Hyperinsulinaemic Hypoglycaemia
Hyperinsulinaemic hypoglycaemia is a serious condition where the pancreas produces too much insulin, causing dangerously low blood sugar levels that can lead to permanent brain damage if not treated promptly.
Table of contents
- What is Hyperinsulinaemic Hypoglycaemia?
- Causes and Types
- Genetic Factors
- Signs and Symptoms
- Diagnosis
- Treatment Options
- Risk of Brain Damage
What is Hyperinsulinaemic Hypoglycaemia?
Hyperinsulinaemic hypoglycaemia is a condition where the body makes too much insulin (a hormone that lowers blood sugar) even when blood sugar levels are already low. Normally, special cells in the pancreas called beta-cells carefully control how much insulin they release to keep blood sugar in a healthy range of 3.5 to 5.5 millimoles per liter.[1]
In this condition, insulin secretion becomes unregulated and continues despite low blood glucose levels. This inappropriate insulin production drives glucose into body tissues like muscles and fat, and prevents the body from making alternative energy sources such as ketone bodies. Without enough glucose and ketones, the brain cannot function properly.[4]
Hyperinsulinaemic hypoglycaemia is the most common cause of severe and persistent low blood sugar in newborns and children.[1] It can be temporary or permanent, and ranges from mild cases that respond well to medication to severe cases requiring surgery.
Causes and Types
Hyperinsulinaemic hypoglycaemia can be divided into two main categories: congenital (present from birth) and acquired (developing later in life).
Congenital hyperinsulinism is caused by genetic defects in genes that control insulin secretion from pancreatic beta-cells. The most severe forms are due to mutations in genes called ABCC8 and KCNJ11, which affect the pancreatic beta-cell potassium channels.[4]
The condition can also be temporary in newborns. Transient neonatal hyperinsulinism may develop in babies born to mothers with diabetes, babies who experienced birth complications, those with growth problems before birth, or premature infants. This form generally resolves by six months of age.[3]
Based on how the pancreas is affected, the condition is classified into different types. In diffuse disease, all the beta-cells throughout the pancreas are affected. In focal disease, only some beta-cells in a small area of the pancreas are involved, usually in the form of a small non-cancerous growth. In transient disease, the low blood sugar resolves with age, lasting from a few weeks to several months.[6]
Several developmental conditions are associated with hyperinsulinaemic hypoglycaemia, including Beckwith-Wiedemann syndrome and certain metabolic disorders.[1]
Genetic Factors
Scientists have identified mutations in at least nine different genes that can cause congenital hyperinsulinism. These genes all play important roles in regulating insulin secretion from pancreatic beta-cells.[1]
The genes involved include ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, and HNF1A.[4] Additional genes have been identified more recently, bringing the total to twelve known genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PMM2).[8]
The incidence of congenital hyperinsulinism varies between populations. In the general population, it occurs in about 1 in 40,000 to 50,000 births. However, in communities with high rates of consanguinity (marriage between close relatives), the incidence can be as high as 1 in 2,500 births.[4]
Despite these genetic advances, approximately 50% of cases that respond to medication and 10% of cases that don’t respond to medication still have no identified genetic cause. This suggests that additional genes may yet be discovered.[3]
Signs and Symptoms
The symptoms of hyperinsulinaemic hypoglycaemia relate to the effects of low blood sugar on the body and brain. Symptoms can develop quickly and vary from person to person.[2]
In infants, common signs include poor feeding, lack of normal skin color, turning blue around the mouth, breathing fast, shaking, seizures, and in rare cases, coma or death. In older children, symptoms may include hunger, shakiness, sweating, anxiety, rapid heartbeat, and confusion.[6]
Many symptoms can be attributed to either the brain not getting enough glucose (neuroglycopenia) or to the body’s stress response to low blood sugar. Neuroglycopenic symptoms include confusion, difficulty concentrating, blurred vision, and slurred speech. Stress response symptoms include shaking, sweating, rapid heartbeat, and anxiety.[2]
The symptoms of low blood sugar caused by excessive insulin can be more dangerous than other types of low blood sugar. This is because insulin lowers not only glucose levels but also alternative brain fuels like ketones, leaving the brain without adequate energy sources.[2]
Diagnosis
