How does Type 2 Diabetes Start in the Human Body? Can we detect early signs a decade before we see it on our blood test?

To understand this, we go back to the very basics of metabolism in the human body. Metabolism is the process by which we take nutrients and break them up for use in the body. So, when we eat carbohydrates, it will be converted into glycogen. 75% of this glycogen goes to the skeletal muscle and rest of it to liver. Liver converts this glycogen back to glucose and releases it as needed. The Insulin hormone secreted by pancreas plays an important role here as it helps shuttle the glucose to where it is needed and most importantly regulates the amount of glucose at any point in time in the blood stream. 

In a sedentary person who has more reserves than he needs, the excess first gets largely stored as subcutaneous fat or ‘under the skin’ fat, which is the safest place to store this excess energy. This fat gets used up when we do exercise by our muscles. But as these subcutaneous fat cells fill up, it goes into blood as triglycerides or liver leading to non alcoholic fatty liver disease or muscle tissue or heart or pancreas. Our body has tremendous capability when it comes to storing fat. Even a relatively lean adult can store upto 10 kilograms of fat in their body.

One of the first places where this overflowing fat causes an issue is the muscle. This is where insulin resistance likely begins, as Dr Gerald Shulman believes. It can occur decades before a person develops Type 2 diabetes. When the muscle cells cannot accept any more glucose, glucose builds up in blood and pancreas secrete even more insulin to push harder to remove excess glucose from blood and move it into the cells. Eventually, blood glucose levels end up rising and we develop Type 2 Diabetes

However, as per Dr Shulman, this "first marker" is highly reversible. His studies showed that just 45 minutes of moderate exercise can unlock the muscles, making them ready to accept more glucose and help restore insulin sensitivity

A natural question is: how does one get this first marker or the first signs of what is going on inside our body? If our blood tests show normal fasting sugar and HbA1c, how do we know if silently there is insulin resistance building up which will likely show up in a few years or may be a decade. Multiple studies refer to various early markers:

TyG Index (Triglyceride Glucose Index) is a powerful marker for insulin resistance which confirms that muscle / liver is already not able to store the excess glucose and insulin resistance is beginning. The TyG index is calculated using your Fasting Triglycerides and Fasting Blood Glucose as follows:

             TyG Index = natural log (ln) of ((Fasting Triglycerides (mg/dL) x Fasting Glucose (mg/dL)) / 2)

A TyG Index of less than 4.5 is considered optimal and this is a lead indicator which is likely to show up much before your fasting sugar shows a blip

GGT Gamma-Glutamyl Transferase (GGT): As your liver gets stuffed with fat, it gets stressed and it starts using the body’s master antioxidant Glutathione. GGT is an enzyme which breaks down Glutathione so that resulting amino acids can help prepare more Glutathione. So, when GGT is high, it implies the body is under oxidative stress. High GGT often appears years before fasting sugar levels start to rise, signaling that the liver is becoming "fatty" and it is also highly correlated with Visceral Fat (fat around the organs). GGT can easily be tracked as part of any standard blood test.

Ideally, it should be upto 25 U/L in men and upto 18 U/L in women. Beyond that, it indicates some form of oxidative stress in the liver.

HOMA IR (Homeostatic Model Assessment for Insulin Resistance): It is measured using two simple markers: fasting glucose and fasting insulin using a standard formula:

             HOMA IR = (Fasting Insulin (µIU/dL) x Fasting Glucose (mg/dL)) / 405

A HOMA IR of >2.0 represents insulin resistance (though thresholds may vary by ethnicity or age, etc). It basically tells if the pancreas are struggling already and pumping  more insulin

While markers like HbA1c rise only after a metabolic dysfunction has persisted for years, markers like HOMA-IR, GGT or TyG Index can potentially flag issues decades before your HbA1c ever turns abnormal. As we know once insulin resistance develops, it triggers a domino effect in terms of increased risk of cardiovascular diseases, cancers or neurodegenerative disorders. So, if you are 40-50 years old and get a regular check up done annually, consider adding these lead indictors to your blood test which can potentially help you add years to your 'healthspan' by detecting any signs of insulin resistance early. 

Sources:

• Yale School of Medicine

• ScienceDirect (https://www.sciencedirect.com/science/article/abs/pii/S1871402122001953)