Please note that genetic diagnosis is only possible in approximately half of all HI children.
Information on genetics taken from:
Flanagen SE, Hussain K, Kapoor RR. Genetics of congenital hyperinsulinemic hypoglycaemia. Seminars in Pediatric Surgery 2011; 20: 13-17.
In order to understand the genetics of hyperinsulinism you need to get your head around how genes code for the proteins that make up your body.
There are a range of different types of proteins in your body:
- Hormones and Neurotransmitters - pass chemical signals around your body
- Enzymes - used to convert one substance into another
- Receptors - found on cell membranes. They receive chemical information and tell the cell what to do
- Channels/Carriers - found in cell membranes and allow substances to go from one side to the other (a bit like specialised doors or tunnels)
Each one of these proteins is made from a line of amino acids. Your DNA contains a code that tells your body which amino acids to use to make each protein. If the code is incorrect the wrong amino acids are put together and the protein doesn’t work properly or isn’t made at all. This incorrect code is called a mutation.
The genes involved in hyperinsulinism.
KATP channel genes (ABCC8 & KCNJ11)
These mutations often lead to a very severe form of HI and many patients will need pancreatic surgery. Many patients are macrosomic at birth and diagnosed early.
The KATP channel is made up from 2 types of proteins, those coded by the ABCC8 and the KCNJ11 genes. If these genes are mutated then the KATP channel is damaged or not formed at all. This means that the cell is always depolarised (contains too many positive K+ ions) and insulin is released all the time whatever the concentration of glucose in the blood.
Diazoxide is used to open this channel. If you have damaged channels then diazoxide can’t open them. Therefore most children with mutations in these genes are unresponsive to diazoxide. In some cases, if the channel is only slightly damaged, diazoxide can stabilise the channel and help slow down insulin release, however this form of mutation is rarer.
Inheritance of these genes come in a number of forms:
- Recessive inheritance - inheriting a mutated gene from each parent (both of whom are carriers). Parents would have a 25% chance of having another child with the same form of HI.
- Dominant inheritance - inheriting a gene from one parent (who may have had HI themselves) or a de novo (spontaneously arisen) mutation. If the former then parents have a 50% chance of having another child with HI.
- Paternally inherited - recessive gene inherited from father. Would usually not lead to HI but in some areas of the pancreas the mother’s working gene has been deleted. This leads to the focal form of the disease.
Glutamate dehydrogenase (GLUD1)
This is a dominant form of protein-sensitive Hyperinsulinism. Children with the GLUD1 form of the condition may not be diagnosed until a few months old. This is likely to be related to the fact that breast milk is relatively low in protein. As the baby is moved onto formula or solids their protein intake increases and they have more hypoglycaemic episodes.
Glutamate dehydrogenase is an enzyme that increases the rate of respiration causing more ATP to be produced, which in turn increases the release of insulin (see step 3 in “Release of Insulin”). In healthy individuals this enzyme is stimulated by the amino acid leucine and inhibited by a molecule called GTP (guanosine-5’-triphosphate).
In children with a mutated form of GLUD1 the enzyme’s shape has been changed so that it no longer binds with GTP and is no longer inhibited. Any leucine in the diet causes GLUD1 to work faster and increase the production of insulin.
If your child is diagnosed with the GLUD1 form of hyperinsulinism they may be prescribed diazoxide. This drug helps keep open the K+ channels that are stimulated to close by the action of the enzyme. However you are also likely to see a dietician to help give advice on how diet can help prevent hypoglycaemia.
Leucine is an amino acid commonly found in many protein-rich foods. Avoiding these foods (meat, eggs, dairy, fish, pulses and nuts) can help control blood glucose levels. Leucine is particularly high in the following foods:
- Soybeans (including soya sauce, soya milk, tofu, edamame, tempeh)
However you should always take advice on your child’s diet from your medical team. All children need protein for growth and their immune system. A dietician will help you put together a plan that works for your child within your family environment.
Hydroxyacyl-coenzyme A dehydrogenase (HADH)
This rare form of protein-sensitive hyperinsulinism is recessively inherited. Abnormalities in this gene prevent the beta cell being able to breakdown fatty acids appropriately. However why this causes HI and why the patients are protein-sensitive is still a subject of research. Because this form of HI does not affect the K+ channels it is responsive to diazoxide.
Hepatocyte nuclear factor 4A (HNF4A)
This form of hyperinsulinism is usually diagnosed very soon after birth and babies are often macrosomic (large). This gene is also associated with a form of diabetes type 2 that occurs in younger people.
Nuclear factors work by controlling which and how many proteins are produced by each cell. Although the exact mechanism of the HNF4A isn’t understood it is thought that it causes one or more of these proteins to be expressed inappropriately. This form of HI varies in severity and is usually diazoxide-responsive.
This form of hyperinsulinism also varies in severity, sometimes asymptomatic with individuals reaching adulthood without knowing they have the gene. It is usually but not always responsive to diazoxide.
Glucokinase is an enzyme involved in respiration by binding with glucose in the first stage of glycolysis. Mutations of this enzyme can cause it to bind more readily with glucose, speeding up respiration and the production of ATP (stage 2 of “Release of Insulin”), which increases insulin production out of proportion with the amount of glucose present.
Solute carrier family 16, member 1 (SLC16A1)
This rare form of HI is linked to strenuous exercise and is dominantly inherited or through a “de novo” mutation.
This gene encodes for a protein that carries a molecule called lactate (lactic acid) into the mitochondria of cells. Lactic acid is produced during anaerobic respiration which occurs when doing exercise such as running or cycling hard. If you are out of breath during exercise or have to continue to breathe heavily after stopping the exercise then you have carried out anaerobic respiration. In the mitochondria the lactic acid is broken down by the addition of oxygen during respiration and ATP is produced. In beta cells ATP causes insulin release (step 3 in “Release of Insulin”) but in healthy individuals the SLC16A1 protein is not made in beta cells so there is no link between the two.
In patients with SLC16A1 the beta cells are producing the protein inappropriately. Therefore heavy exercise can lead to the production of lactic acid and therefore increased ATP production and insulin release. This insulin release coupled with the individual using glucose for exercise means they can become severely hypoglycaemic very quickly. Although this is a very severe form of HI it is generally treated through prevention (no strenuous exercise) rather than medication.