Neonatal diabetes should be treated with oral medication if possible
Author: Dr Sorin Ioacara | Last update: 30 August 2020
Discover here: Insulin secretion in neonatal diabetes | Classification of neonatal diabetes | Causes of neonatal diabetes | Treatment of neonatal diabetes | High and low blood glucose levels risk | Genetic analysis
The onset of diabetes in the first months after birth is often associated with life-threatening hyperglycemia. The diabetic ketoacidosis often accompanies hyperglycemia. Unfortunately, it is also challenging to treat such a small child. These children receive the diagnosis of type 1 diabetes, which is not appropriate in these forms of diabetes. Type 1 diabetes is the correct diagnosis for most kinds of pediatric diabetes, but only starting after the age of six months. Instead, the accurate diagnosis in the first six months of life is neonatal diabetes.
Neonatal diabetes falls into the category of rare diseases. The incidence is about one case per 100,000 inhabitants per year. In this form of diabetes, pancreatic beta cells are still present. However, they are not functional for various reasons. The situation is radically different from type 1 diabetes. In type 1 diabetes, the immune system destroys the pancreatic beta cells. Therefore, detailed knowledge of the classification of diabetes is essential in children.
Insulin secretion in neonatal diabetes
Insulin secretion deficiency is generally similar in type 1 and neonatal diabetes. Consequently, neonatal diabetes often begins with ketoacidosis. The treatment of diabetic ketoacidosis at the onset of neonatal diabetes is very similar to that associated with type 1 diabetes. Insulin therapy should be initiated promptly and will save the child’s life.
However, there is a better therapeutic option than insulin. The correct subsequent treatment for neonatal diabetes mellitus should be with oral medication, where possible. Indeed, you can almost always switch medication to some special pills that try to restart the non-functional beta cells. This switch is possible because the beta cells are still present in a typical number in the pancreas.
The consequence can be spectacular, with complete cessation of insulin treatment and perfect metabolic control using only oral antidiabetics.
Classification of neonatal diabetes
Neonatal diabetes classifies according to severity into three subcategories:
- Transient neonatal diabetes
- Permanent neonatal diabetes
- DEND syndrome
Transient neonatal diabetes resolves spontaneously after one year of age. However, hyperglycemia can sometimes recur after the age of 20 years. Permanent neonatal diabetes involves hyperglycemia that persists from the onset for the rest of the life. DEND syndrome is the association of neonatal diabetes with neurologic developmental deficit and epilepsy.
Causes of neonatal diabetes
Neonatal diabetes occurs as a consequence of a genetic mutation that affects one of the essential components of the pancreatic beta-cells. Consequently, the beta-cells become entirely dysfunctional. Though, they are still present in the pancreas, within the Langerhans islands. In more than two-thirds of the cases, the mutation affects a very special relay. This relay connects the blood glucose measuring system to the insulin delivery system. This relay is known as the ATP potassium channel. The closed position of this relay leads to insulin secretion. When switched to the open position, it stops the insulin secretion. Usually, the potassium ATP (K/ATP) channel is in the open state.
The hyperglycemia detection system is responsible for switching it to the closed position. Consequently, the release of insulin ensues. There are almost 100 genetic mutations that can affect this vital relay (K/ATP channel). Most involve two genes, with very technical names, KCNJ11 and ABCC8.
Imagine the K/ATP channel as an elastic rubber tube inserted into the cell membrane. When open, potassium continuously leaves the cell through this channel. So, the human cell manage to prevent its over-accumulation. Another word for potassium is kalium, and hence the symbol K used in the K/ATP channel.
ATP is a substance usually found in human cells. Here, its role is to store energy for later use. Interestingly, the K/ATP channel has a sensor for the ATP concentration inside the cell. Consequently, the K/ATP channel closes each time the ATP concentration rises above a certain threshold. This event quickly triggers a cascade of exciting actions that lead to the release of insulin from the pancreatic beta-cell.
The amount of ATP in the pancreatic beta cells can increase rapidly due to increased blood sugar. Thus, the growing glucose from the outside will quickly enter the cell. Here, glucose transforms into ATP molecules, whose concentration will increase.
In neonatal diabetes, genetic mutations will turn the K/ATP channel into a rigid rubber tube. The cell can no longer close this tube using the force resulting from the increase in ATP levels. However, this rigid tube can be closed by the joint effort made from the following three components:
- Increasing the level of ATP
- Binding of a sulfonylurea to the sleeve that completely envelops the K/ATP channel
- Increasing the extracellular level of a hormone called GLP1
It is enough that only one of the three things listed above to miss and the whole effort to close the K/ATP channel becomes inefficient. Consequently, no insulin secretion will occur.
Neonatal diabetes and brain damage
About one in five patients with neonatal diabetes caused by mutations in the K/ATP channel will have varying degrees of brain damage. These patients have K/ATP channel that are very rigid. Therefore, they cannot close when needed. No channel closure means no insulin secretion. However, these channels are essential not only in the beta cells, but also in the brain. Consequently, different degrees of delay in neuro-psycho-motor development can occur during infancy (e.g. walking and talking later).
Other symptoms associated with developmental delay are muscle weakness and epilepsy. DEND syndrome is the association between neonatal diabetes and significant brain damage. DEND is an abbreviation for Developmental delay, Epilepsy and Neonatal Diabetes. Still, epilepsy may not occur from the beginning, and then the proper name is intermediate DEND syndrome.
The mechanism of nerve damage
The same K/ATP channel from the pancreatic beta-cell is also present in the brain. Here, it also performs a vital activity, the only difference being the generation of a nerve impulse instead of insulin secretion. Unfortunately, this critical relay is also dysfunctional in the brain. The compensatory mechanisms existing here cannot supplement the work of this essential channel. Consequently, nerve cells cannot function at full capacity in patients with severe mutations in this channel.
