greater impairment of insulin release when consuming alcohol, especially with chronic consumption. Magnesium is a cofactor here.[ref]
ABCC8 gene (pancreas, insulin release):
Check your genetic data for rs757110 (23andMe v4, AncestryDNA):
- A/A: increased risk of type 2 diabetes[ref]
- A/C: typical risk
- C/C: typical risk
Members: Your genotype for rs757110 is —.
Lifehacks for ABCC8: Resveratrol has shown in animal and cell studies to block the ABCC8 (SUR1) channel.[ref] Resveratrol (500mg/day) has shown in clinical trials to reduce fasting glucose levels.[ref]
GCK gene (pancreas, insulin release):
Check your genetic data for rs1799884 (23andMe v4, v5; AncestryDNA):
- C/C: typical
- C/T: increased fasting plasma glucose, (slight) increased risk of diabetes in Caucasians
- T/T: increased fasting plasma glucose, (slight) increased risk of diabetes in Caucasians[ref]
Members: Your genotype for rs1799884 is —.
CDKAL1 gene: decreased insulin release in response to glucose
Check your genetic data for rs7754840 (23andMe v4, v5; AncestryDNA):
- G/G: typical risk for diabetes
- C/G: increased risk for type 2 diabetes, decreased insulin release, impaired proinsulin to insulin conversion,
- C/C: increased risk for type 2 diabetes, decreased insulin release, impaired proinsulin to insulin conversion, increased diabetes risk even in people who are normal weight[ref][ref][ref][ref][ref]
Members: Your genotype for rs7754840 is —.
Lifehacks for CKDAL1: Try a 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]
#2 -Variants related to receiving the insulin signal
IRS1 gene (receiving the insulin signal): Genetic variants in this gene have associations to insulin resistance and hyperinsulinemia, rather than impaired beta-cell function.[ref]
Check your genetic data for rs2943641 (23andMe v4, v5; AncestryDNA)
- C/C: most common genotype, but a higher risk for diabetes compared to T/T[ref] lower fasting glucose levels in people without diabetes[ref]
- C/T: typical risk
- T/T: lower risk of type 2 diabetes in people with high vitamin D levels.[ref]
Members: Your genotype for rs2943641 is —.
Check your genetic data for rs1801278 G972R (23andMe v4):
- C/C: typical
- C/T: impaired IRS1 signaling, increased risk of insulin resistance and diabetes
- T/T: impaired IRS1 signaling,[ref][ref] increased risk of insulin resistance and diabetes[ref][ref] (rare genotype)
Members: Your genotype for rs1801278 is —.
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 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 diets found that a low-fat diet (high in whole-grain carbs plus 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, high carb worked best for those with rs1801278 C/T or T/T genotype.[ref] Note that in both of these studies, the researchers were looking at varying fat intake in conjunction with still eating some carbohydrates in the diet. So the results may be different if you are considering a low-carb, keto-type diet.
- Bitter melon extract is often promoted as a supplement that lowers blood sugar levels. Animal studies point to bitter melon extract as increasing the expression of IRS1.
ENPP1 gene (receiving the insulin signal):
Check your genetic data for rs1044498 (23andMe v4; AncestryDNA):
- C/C: increased risk of insulin resistance, metabolic syndrome[ref]
- A/C: increased risk of insulin resistance, metabolic syndrome
- A/A: typical
Members: Your genotype for rs1044498 is —.
Lifehacks for ENPPI: Exercise! The good news here is that a randomized controlled trial has shown that lifestyle intervention — exercising and weight loss — completely mitigated the increased risk from this variant.[ref] This ENPP1 variant essentially downregulates the signal from insulin to GLUT4 (which brings the glucose into the cell). Exercise is a way around this. Exercising skeletal muscles causes the muscle cells to move GLUT4 receptors to the cell membrane, thus reducing blood glucose levels.
#4 – Glucagon related genetic variants:
KCNH2 gene: encodes the voltage-gated potassium channel controlling glucagon release from pancreatic alpha-cells.[ref] (Also important in heart rhythm)
Check your genetic data for rs1805123 (23andMe v4):
- G/G: decreased fasting glucagon levels, but also lower fasting insulin[ref]
- G/T: decreased fasting glucagon levels, but also lower fasting insulin
- T/T: typical
Members: Your genotype for rs1805123 is —.
Lifehacks for KCNH2: To be honest, I don’t really know…The research on this is really new and there seem to be a lot of unanswered questions here as far as how to mitigate the effects of this variant. Perhaps a lower-carb diet would work well with the overall lower fasting insulin levels.
