While Type 2 diabetes is fairly common and prevalent, it is the treatment of Type 1 diabetes that is more challenging
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Diabetes has evolved over time into a chronic health condition faced by billions of individuals around the world. While Type 2 diabetes is more common and prevalent, it is the treatment of Type 1 diabetes that is relatively more challenging.
For years, the treatment of type 1 diabetes was dependent on an insulin regimen — injections. Insulin therapy manages blood glucose levels very well, but could put the person at risk of hypoglycaemic episodes. A hypoglycemic episode occurs when a person’s blood sugar drops very low, causing varying effects ranging from slight dizziness and confusion to seizures and coma, with loss of consciousness.
However, finally there is hope on the horizon for those dependent on insulin and those who are prone to hypoglycaemia, thanks to the development of a smart version of insulin that will reportedly adjust itself as per the body’s requirement of glucose.
In mid-October, Thomas Hoeg-Jensen et al wrote in Nature that preclinical studies of an insulin candidate named NNC2215 have shown promise. With this glucose-responsive insulin, it is likely that diabetics may not experience dangerously low blood sugar levels.
How does insulin work?
After breaking down the sugar and carbohydrates in meals, the body turns them into glucose, a unique type of sugar. This glucose serves as the body’s fuel. Excess blood glucose is transformed into glycogen, which serves as a store of energy. The pancreatic hormone insulin is necessary for this procedure. Whenever we eat, our blood glucose level experiences a spike, triggering insulin secretion. This promotes metabolism and storage of glucose in fat and muscles, thereby helping to lower blood glucose to normal levels, which stops further insulin release. Now, what if the pancreas are unable to produce insulin? This causes a condition called hyperglycaemia (high blood glucose) and an individual with this condition is said to be diabetic. Uncontrolled diabetes can cause long term effects like blindness, kidney failure and nerve damage.
The risk of these complications can be reduced by controlling blood sugar levels. Injecting insulin as recommended by a doctor, along with a strict diet and regular exercise is the traditional method of blood sugar control that has been applied for decades, but this approach comes with the risk of hypoglycemia, a condition where the blood glucose level drops below normal levels of 70 mg/dL. This raises concerns, because it brings the immediate risks of cardiac arrythmia, loss of consciousness, coma or even death.
When insulin is injected beneath the skin, it is slowly absorbed and takes a long time to enter into blood circulation, whereas insulin released by the pancreas is metabolised in minutes and is then quickly eliminated from the bloodstream. Once in the bloodstream, injected insulin can stay active for up to 40 hours and lower blood glucose levels to dangerously low levels. Many diabetics choose conservative insulin dosages to prevent hypoglycaemic episodes, which can be fatal, particularly if they occur at night. However, the risk of consequences from long-term hyperglycaemia (high blood sugar levels) is increased when the insulin dosage is compromised out of concern about hypoglycaemia (low blood sugar levels), and may lead to suboptimal glucose control.
Efforts to create better insulin
Since the 1970s, efforts have been on to create an insulin that can alter its bioactivity in response to changing blood glucose levels in order to provide better glycaemic control without the danger of hypoglycaemia, similar to human insulin. Until now, no technique has been able to resolve this problem to the point that it can be used to treat diabetes, despite several research papers and patents in this area.
Most available resources in this area involve polymers that are purportedly capable of releasing insulin from subcutaneous depots in response to fluctuations in glucose levels. However, these systems are limited by the slow diffusion of glucose to the subcutis (layer beneath the outer layer of the skin) and a slow circulation of the released insulin into the blood. Moreover, these systems are irreversible in the release of insulin; therefore once insulin is released from the depot, it cannot be glucose dependent again.
What does the new smart insulin do?
This is why Hoeg-Jensen and colleagues’ smart glucose-regulated insulin that can alter its own activity in response to glucose concentration, presents a picture of hope. Picture a lock and a key where the lock represents the insulin molecule and glucoside represents the key. In regular insulin, glucoside is inserted into the lock of insulin, and the insulin remains ‘lock closed’ and is less effective. These researchers added a new component into the insulin, called macrocycle. This macrocycle has a pocket filled with glucose. When there is an abundance of glucose in the body, it occupies the pocket thereby expelling the key (glucoside) from the lock (insulin), thereby rendering the insulin – ‘open’ and more functional. This altered, experimental insulin is NNC2215.
NNC2215 functions as a dual acting ultra-long disappearing insulin, active only during high blood glucose levels. This mechanism also reduces the risk of hypoglycemia. This insulin variant is activated solely when blood sugar levels are elevated, mirroring the behavior of the insulin secreted by the pancreas. When blood sugar levels are high, the key fits into the lock, activating the insulin. Conversely, when blood sugar levels are low, the key fails to engage with the lock, preventing insulin activation.
Preclinical studies on rats and pigs exhibit promise, but several aspects require further investigation. Firstly, it is essential to determine its efficacy in responding to subtle fluctuations in blood sugar levels. Secondly, the insulin must be capable of being produced in substantial quantities in response to significantly elevated blood sugar levels, comparable to the output of the pancreas. Lastly, clinical trials are necessary to assess the safety and effectiveness of NNC2215 for patient care.
Despite these unanswered questions, research on NNC2215 suggests that the creation of a truly intelligent insulin capable of revolutionising the lives of individuals with diabetes is an attainable goal.
Published – October 29, 2024 02:33 pm IST