Neonatal diabetes treatment
Insulin treatment can save the life of a patient with neonatal diabetes. Still, the significant brain damage associated with the DEND syndrome will continue to deepen. The reason is that insulin therapy will not start the K/ATP channels in the brain, just as it does not start the ones in the pancreas. This situation can eventually lead to a neurological disability that can sometimes be severe. There is a class of oral antidiabetic drugs that can solve this problem.
Treatment with sulfonylureas succeeds in restarting the K/ATP channels, with most often complete cessation of insulin therapy. Also, these pills manage to solve the blockage in the brain. There is thus a significant, but not total, improvement in the problems that have arisen at the brain level.
It would be best if you had a prompt therapeutic intervention for maximum brain benefit. The reason is that in the first 18 months of life, the brain is extremely vulnerable. Hardly or no reversible changes may occur during this period.
Some K/ATP channel mutations are so severe that the pill switching procedure may fail. In this situation, the patient will remain on insulin treatment, without which he cannot survive. As the international experience in this field grows, new solutions are continually emerging.
Oral antidiabetics in neonatal diabetes
In the very likely situation of a mutation affecting the K/ATP channel, oral medication instead of insulin is the right treatment. Switching from insulin to pills is accompanied by great benefits both in the short term and especially in the long run.
The mode of action of the pills has similarities with what happens in type 2 diabetes. However, it differs sometimes radically from this in many aspects. Thus, in both types of diabetes, the sulfonylurea pill is bound to the sleeve that envelops the K/ATP channel. After binding, sulfonylureas adhere to this shell surrounding the K/ATP channel.
In type 2 diabetes, this tightness can close the channel and trigger insulin secretion. In neonatal diabetes, this tightening from the outside contributes, among other things, to the final closure of the channel. The channel is very rigid due to the genetic mutation.
Sulfonylureas can lead to low blood glucose in type 2 diabetes, but cannot do that in neonatal diabetes. The use of sulfonylureas in type 2 diabetes is associated with a gradual reduction in their effectiveness. Thus the need to increase the doses, which at some point reach the maximum allowed. At this time, insulin therapy becomes inevitable.
The use of sulfonylureas in neonatal diabetes is associated with maintaining and even improving their effectiveness over the years (decades). The dose is generally constant per kilogram of body weight. It increases, of course, if you gain weight with age. In general, it is not necessary to initiate insulin therapy in the future.
Risk of hyper and hypoglycemia in neonatal diabetes
The risk of hypoglycaemia in neonatal diabetes is almost zero. Although it seems hard to believe, insulin secretion is absent when blood sugar is low. Still, the insulin secretion is very high when the blood sugar is increasing. In other words, the insulin secretion is strictly dependent on glucose (carbohydrates) from the diet. As you probably anticipate, hyperglycemia is challenging to appear under this proper treatment. Metabolic control is excellent, with a glycosylated hemoglobin of around 6.0-6.5% (42-48 mmol/mol). The combination of absent low and rare high blood glucose levels is just perfect. Therefore, blood glucose levels usually have small oscillations.
Risk of hyperglycaemia
If the patient does not feed for more than six hours, the blood sugar has a spontaneous tendency to increase. Attempting to administer additional doses of pills (sulfonylureas) will be to no avail. Blood glucose will continue to rise to 400-500 mg/dl (22.2-27.8 mmol/l). Diabetic ketoacidosis can even set in after a 12-24 hour fasting.
The reason is that the level of a hormone called GLP1 is deficient as long as food is not present in the digestive tract. Thus, only two of the three mandatory components for obtaining insulin secretion are available:
- Increasing the level of ATP
- Binding of a sulfonylurea to the sleeve that completely envelops the K/ATP channel
Risk of hypoglycaemia
The solution to lower the blood sugar raised to 300 mg/dl (16.7 mmol/l) by this mechanism (fasting) is not to administer a dose of sulfonylurea. Why? Because it is already at sufficient blood levels since the last administration.
Instead, the solution is to take a “dose” of food. In other words, eat a meal. As soon as food reaches the digestive tract, a prompt secretion of GLP1 will follow. GLP1 availability comes to fill the missing criterion. Consequently, the insulin secretion starts at maximum capacity. Blood glucose can drop from 300-400 mg/dl (16.7-22.2 mmol/l) to 80 mg/dl (4.4 mmol/l) in just 60 minutes. However, the decrease in blood sugar stops miraculously before the onset of low blood sugar.
The reason is that another mandatory criterion for insulin secretion, elevated ATP levels, will disappear. The level of ATP depends on the glucose concentration around the pancreatic beta-cell. This decrease in ATP levels is a standard mechanism that remains intact in neonatal diabetes.
Decreased blood glucose levels below 90 mg/dl (5 mmol/l) will result in a rapid decrease in ATP levels inside the pancreatic beta-cell. So, insulin secretion stops regardless of the level of sulfonylurea or GLP1 in the blood.
Genetic analysis is available for free
Genetic analysis for neonatal diabetes is available free of charge at Elias Hospital, Bucharest, Romania, for any patient with diabetes that begins in the first 9 months of life. The highest chances of confirming a neonatal diabetes are for those with an onset in the first six months of life. You can apply for a free genetic analysis regardless of the patient’s current age. The oral medication is effective even at an advanced age (e.g. over 40 years). Patients who were switched from insulin to oral treatment will then be able to stay on pills for the rest of their lives. In this form of diabetes, the metabolic control on tablets is better as compared to that obtained on insulin.