Series Overview:  GenomicMD’s Deep Dive blog series is designed as a casual guide on the journey to better understanding the many details associated with medical conditions on our test panels. Our hope is that this knowledge empowers our readers to start conversations with their healthcare teams about taking proactive measures which can lead to longer and healthier lives. If this sounds interesting to you, please read along as we dive deeper into the subject of diabetes (Type 2 in particular) and learn more about its biology, symptoms, genetic links, and impact on the human body.

**Please note that the Deep Dives blog series is not intended to be an exhaustive resource, but rather a small window into the knowledge available on the diseases we cover on our test panels. Our goal is to assist patients in learning more about these conditions in order to establish a conversation with their healthcare providers, and as such these blogs should not be taken as medical advice. Please discuss any concerns or personal risks associated with the diseases found in this series with your healthcare team.

A Genetic Deep Dive: Type 2 Diabetes (T2D)

37 million. 1 in 10. These numbers represent the US population currently diagnosed with diabetes. Beyond these statistics, studies suggest that there may be approximately 28.7 million more people who remain undiagnosed - so chances are you know somebody who is currently living with this condition. Most people know that diabetes has something to do with ‘blood sugar,’ but beyond that understanding can get a little fuzzy. For example, many people don’t know how serious uncontrolled diabetes can be or just how much it can negatively impact individual organ systems. Extended periods of time with elevated blood sugar levels can cause damage throughout the body’s blood vessels - leading to pain, vision problems, and much more serious complications like diabetic ketoacidosis (DKA). Early diagnosis and diligent management of diabetes is important to prevent these sorts of risks.

Type 2 Diabetes is a ‘blood sugar’ disease - but what does that mean, exactly? Well, Glucose is a type of sugar that our bodies use as a source of energy. The human body carefully maintains very specific levels of glucose in the bloodstream to ensure it is functioning well at all times. Any time an organ is in need of an energy boost, they use a hormone created in the pancreas called insulin to transfer this glucose from the bloodstream into their individual cells. When this happens the bloodstream’s glucose levels naturally dip, so another pancreatic hormone - glucagon - jumps in to help the body raise those blood glucose levels back up. It does this by using fancy tricks like telling the liver to convert its stored glucose into a usable form that can be released into the bloodstream. This delicate dance between insulin and glucagon is essential for healthy metabolic function in our bodies, and ensures that we are able to maintain enough glucose in the bloodstream to be prepared for any sudden demands for energy. 

So, how does all of this information relate to diabetes, why are there multiple types, and what actually causes it? (I’m glad you asked!) Diabetes can be caused by a numberb of breakdowns in a step in this ‘insulin to energy’ process, including:

1. 1. The pancreas deciding not to make any insulin at all (This is called Type 1 Diabetes, and it is a story for another day)
      
      
   2. The pancreas being unable to create ENOUGH insulin to properly support the body’s processes (This is T2D)
      
      
   3. The pancreas is able to make insulin, but the body becomes resistant to it and is thus unable to use it. (This is also T2D)

Actionability Factors (why is knowing your risk important?): 

All of the issues listed above lead to an improper amount of glucose in the bloodstream. This can cause damage to blood vessels, resulting in: 

• Heart disease
• Stroke
• Chronic kidney disease and kidney failure leading to dialysis if not treated
• Blindness - Caused by blood vessel damage in a part of the eye called the retina, cataracts, and/or glaucoma.
• Nerve damage (neuropathy) - this causes numbness and pain, usually in the legs and feet
• Amputation - if blood vessels are damaged from diabetes, it can lead to infections severe enough to require the amputation of limbs

Modifiable Diabetes Risk Factors (Risks you can control):

• Obesity
• Low levels of HDL cholesterol (‘good’ cholesterol) and high triglycerides (a type of fat). 
  • It is important to note that in some cases, cholesterol issues can be inherited and difficult or impossible to control with diet and exercise alone.
• Living a sedentary lifestyle (being physically active less than 3x per week)
• A history of Gestational Diabetes
• A history of Pre-Diabetes

Non-Modifiable Diabetes Risk Factors (Risks outside of your control):

