Treatment of KCNJ11 and ABCC8 Permanent Neonatal Diabetes with sulphonylureas
Most people (>90%) with permanent neonatal diabetes caused by a KCNJ11 or ABCC8 genetic change can stop insulin and achieve better glucose control with sulphonylurea tablets. The KCNJ11 and ABCC8 genetic changes affect the Kir6.2 and SUR1 subunits of the potassium channel which provide the link between the sensing of glucose (testing how high the blood glucose is) and the release of insulin from the pancreatic beta-cell. Sulphonylureas bind to the channel to enable the pancreatic beta-cell to respond by secreting insulin when food is eaten.
The Exeter team discovered that genetic changes in KCNJ11 and ABCC8 cause permanent neonatal diabetes and did the major studies on sulphonylurea treatment in patients with potassium channel diabetes. This information about treating this rare condition is based on our experience since 2004 with more than 400 patients worldwide.
How do sulphonylureas work in KCNJ11 and ABCC8 neonatal diabetes?
Sulphonylurea tablets have been used to treat Type 2 diabetes for more than 50 years. However doses that are 3-4 times higher (than those used in Type 2 diabetes) are used to treat neonatal diabetes and the tablets work very differently. In Type 2 diabetes the sulphonylureas stimulate insulin release directly and allow response to a raised glucose, but in patients with KCNJ11 or ABCC8 neonatal diabetes they enable the pancreas to release insulin in response to food predominantly via the hormone GLP-1 released from the gut when food is present in the gut.
What does this mean for people with sulphonylurea treated permanent neonatal diabetes?
Blood sugars are often lower after meals rather than before meals. Blood glucose values will tend to be highest in the morning, as it’s the longest time since eating food.
Careful management of diabetes during/after surgery is important since glucose given via a drip into the veins in the absence of food will not trigger insulin release – insulin treatment is advised when patients are not eating.
Which sulphonylurea should be used in neonatal diabetes?
There is most evidence from using Glibenclamide (Glyburide) in neonatal diabetes with over 90% of patients treated with this worldwide. Other sulphonylureas have been used and have been effective but they do not seem to offer an advantage over Glibenclamide. Glibenclamide has been shown to give some benefit for patients with (or at high risk of) developmental delay (see below) and should be used in this situation at present.
What about hypos on high dose sulphonylureas?
Hypos are unusual and mild: Hypoglycaemia is far less frequent than in insulin treated patients and excellent glycaemic control HbA1c < 6.5% (48 mmol/mol) can easily be achieved (and should be aimed for) without risk of severe hypos. Hypos in potassium channel patients are mild, do not lead to unconsciousness or fitting, and are usually identified by blood glucose testing rather than symptoms. We are not aware of any patient with KCNJ11 or ABCC8 neonatal diabetes who has become unconscious due to hypoglycaemia on sulphonylureas (although many did so when they were previously treated with insulin).
When and why do hypos occur in potassium channel patients: If low blood glucose levels (hypos) do occur they are very different and have a very different cause from hypos in Type 1 and Type 2 diabetes. They will happen after a meal (not before) as a result of an imbalance between food eaten and insulin secretion that results from the food. For example, hypos occur when food stimulates the gut hormone GLP-1 which in turn stimulates the pancreatic beta-cell to secrete insulin but there is not enough carbohydrate in the food to counter balance the insulin released. This is seen after eating low or no carbohydrate foods like cheese or small meals with only short acting or small amounts of carbohydrate. These hypos are mild and rarely produce symptoms.
Hypos are not related to the dose of sulphonylureas. This is another difference from Type 1 and Type 2 diabetes is that hypos are not related to the dose of sulphonylureas. When people with KCNJ11 and ABCC8 neonatal diabetes are well controlled increasing the dose of sulphonylureas will not increase the risk of hypoglycaemia. Taking a very high dose will not lead to hypoglycaemia in the way it would in someone with Type 2 diabetes. We know of patients who have accidently taken 10 times their normal dose without suffering any adverse effect and many patients have increased their regular dose 2-5 times without experiencing symptomatic hypoglycaemia.
When should the dose of sulphonylureas be increased?
If HbA1c is above 6.5% (48mmol/mol) then the dose should be increased. The dose should be increased as a child grows, especially when close to puberty (ie 10-14 years). In pre-puberty there is rapid growth and during puberty adolescents become less sensitive to insulin action, so it’s best to have excellent blood glucose control and a high dose of sulphonylureas (more than 0.4mg/kg/day) before puberty starts.
Those with developmental delay (also caused by the genetic change in the potassium channel ) are helped by having a higher dose of sulphonylurea (see our information on ‘KCNJ11 and ABCC8 Neonatal Diabetes: Effects on the brain’). This is most important when the brain is developing but can be beneficial even in older children. In these cases a higher dose is best. We therefore suggest all children with developmental delay (or at risk of developmental delay because of the specific mutation they have inherited) are on high dose glibenclamide (0.5-1 mg/kg/day). Glibenclamide is recommended in those with developmental delay as we know it crosses the blood / brain barrier. Many families have reported improvements in concentration and speech after the glibenclamide dose is increased but these are small improvements and certainly not a “cure”.
Increasing the dose is safe and is unlikely to cause any increase in hypoglycaemia.
Who is unlikely to manage on sulphonylurea tablets?
We know that people with some specific genetic changes within the KCNJ11 or ABCC8 gene do not respond to sulphonylurea tablets.
People who try to change from insulin to sulphonylureas as adults (especially if they are over 30 years of age) are less likely to be able to transfer and need higher doses (often 1mg/kg/day). In contrast their children with the same genetic change may manage very well on sulphonylurea tablets. However we know of individuals up to 60 years of age who have successfully transferred from insulin to sulphonylureas so a trial with sulphonyureas is recommended.
It may be worth considering the addition of sitagliptin to a sulphonylurea if glycaemic control is not ideal. Some patients find that a combination of insulin and sulphonylureas works better for them than insulin alone.
Management of neonatal diabetes during pregnancy
There is very limited information about pregnancy in women with KCNJ11 or ABCC8 neonatal diabetes. We can provide up to date advice for any patient planning a pregnancy and are following up these pregnancies to learn more about the best management, so please do contact us in advance. As for any woman with diabetes, the aim is achieve excellent blood glucose control before conception so the fetus is developing in a near normal glucose and this needs to be maintained during pregnancy to help the babies development and ensure growth is normal.
In most cases there is a 50% risk that the baby will inherit the genetic change and be affected with neonatal diabetes. These babies will have reduced insulin secretion whilst in the womb and will be small at birth (2.5kg or less).
Recent research shows that glibenclamide crosses the placenta to the baby; this will be helpful for those babies affected with neonatal diabetes but not for the babies without the genetic change.
Pearson ER et al Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006 Aug 3;355(5):467-77. PubMed PMID: 16885550.
This paper describes how sulphonylurea treated Kir6.2 (KCNJ11) patients do not respond to glucose given into a vein but do respond to oral glucose and that this is mediated through GLP-1.