Many patients with type 2 diabetes wonder how their blood sugar levels can be high when they have not eaten anything. The answer to this counterintuitive phenomenon lies in what is known as insulin resistance.
Insulin resistance prevents cells from taking up glucose properly, but it also causes the liver to continue producing it. Here, we will look at how this happens, and at what current research is being carried out to treat this condition.
Available energy
Generally speaking, our blood glucose levels are regulated by a balance between the intake of this type of sugar from food and its uptake by tissues. This balance mainly depends on the hormone insulin.
After a meal, a rise in blood glucose causes the beta cells of the pancreas to secrete insulin. This hormone facilitates the absorption, utilisation and storage of glucose by body tissue, ensuring that the body has energy available when it needs it.
However, if we go many hours without eating, the body still has to maintain a minimum level of blood glucose. This is to prevent hypoglycaemia (low blood sugar), and to ensure that energy is supplied to the tissues – particularly the brain, which depends almost exclusively on glucose.
In the first few hours of fasting, the liver produces glucose by breaking down reserves of glycogen, the form in which glucose is stored in the body. As fasting continues and glycogen is depleted, the liver begins to synthesise glucose from non-carbohydrate precursors, a process known as gluconeogenesis.
This mechanism is essential, as it ensures that our organs – and above all the brain – continue to function while we are fasting.
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The broken lock
Type 2 diabetes completely disrupts the normal regulation of blood glucose levels, as it causes patients to develop insulin resistance.
A simple way to explain this is to imagine insulin as a key that unlocks the door to the cells so that glucose can enter and be used for energy. In a healthy person, the key fits the lock perfectly. The door opens, and the glucose passes from the blood into the cells.
But in patients with insulin resistance, the lock is faulty. Although the body produces the hormone and there are keys available, the door does not open wide enough. The result is that some of that glucose cannot enter the cells. Instead, it accumulates in the blood, causing chronic hyperglycaemia (high blood sugar).
But this is not the only purpose of insulin. Another of its key functions is to curb glucose production in the liver – a process known as hepatic gluconeogenesis.
In type 2 diabetes, insulin resistance prevents insulin from doing this properly, causing the liver to continue producing glucose even when it is not needed. The result is that blood glucose levels stay high, even on an empty stomach.
It has been reported that levels of hepatic gluconeogenesis in people with type 2 diabetes may anywhere from 40% to 200% higher than in healthy individuals.
For this reason, reducing hepatic glucose production has become a promising way to improve the efficacy of currently available treatments to reduce blood sugar levels.
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New treatment goals
One of the possible keys to controlling excessive glucose production by the liver in type 2 diabetes is a stress molecule called GDF15. Mice lacking this molecule show increased hepatic gluconeogenesis, suggesting that regulating its levels could help curb glucose production in the liver.
Previous studies in patients with type 2 diabetes have shown that treatment with metformin – the most commonly prescribed antidiabetic drug for treating type 2 diabetes, which acts primarily by inhibiting hepatic gluconeogenesis – also increases GDF15 levels.
This suggests that part of the drug’s antidiabetic effect could be explained by its ability to raise GDF15 levels and, in doing so, reduce glucose production in the liver. Our research group recently observed that this effect is not seen in GDF15-deficient mice.
Furthermore, in our latest study we have observed that metformin fails to increase blood levels of this molecule in mice that lack the PPARβ/δ receptor. This is likely because PPARβ/δ is crucial for the maturation of GDF15 and, consequently, for the increase in its blood levels.
Taken together, these findings gradually reveal the key determinants of GDF15’s regulation and function, offering promising new avenues for improving glucose control in patients with type 2 diabetes.
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