What is Congenital Hyperinsulinism (congenital HI)?


Brain power. It can mean getting good grades or having a knack for figuring things out quickly. But in more literal terms it simply means getting the brain the energy, or in this case sugar (glucose), it needs to function. This sounds simple enough, but there are many things that can go wrong with the steps involved in delivering the right amount of glucose to the brain.

When something goes wrong with those steps, the brain can’t do its job. This may be the case for patients who have congenital hyperinsulinism (HI), a very rare disease involving the levels of glucose and insulin in the body, and how the body does – or doesn’t – regulate these levels. Basically, glucose is a nutrient and insulin, which is made by the pancreas, is what the body needs to use this glucose. Glucose and insulin normally work together to keep the glucose levels “just right.” When glucose goes up (like after a meal), the pancreas secretes insulin to return it to normal levels, and when glucose levels decrease insulin secretion is suppressed. Insulin also tells the rest of the body “I’m fed” so the body stores energy in the muscle, in the liver and in fat, rather than tapping into those reserves to give energy to the brain.

Life with HI is like a roller coaster ride. Sometimes you’re high; sometimes you’re low. But with research, funding, and new developments you never run out of hope.

— Jiliani's parent

In patients with congenital HI, the pancreas has a problem and insulin secretion continues even when glucose levels are low. This leads to hypoglycemia, a low glucose level, which leaves little glucose available for the brain to convert into energy and maintain proper function. But it doesn’t end there. HI causes a particularly damaging form of hypoglycemia because the elevated insulin tricks the body to think “I’m fed” and prevents the body from using fat and muscle to generate alternate brain fuel. This hypoketotic hypoglycemia leaves the brain starved of any ability to generate the energy it needs to function. This can have severe consequences, including developmental delay and permanent brain damage if the condition is not recognized or if treatment for the hypoglycemia is ineffective.1

As the name implies, congenital HI is primarily a disease of neonates, infants, and children. Although congenital HI is a rare disease, it is actually the most frequent cause of severe, persistent hypoglycemia in newborns and infants. In many patients, by early adolescence the disease has resolved or progressed to diabetes, but any neurocognitive damage is permanent. At this time, however, HI cannot be detected or diagnosed before birth in utero, so it is important that physicians are equipped with the knowledge to diagnose and treat this disease to prevent life-threatening consequences.

A DOCTOR’S VOICE

There’s such an art to treating congenital HI. There’s an incredible amount of nuance with each patient because it’s so different for everyone.

— Chris Ferrara-Cook, M.D., Ph.D.

congenital hyperinsulinism beta cell somatostatin uai

Pathophysiology


The pancreas is an organ in the body that has many different functions. One of the most important is regulating blood glucose, and it does so by secreting insulin from specialized cells called beta cells.

Under normal circumstances, high glucose stimulates insulin secretion from the beta cells and low glucose suppresses it. Glucose enters the beta cell and is converted to energy called ATP (adenosine triphosphate). ATP closes the ATP-dependent potassium (KATP) channel, which changes the cell’s electrical charge. This, in turn, causes an influx of calcium and triggers events in the cell to secrete insulin, as seen in the diagram. Somatostatin is another hormone secreted by cells in the body (including cells in the pancreas) and acts on the beta cell to suppress insulin secretion. Importantly, Somatostatin acts at one of the last steps of the insulin secretion pathway.

Patients with congenital HI have a disruption in this pathway in the beta cell, most often due to a genetic mutation. There are several different ways one can occur but, in general problems in glucose sensing, metabolism, and the insulin secretion pathway cause the beta call to think there is a “high glucose state” and a need for more insulin. Thus insulin secretion occurs in an unregulated manner, independent of the glucose levels in the body, which may actually be dangerously low.

Epidemiology


Incidence, U.S.

1:25,000 – 1:50,000

Incidence, global

1:35,000 up to 1:2,500 in regions of cosanguinity2

Diagnosis9

60% within first month of life
30% later in the first year

About Congenital Hyperinsulinism


Many of the symptoms of congenital HI are subtle, making it difficult to recognize the disease when it’s present. But considering that 50-75% of patients with congenital HI end up with a developmental delay or defect17, timely recognition, diagnosis and treatment are crucial to prevent fatality and preserve brain function. Common signs and symptoms of congenital HI include:

    • Irritability
    • Sleepiness
    • Lethargy
    • Excessive hunger
    • Difficulty feeding
    • Rapid heart rate

A key indication of hypoglycemia: A new normal

After the first 48 hours of life, blood glucose and the physiology of glucose homeostasis is similar in infants and adults. So hypoglycemia persisting after two days in any infant is not normal and should prompt a workup. For diagnostic purposes, failure to maintain a blood glucose >60 mg/dl after 48 hours of life should warrant a workup to find the cause of hypoglycemia.