• Increasing age (age 45 and older)
• A history of Polycystic Ovarian Syndrome (PCOS)
• Having a first generation relative (Parent or sibling) with diabetes
• Having a body type with fat distribution pr in the abdominal area
• People of certain ancestries are more likely to develop T2D, including those of African, Hispanic, Native American, Pacific Island, and Asian descent.
• Certain genetic variants or changes 
  • This is described in more detail in the genetics section below

Family History Considerations:

One of the main genetic risk factors for Type 2 Diabetes is having a family history of the condition.  If a person’s biological mother, father, or siblings have T2D, they are more likely to develop it as well. This is believed to be due to 2 main causes: inherited genetic variants or risk (which we have explained in past blogs) and shared environmental & behavioral factors. For example, a family which lives in an environment without access to healthy food may not be able to develop healthy cooking and eating habits to pass down from generation to generation. Over time this can cause a family history of obesity, which is a significant contributor to diabetes risk.

Polygenic Risk Assessment (PRA) Considerations:

As discussed in previous Gen101 blogs, a polygenic risk assessment is a numerical score that is calculated based on your personal genetic information, and it can estimates your specific genetic risk for developing certain diseases. In regards to T2D, recent studies have pointed towards the utility of PRA as both an independent and collaborative source of information on diabetes risk. Studies have shown that its use alongside integrative methodologies (such as serum metabolites) and other clinical variables can help predict future risk and improve already existing models of conventional Type 2 Diabetes care.

Other Notable Genetic Variants:

Some people may inherit certain genetic changes (variants), in genes such as HNF1A, GCK, HNF4A, or HNF1B, which can cause a condition called “MODY” (Maturity-onset diabetes of the young). MODY is characterized by abnormally high blood sugar levels and earlier onset (typically before age 30), and it is estimated to account for 1-3% of all cases of diabetes. Patients found to be at high risk for MODY should speak with their healthcare team about whether additional genetic testing may be appropriate for them.

Here are some things to consider when examining the prevention, symptoms, and diagnosis of Type 2 Diabetes.

Prevention:

• There is no way to “100% guarantee” the prevention of T2D, but the following tips are known to reduce the risk of developing it:
  • Maintain a healthy weight/body mass index (BMI)
  • Eat healthy foods, limiting the intake of sweets
  • Exercise regularly (Aim for at least 30 minutes of physical activity 5 days a week)

Symptoms:

• Symptoms of T2D usually develop slowly over time, sometimes causing a delay in diagnosis. They include:
  • Excessive thirst or hunger
  • Excessive urination
  • Increased fatigue
  • Unexplained weight loss
  • Blurred vision 
  • Slow healing of cuts/sores
  • Frequent penile or vaginal thrush

Diagnosis:

• The diagnostic process for T2D typically includes three main tests:
  • A glycated hemoglobin blood test, also called an “A1C”
    • This test can provide an estimate of a person’s blood sugar levels for the previous 2-3 months. 
    • A level over 6.5% is considered diabetes.
  • A Fasting Plasma Glucose (FPG) blood level test. 
    • A level over 126 mg/dL is considered diabetes.
  • An Oral Glucose Tolerance Test (OGTT)
    • This test checks blood glucose levels before and after drinking a sugary drink. 
    • A result of 200 mg/dL or higher is considered diabetes.

Living With T2D

The primary goal of any diabetes management technique is to keep blood sugar levels within the appropriate range for any given person. This can be done using a combination of methods including but not limited to dietary modifications, lifestyle changes (e.g. exercising regularly), monitoring, and medications.

Common Medications

There are a variety of medications available for T2D. Some are taken orally (such as Metformin), while others are injected (such as insulin). Some of the more common non-insulin classes of T2D medications include (warning, giant words you'll likely never need to remember ahead): DPP-4 Inhibitors, GLP-1 and dual GLP-1/GIP receptor agonists, SGLT2 inhibitors, sulfonylureas, and thiazolidineadiones. 

Technology and T2D Management

Recently, the use of Remote Patient Monitoring (RPM) technology has emerged as a way for healthcare providers to monitor a patient’s condition remotely, rather than needing frequent in-person clinic visits. Common RPM’s for T2D include glucose monitors and insulin pumps that can transmit blood sugar data to a healthcare team in real time.