Diagnosing hyperinsulinaemic hypoglycaemia requires specific blood tests taken when blood sugar is low. The key diagnostic criteria include plasma glucose levels less than 3 millimoles per liter with detectable insulin and C-peptide in the blood, low ketone bodies, and low fatty acids.[3]
A particularly important finding is that patients need high rates of intravenous glucose infusion (greater than 8 milligrams per kilogram per minute, compared to the normal 4 to 6 milligrams per kilogram per minute) to maintain normal blood sugar levels. This strongly supports the diagnosis.[3]
Healthcare providers may need to conduct a fasting test, which involves monitoring blood sugar levels while the patient goes without food. This test is done under medical supervision to safely demonstrate how blood sugar drops and to collect the necessary blood samples for diagnosis.[1]
Advanced imaging techniques can help determine whether the condition is focal or diffuse. A special scan called 18F-DOPA PET-CT can identify focal lesions in the pancreas, which is crucial for planning treatment. If a focal lesion is found, it can often be completely cured by surgical removal of just that small area.[4]
Genetic testing is also an important part of diagnosis. Identifying the specific gene mutation can help predict how the condition will respond to different treatments and inform family planning decisions.[8]
Treatment Options
The main goal of treatment is to keep blood sugar levels above 3.5 millimoles per liter to prevent brain damage. Treatment approaches vary depending on the severity of the condition and whether it responds to medication.[7]
Diazoxide is the first-line medication for controlling low blood sugar in hyperinsulinaemic hypoglycaemia. It works by opening potassium channels in beta-cells, which reduces insulin secretion. Studies show that 84% of patients received diazoxide treatment. The average dose is 12.5 milligrams per kilogram per day, and treatment typically continues for an average of 57 months until the condition resolves.[13]
However, diazoxide doesn’t work for all patients. Those with certain genetic mutations affecting potassium channels (KATP-channel defects) typically don’t respond to this medication.[3]
For patients who don’t respond to diazoxide, somatostatin analogues such as octreotide or lanreotide may be used. About 16% of patients in large studies received these medications. The average octreotide dose is 14.9 micrograms per kilogram per day. Treatment with somatostatin analogues typically continues for an average of 49 months.[13]
Other medication options include calcium channel blockers like nifedipine (used in 4% of patients) and continuous glucagon infusions (used in 1% of patients).[13] A newer medication called sirolimus has shown promise in some patients who don’t respond to other treatments.[8]
For severe cases that don’t respond to any medication, surgery may be necessary. If a focal lesion is identified on imaging, removing just that small area of the pancreas can completely cure the condition. For diffuse disease, a near-total pancreatectomy (removing most of the pancreas) may be required, though this carries risks of developing diabetes later in life.[4]
Frequent feeding schedules and sometimes continuous feeding through a tube may be needed to maintain adequate blood sugar levels, especially in infants with severe disease.[9]
Risk of Brain Damage
The most serious concern with hyperinsulinaemic hypoglycaemia is the risk of permanent brain damage. The brain requires a constant supply of glucose to function properly, and young children’s brains are particularly vulnerable because they consume glucose at higher rates than adult brains.[12]
When blood sugar drops too low, the brain cannot get enough energy. Normally, the body produces ketone bodies as an alternative fuel source during low blood sugar. However, in hyperinsulinaemic hypoglycaemia, excess insulin blocks the production of these ketone bodies. This means the brain has neither glucose nor alternative fuels available, making the situation particularly dangerous.[4]
Children who experience prolonged or repeated episodes of severe low blood sugar in infancy can suffer various types of brain injury. This may result in developmental delays, learning disabilities, epilepsy, or cerebral palsy.[2]
Because of these serious risks, prompt diagnosis and immediate treatment are essential. Blood sugar levels should be monitored carefully and maintained above safe levels at all times. Even short delays in treatment can result in irreversible brain injury.[8]
With early identification and proper management, most children can develop normal cognitive, emotional, and social skills. In many successfully treated cases, the condition may go into remission after several years, allowing medication to be stopped.[13]