The differential diagnosis of hypoglycemia is quite broad and falls under two main categories.

Transient & Environmental Hypoglycemias

These include transient and prolonged neonatal hypoglycemia stemming from a variety of causes, including:

    • Prematurity
    • Maternal diabetes
    • Medications such as oral hypoglycemics
    • Birth asphyxia
    • Maternal toxemia/preeclampsia

The treatment goal for congenital HI is to rapidly correct hypoglycemia and maintain plasma glucose level above 70mg/dl. This threshold is higher than neonates without a hypoglycemic disorder because of the dangerous hypoketotic nature of the hypoglycemia in congenital HI.

Despite advances in recognizing and caring for this disease, it remains difficult to predict insulin and glucose, which may fluctuate throughout the day, from day to day, and even from week to week. Because of this, the disease puts patients and caregivers in a constant reactive state, leaving few options.  In severe cases, part or all of the pancreas must be surgically removed in hopes of lessening the hypoglycemia to a point where medical management may be possible.

A PARENT’S VOICE

We must be constantly vigilant to make sure he is in a safe range.

— James’ Parent

Congenital HI families live in a constant state of fear

Congenital HI is a disease that always hangs over the heads of patients and their loved ones. Dealing with HI requires 24/7 vigilance and reaction to detect and treat low blood sugar. This forces patients and families to live in a perpetual state of preparedness and emergency for fear of hypoglycemia and what could happen in an instant. As you can imagine, it’s exhausting, stressful, and very challenging.

Crinetics is developing an oral, selective, nonpeptide somatostatin receptor 5 (SST5) agonist designed to suppress insulin secretion and prevent the hypoglycemia observed in children with congenital hyperinsulinism. Similar to other somatostatin agonists, the SST5 agonist is anticipated to act in one of the very last steps of the insulin secretion pathway so that it is effective in all patients with HI, regardless of what type they have. We have entered preclinical development with this therapy, called CRN04777, and our ongoing efforts focus on advancing this innovative treatment into human clinical trials.

 

Stay in the loop

Crinetics is committed to redefining what’s possible in the field of endocrinology. Patients are critical to our continued research in developing effective treatments for congenital hyperinsulinism and other rare endocrine diseases. If you or any of your patients are interested in our work and would like to stay informed, subscribe to our newsletter here.

Crinetics is committed to supporting congenital HI patients and their families, who must deal with the unrelenting physical burdens and considerable mental challenges that come with a diagnosis of this rare endocrine disease. As we focus intently on developing better treatment options, we are working with healthcare practitioners to spread the word so that awareness expands and outcomes improve. We are also engaging with the following organizations and encourage you to do the same for education, support, and other helpful resources. And, by all means, tell them Crinetics sent you.

Congenital Hyperinsulinism International
Childrens Hospital of Philadelphia
Cook Children’s Hospital, Fort Worth, TX
Great Ormond Street, London, England
The Children’s Hyperinsulinism Charity

The Final Word


Congenital HI is a life-threatening condition that urgently warrants greater awareness, and Crinetics is dedicated to making that happen. You can help when you:

Learn the markers for congenital HI and keep them in mind when you examine neonates.
Listen to parents who present with odd-sounding symptoms in their infants.
Be the one who diagnoses it because you knew.
Prescribe treatments that can save their lives.
Spread the word about this disease’s signs and symptoms.
Connect with the HI community to keep on top of the latest treatments.

Let’s work together to bring these underserved patients and their families Better therapies for Better lives.

Contact


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    1Andrew A. Palladino, Michael J. Bennett, and Charles Al. Stanley. Hyperinsulinism in Infancy and Childhood: When an Insulin Level is Not Always Enough
    2Arnoux et al., 2011
    3Grant CS. Insulinoma. Best Pract Res Clin Gastroenterol 2005;19:783–98.
    4DeLeonlay 2012
    5Adzick et al., 2019
    6DeCosio and Thornton, 2019; Vajravelu et al., 2019
    7Palladino and Stanley, 2011
    8Beltrand et al., 2012; Lord et al., 2015; Meissner et al., 2003)
    9National Organization for Rare Disorders (NORD); rarediseases.org
    10DeLeon and Stanley, 2017
    11Stanley, 2016
    12Snider, et al., 2013
    13van der Steen et al., 2018
    14Corda et al., 2017
    15Hawkes et al., 2019
    16Lord and De León, 2013; Snider et al., 2013; Sperling, 2008; Stanley, 2016.
    17Lord, et al., J Clin Endocrinal Metab, November 2015, 100(11):4133–4139.
    18CDER, 2015