#5 – GLP1 Genetic variants
GLP1R: GLP-1 receptor
Check your genetic data for rs6923761 G168S (23andMe v4; AncestryDNA):
- A/A: decreased BMI, weight, triglycerides, and insulin resistance (compared to G/G)[ref][ref]
- A/G: slightly decreased BMI, weight, triglycerides, and insulin resistance (compared to G/G)
- G/G: typical – but better response to gliptin, liraglutide (diabetes med)[ref][ref]
Members: Your genotype for rs6923761 is —.
#6 -Overnight fasting glucose variants:
MTNR1B gene: The MTNR1B gene codes for the melatonin receptor, which impacts overnight insulin release from the pancreas.
Check your genetic data for rs10830963 (23andMe 4, v5; AncestryDNA):
- G/G: increased fasting glucose levels, increased risk of type 2 diabetes (2-fold) when eating late at night[ref][ref][ref][ref][ref][ref][ref]
- C/G: increased fasting glucose levels, slightly increased risk of type 2 diabetes
- C/C: typical
Members: Your genotype for rs10830963 is —.
Lifehacks for MTNR1B:
- Eat dinner earlier: Simply shifting your dinner to be earlier and not snacking at night has 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]
Lifehacks for lowering blood glucose levels:
In addition to the specific, genetic variant-related lifehacks above, here are several more research-based methods for lowering blood glucose levels.
Obviously, reducing sugar and all carbohydrate intake should decrease blood glucose levels. But it isn’t as necessarily as simple as just looking up the glycemic index of food. That’s a starting point, but a large individual variation exists in how different foods affect blood sugar levels. For example, eating a banana will spike blood glucose levels for some, but for others, it may not have an effect. A study of 800 people wearing continuous blood glucose monitors showed that individual glucose responses varied widely and depended on many variables including the gut microbiome, normal dietary habits, and physical activity level.[ref]
The best way to know how foods affect you would be to wear a continuous blood glucose monitor. Unfortunately (at least in my opinion ;-), you need a doctor’s prescription to get a continuous blood glucose monitor.
The regular, stick-your-finger type of blood glucose meters are available without a prescription, so this is an option for spot-checking to see how certain foods affect your blood sugar. It’s also a great way to know your baseline fasting blood glucose. A poor night’s sleep significantly affects morning glucose levels, so you would need to track for a week or so and average out the readings.
Higher blood glucose levels increase advanced glycation end products and oxidative stress. Vitamin C acts as a direct antioxidant to reduce the effects of higher blood glucose levels.[ref]
Supplemental vitamin C has shown to reduce fasting blood sugar. For example, one study found that 1000 mg/day of vitamin C lowers fasting blood glucose.[ref] Another clinical trial showed that 500mg of vitamin C is effective for some people in lowering fasting blood glucose levels.[ref]
Metformin plus vitamin C is twice as likely to reduce fasting blood glucose and HbA1c than metformin alone.[ref]
A randomized control trial showed that 50,000 IU of vitamin D per week (oral tablet) decreases insulin resistance.[ref] This may tie back to the IRS1 variant, or it may be that maintaining sufficient vitamin D levels is important for everyone with insulin resistance.
Exercise decreases blood glucose levels:
Moderate to intense exercise causes the GLUT4 receptors to translocate to the cell membrane in muscle cells. This increases the uptake of glucose into the muscle cells, and thus lowers blood glucose levels.[ref] (This is also why hard exercise could cause hypoglycemia in people who are prone to low blood sugar.)
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, new options on the market may help- talk with your doctor and make quality sleep a priority.[ref][ref]
In addition to sleep quality, the quantity of sleep is also important. 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]
Decrease liver fat (reversing NAFLD):
Advanced fatty liver disease with fibrosis causes an almost 5-fold increase in the risk of diabetes.[ref]
TUDCA, a taurine conjugated bile acid, is 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]
Getting a little more complicated: Your genetic variants interact with combinations of foods to influence your blood glucose response.
A study found that people with certain ADORA2A and caffeine metabolism variants had differing blood glucose responses to the combination of caffeine plus carbohydrates. Check your Caffeine + Carbs Genes and read the study details.
Amylase is the enzyme that breaks down starches into glucose. There is a big variation across the population in how much amylase an individual produces — and thus how quickly starches are broken down. People with higher amylase production, and thus a quicker dumping of glucose into the bloodstream, may want to try to slow the breakdown of starches by including tea with their meals. Read about Amylase and check your genes.
Related Articles and Genes:
Top 10 Genes to Check in Your Genetic Raw Data
These are 10 genes with important variants that can have a big impact on health. So check them out, cross them off your list if you don’t have them — and read the articles to learn more if you do carry the variant.
Diabetes: Genetic Risk Report
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.
Intermittent Fasting: Benefits from changing Gene Expression
What is interesting about IF is that it can change the gene expression in different tissues in the body. Something as simple as ‘not eating’ can cause an upregulation of proteins associated with longevity. This article digs into the recent research on intermittent fasting, focusing on how it changes gene expression.