• 462 million individuals affected with diabetes worldwide, 
  • That’s 6.28% of the world’s population! 
• Approximately 96 million Americans (18 yrs +) are diagnosed with prediabetes
• Researchers estimate that those with Diabetes have: 
  • A 9% higher risk of developing cancer 
  • A higher risk of developing circulatory and other heart conditions.
  • Medical expenditures up to 2.3 time higher than those without diabetes

As we conclude our deep dive into the world of T2D, our hope is that this knowledge empowers you to engage with your healthcare team, ask informed questions, and make empowered choices when it comes to your health. With millions currently affected by this condition and millions more at risk, there is no time better than now to take proactive measures to prevent the development of diabetes. Stay tuned for more explorations into the conditions that make up our panels with our next installment of GenomicMD's Deep Dives.

Diabetes - A chronic condition wherein the body is unable to regulate its insulin production properly, resulting in elevated glucose (blood sugar) levels which (when left untreated) can cause damage to other organ systems.

Diabetic Ketoacidosis (DKA): A serious condition caused by the body not producing enough insulin to allow glucose (blood sugar) into its cells for use as energy. When this happens, cells are deprived of nutrition they need to function, so the body must instead break down muscle and fat for the energy it needs. This process produces acids in the blood called “ketones,” which can build up to dangerous levels in the body.

Ketones: Chemical produced when the body breaks down fats for energy in the absence of glucose. Too high levels of ketones can lead to DKA and excess acid in the body. 

Insulin - A hormone produced in the pancreas which regulates the amount of glucose (blood sugar) in the blood. Lacking insulin in the body can cause a form of diabetes.

Glucagon - A hormone produced in the pancreas that works together with insulin to regulate glucose (blood sugar) in the body.

Glucose - a simple sugar that is an important energy source for living organisms.

Maturity Onset Diabetes of the Young (MODY) - A diabetic condition characterized by abnormally high blood sugar levels and an earlier onset (typically before age 30). It is estimated to account for 1-3% of all cases of diabetes. 

Polygenic Risk Assessment (PRA) - This is a generic term that can be used to describe various methods of polygenic testing like GRS (Genetic Risk Scores), PGS (Polygenic Scoring or Screening - not to be confused with Preimplantation Genetic Screening for embryos), PRS (polygenic risk scores), PRI (Polygenic Risk Index), and PSPGS (Population Standard PGS); these types of genomic tests compile the risks of up to millions of small, mostly mild to moderate genetic variants called SNPs to quantify one’s individual lifetime risk of developing a particular disease or condition.

Pre-Diabetes: - a term describing the condition of an individual with higher than normal blood sugar just below reaching Type II levels. People with pre-diabetes may have limited symptoms of diabetes.

Gestational Diabetes - a type of diabetes that develops during or because of pregnancy, usually occurring when blood sugar levels get too high in later trimesters.

Polycystic Ovary Syndrome (PCOS) -  is a hormonal condition in those assigned female at birth, resulting in menstrual irregularities, excessive androgen, and multiple cysts on the ovaries - among other symptoms.

Glycated Hemoglobin (A1C) Test - A blood test that reveals the average blood sugar level over a period of two to three months. A normal level is below 5.7%.

Fasting Plasma Glucose (FPG) test - A blood level test used to diagnose diabetes. A level over 126 mg/dL is considered diabetic.

Oral Glucose Tolerance Test (OGTT) - This test checks blood glucose levels before and after drinking a sugary drink. A result of 200 mg/dL or higher is considered diabetic.

Remote Patient Monitoring (RPM) - a term encompassing the ability of healthcare providers and patients to monitor and manage their condition from their own homes, often enabled by the use of technology.

• CDC Diabetes Management Index
• CDC Pre-Diabetes Resources
• CDC: Diabetes Self Management, Education, and Support
• Endocrine.org
  
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• American Diabetes Association (ADA)
• The Non-Communicable Disease Alliance (NCDA)
• Diabetes UK

• Prediction of type 2 diabetes using genome-wide polygenic risk score and metabolic profiles: A machine learning analysis of population-based 10-year prospective cohort study
• Developing risk prediction models for type 2 diabetes: a systematic review of methodology and reporting
• Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent
• Evaluation of polygenic risk scores to differentiate between type 1 and type 2 diabetes
• Epidemiology of Type 2 Diabetes – Global Burden of Disease and Forecasted Trends