An introduction for families to CHI, including its genetic causes, effects on the body, and current and emerging treatments.
What CHI does, and why treatment matters
To function properly, our brain cells need a reliable supply of glucose from our blood. Congenital means the underlying condition is present from birth, even if it is not recognized until later. Hyperinsulinism means there is too much insulin activity for the current blood glucose level. is the most common cause of severe, persistent low blood glucose, also called low blood sugar or hypoglycemia, in newborns and children. In CHI, pancreatic beta cells continue releasing insulin when blood glucose has fallen too low, instead of quieting down as they should.
Normally, especially after eating, insulin helps cells take up glucose from the bloodstream and tells the liver to store some glucose as glycogen. Between meals, as insulin levels fall, the liver releases stored glucose and makes new glucose to help keep blood glucose steady.
In CHI, insulin remains active when glucose is low. It continues encouraging cells to take up glucose and prevents the liver from providing its normal backup supply. Insulin also limits the breakdown of fat and the production of ketones, which are fuels the brain could otherwise use when glucose is scarce. A child can therefore become short of both glucose and backup fuels. Severe, repeated, or prolonged episodes can cause seizures and permanent injury to the developing brain.
The first priority is to raise low glucose and prevent it from falling again. The clinical team then works out how much glucose or feeding support the child needs, whether medicines such as diazoxide reduce insulin release, and what genetic and pancreatic form of CHI is involved. Those answers help shape a plan using medicine, a nutrition plan that may include feeding-tube support, glucose monitoring, and sometimes surgery. The team also reassesses the plan as the child grows because CHI severity can change over time, and some children eventually need less treatment or enter remission.
The rest of this page describes some of the biology of CHI, including how beta cells release insulin, how focal and diffuse CHI differ, and how genetic changes can cause the condition. It then explains how clinicians diagnose CHI, identify its form, and decide next steps. From there, you can continue to the Current and Emerging Treatments page.
01 · How a beta cell decides when to release insulinThe normal sequence from rising glucose to insulin release—and how it is disrupted in ABCC8- and KCNJ11-related CHI.
The steps below show how a beta cell turns rising glucose into an electrical signal that triggers insulin release. This process is especially useful for understanding ABCC8- and KCNJ11-related CHI.
Step 1Glucose rises
After a meal, carbohydrates are digested, raising blood glucose and making more glucose available to the beta cell.
Step 2Cell energy rises
Processing glucose raises the cell’s ATP is often called a cell’s energy currency because it carries usable energy. ADP is what remains after ATP releases some of that energy. When blood glucose rises, beta cells make more ATP relative to ADP..
Step 3K is the chemical symbol for potassium, and ATP stands for adenosine triphosphate, a molecule cells use to transfer energy. KATP therefore means ATP-sensitive potassium channel. These channels occur in several tissues. In pancreatic beta cells, they link the cell’s energy level to its electrical activity. close
The higher ATP-to-ADP ratio causes these potassium gates in the beta-cell membrane to close, making the cell electrically active.
Step 4Calcium enters the beta cell
The electrical change opens separate calcium channels, allowing calcium from the fluid around the cell to enter the cell.
Step 5The beta cell releases insulin
Calcium causes insulin-filled storage granules within the beta cell to The beta cell makes insulin and packages it in tiny membrane-bound storage sacs called granules. When a granule joins with the cell’s outer membrane, it releases the insulin stored inside. This process is called exocytosis. The beta cell makes more insulin to replenish what it releases. Insulin does not pass through the KATP or calcium channels. with the beta-cell membrane. This releases insulin outside the cell, where it can enter the bloodstream.
The diagram shows what happens as glucose rises. When glucose falls, the KATP channels should reopen, helping the beta cell become electrically quiet and reduce insulin release. The beta-cell KATP channel is built from two kinds of protein components, called SUR1 is short for sulfonylurea receptor 1. It is the channel’s regulatory component and helps control whether the channel is open or closed. and Kir6.2 is short for inwardly rectifying potassium channel 6.2. It forms the central opening through which potassium ions pass.. The gene ABCC8 provides instructions for making SUR1; the gene KCNJ11 provides instructions for making Kir6.2. Some A disease-causing variant is a DNA change that disrupts how a gene works and contributes to disease. It may also be called a disease-causing gene mutation. in either gene prevent enough working KATP channels from reaching the cell surface or functioning normally. As a result, the beta cell may continue releasing insulin even when blood glucose is low.
This website gives particular attention to KATP-channel CHI, the most common genetic form of CHI, which is caused by disease-causing variants in ABCC8 or KCNJ11. Other forms disturb the way beta cells sense nutrients, process metabolic signals, or develop and regulate gene activity.
02 · The location of affected beta cells mattersDifferences among focal, diffuse, and atypical patterns—and why the location of affected cells can change treatment decisions.
CHI is not one uniform pancreatic pattern. Genetic testing, specialized imaging, response to medicine, and sometimes examination of pancreatic tissue obtained during surgery help a specialist team distinguish among forms.
Localized area
Focal CHI
A focal lesion is a small region of abnormal beta cells. The usual mechanism begins with a recessive ABCC8 or KCNJ11 variant inherited from the father. Cells in one pancreatic region then lose the working maternal copy and other nearby maternal genes. Outside the focal area, the pancreas generally regulates insulin normally.
When specialized 18F identifies the radioactive fluorine tracer, DOPA refers to L-3,4-dihydroxyphenylalanine, and PET means positron emission tomography. The scan is usually combined with CT or MRI. It helps an experienced team locate a focal area of unusually active beta cells. Only specialized centers offer and interpret this scan. locates the focal area and surgery can remove it completely, surgery In a large CHOP surgical series, 97% of children who underwent surgery for focal CHI were cured. Success depends on accurately locating and completely removing the focal area, as well as the experience of the imaging, pathology, and surgical teams. the CHI while preserving the rest of the pancreas.
Throughout the pancreas
Diffuse CHI
In diffuse CHI, abnormal insulin regulation is spread across most or all of the pancreas rather than confined to one lesion. It can result from This is called recessive inheritance. The child has a disease-causing variant in both copies of the same gene, often one inherited from each parent. One affected copy alone generally does not cause this recessive form. disease-causing variants affecting both copies of ABCC8 or KCNJ11, from a variant in one copy that Dominant means that a disease-causing variant in one copy of a gene can be enough to affect insulin regulation. It may be inherited from a parent or arise as a new genetic change., or from changes in several other CHI-related genes.
Diffuse does not necessarily mean that every beta cell or every KATP channel is affected identically. It means that abnormal insulin regulation is spread broadly across the pancreas rather than confined to one focal area.
Because there is no single lesion to remove, treatment decisions follow a different path. The treatments guide explains why surgery has different goals and outcomes in focal and diffuse CHI.
Patchwork pattern
Atypical or Mosaic means that not all cells have the same genetic change. A change that arises after conception may be present in only some pancreatic cells and may not be detected by standard testing of blood or saliva. Some atypical CHI is mosaic, but not every atypical case has an identified mosaic variant. CHI
Some pancreases show a patchwork of more-active and less-active islets that does not fit the classic focal or diffuse patterns. The affected area can be regional, and the underlying genetic change may exist in only a fraction of pancreatic cells.
These forms are less common and can be harder to classify before surgery. Some regional atypical forms can be treated successfully with In a study of 12 children with LINE-HI, partial pancreatectomy resulted in normal glucose regulation in 75% of cases. This was a small study of one particular regional form, so the percentage should not be applied to all atypical or mosaic CHI., but atypical CHI is too varied for that approach or its reported outcomes to apply to everyone.
03 · Different genes can disturb different controlsThe effects of different genes on insulin channels, nutrient sensing, metabolism, and beta-cell regulation—and why inheritance patterns matter.
More than one molecular route can produce the same outward problem: insulin remains too active when glucose is low. A few examples show why the exact diagnosis can matter.
ABCC8 · KCNJ11
Channel machinery
The genes ABCC8 and KCNJ11 encode the two parts of the KATP channel. Disease-causing variants can disrupt how the KATP channel is assembled, transported to the beta-cell surface, or functions once there. Together, these variants are the most common identified genetic cause of CHI, with ABCC8 involved more often than KCNJ11.
GLUD1 · GCK · HADH · HK1
Nutrient sensing and metabolism
These genes affect how beta cells interpret glucose, amino acids, or metabolic pathways. Some forms have recognizable patterns, such as protein-sensitive hypoglycemia.
HNF4A · HNF1A · others
Gene regulation and cell identity
Some genes help control networks of beta-cell genes. Changes can affect insulin regulation in infancy and, in certain genetic forms, glucose control later in life.
One genetic result can follow different inheritance patterns
Recessive
Disease-causing variants affect both gene copies, often with one inherited from each parent. The parents may be healthy carriers.
Dominant
One altered copy can be enough to affect insulin regulation. It may be inherited from a parent or arise as a new variant in the child.
Focal “two-hit” pattern
A recessive ABCC8 or KCNJ11 variant is usually inherited from the father, followed by a second genetic event limited to a small region of the pancreas.
A genetic test does not always produce a complete answer. Genetic testing can identify many established causes, but studies have found no identifiable genetic cause in approximately 35% to 55% of people with confirmed CHI. The percentage varies with the population and testing methods used. A variant of uncertain significance, often shortened to VUS, is a DNA change that the laboratory cannot yet classify confidently as harmful or harmless. It should not be treated as proof by itself.
04 · How clinicians work out what is happeningCritical-sample results, treatment response, genetic testing, and imaging used to identify the form of CHI.
The diagnosis starts with the body’s chemistry during hypoglycemia, not with a gene test alone. A blood sample collected while glucose is low is often called a critical sample or hypoglycemia screen.
Clues that insulin is still acting when glucose is already low
Clinicians usually look for several findings together:
Ketones and free fatty acids are backup fuels derived from fat. They normally rise when glucose falls, but insulin suppresses them. stay unusually low even though glucose is low. These are backup fuels that should normally become available.
Blood glucose rises substantially after Glucagon is a hormone that tells the liver to release stored glucose. International guidelines define a rise of at least 30 mg/dL after a test dose during hypoglycemia as evidence of excessive insulin action. is given, showing that the liver still had stored glucose available.
The child needs Clinicians call this the glucose infusion rate, meaning the amount of glucose delivered each minute for each kilogram of body weight. In a newborn, needing more than 8 mg/kg/min of glucose through an IV to keep blood glucose from falling too low is an important clue that excessive insulin action may be causing the hypoglycemia. to keep blood glucose in a safe range.
Insulin or C-peptide is a substance released when the pancreas makes insulin. Detecting it can help show that the child’s pancreas is producing insulin. remains detectable while glucose is low, even though insulin release should normally fall to a very low level.
Why one insulin number is not enough
Insulin may be low or even undetectable in some samples despite clear evidence that it is acting. Timing, sample handling, and the sensitivity of the assay all matter.
The broader metabolic pattern can therefore be more informative than whether an insulin result looks dramatically elevated.
What may come next
Genetic testing is usually started early once the diagnosis is confirmed, especially when diazoxide does not work, because rapid results can identify a cause, clarify inheritance, guide focal imaging, and sometimes point toward a treatment response. Guidelines recommend it for most children, except when Perinatal-stress HI is a usually non-genetic form associated with stresses around birth, such as poor fetal growth or reduced oxygen around delivery. It often improves over time, but it still requires careful treatment while present. is considered likely.
Parental testing may be performed alongside or after the child’s testing. It can show which parent a variant came from and help specialists interpret focal, recessive, or dominant possibilities.
Specialized 18F-DOPA PET imaging, available at a limited number of specialist CHI centers, can look for a focal lesion when the genetic and clinical findings make that form plausible.
Follow-up testing shows how safely glucose can be maintained and how treatment needs change. A gene result helps explain biology, but it does not by itself predict one person’s complete course.