|Year : 2019 | Volume
| Issue : 4 | Page : 193-202
Physiological and phased approach to newborns at-risk of hyperinsulinemic hypoglycemia: A neonatal perspective
Suresh Chandran1, Victor Samuel Rajadurai1, Khalid Hussain2, Fabian Yap3
1 Department of Neonatology, KK Women's and Children's Hospital; Department of Neonatology, Duke-NUS Medical School; Department of Neonatology, Yong Loo Lin School of Medicine; Department of Neonatology, Lee Kong Chian School of Medicine, Singapore
2 Department of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha, Qatar
3 Department of Neonatology, Duke-NUS Medical School; Department of Neonatology, Lee Kong Chian School of Medicine; Department of Endocrinology, KK Women's and Children's Hospital, Singapore
|Date of Submission||03-Apr-2019|
|Date of Decision||14-Jul-2019|
|Date of Acceptance||31-Jul-2019|
|Date of Web Publication||04-Oct-2019|
Prof. Suresh Chandran
Department of Neonatology, Neonatal Hypoglycaemia Prevention Program and Hyperinsulinemic Hypoglycaemia Center, KK Women's and Children's Hospital, 100 Bukit Timah Road
Source of Support: None, Conflict of Interest: None
A neonatologist plays a critical role in the management of babies with hypoglycemia. Although neonatal hypoglycemia has been conventionally defined as glucose ≤2.5 mmol/L, levels ≤2.8 mmol/L among neonates raise concerns of neuroglycopenia, supporting the Pediatric Endocrine Societies' suggestion to target plasma glucose levels >2.8 mmol/L in at-risk infants <48 h of age and >3.3 mmol/L for those aged >48 h. The neonatologist needs to identify at-risk babies and enroll them into a pathway that ensures safe, physiological transition to extrauterine life. Physiological transition constitutes early enteral feeding, navigating the glucose nadir while maintaining mother–child bonding. Smooth umbilical to enteral transition of glucose homeostasis following birth needs adequate glycogen stores and appropriate counter-regulatory hormone responses. When stores are inadequate and counter-regulatory responses fail, glucose regulation becomes more dependent on appropriate β-cell responses. However, β-cell dysregulation may cause inappropriate insulin secretion when hypoglycemic (hyperinsulinemic hypoglycemia [HH]) that can be transient, prolonged, or persistent. The majority comprise transient and prolonged forms of HH that recover in days to weeks with feeds or short-term parenteral glucose infusion or rarely with use of KATP channel agonist, diazoxide. The minority with persistent forms may have genetic mutations in at least 12 genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PGMM2) and need medical and/or surgical intervention, as well as long-term multidisciplinary specialist care. Although there is complexity to a management framework that begins in the first hours to days of life, a gentle, physiological, and phased approach can lead to better outcomes. This review article describes such an approach.
Keywords: Congenital hyperinsulinism, diazoxide, hyperinsulinemic hypoglycemia, octreotide, resolution fast study, safety fast study
|How to cite this article:|
Chandran S, Rajadurai VS, Hussain K, Yap F. Physiological and phased approach to newborns at-risk of hyperinsulinemic hypoglycemia: A neonatal perspective. J Clin Neonatol 2019;8:193-202
|How to cite this URL:|
Chandran S, Rajadurai VS, Hussain K, Yap F. Physiological and phased approach to newborns at-risk of hyperinsulinemic hypoglycemia: A neonatal perspective. J Clin Neonatol [serial online] 2019 [cited 2019 Oct 19];8:193-202. Available from: http://www.jcnonweb.com/text.asp?2019/8/4/193/268586
| Introduction|| |
Hypoglycemia remains the most common metabolic problem in neonates. Congenital hyperinsulinism (CHI), due to dysregulated insulin secretion from pancreatic β-cells, has increasingly been reported to cause intractable hypoglycemia in infants. Glucose is the principal neuronal energy source, and in hyperinsulinism, there is an increase in consumption of glucose and inhibition of glycogenolysis, gluconeogenesis, and ketogenesis, depriving the brain of both its primary (glucose) and secondary energy fuels (ketone bodies). Hypoglycemia is known to cause irreversible neuronal injury warranting prompt recognition and treatment. Knowledge of glucose homeostasis, appropriate laboratory investigations for intermediary metabolites during hypoglycemia, and prompt initiation of medical therapy are vital in the management of hyperinsulinemic hypoglycemia (HH).,,,
Neonatal hypoglycemia has been conventionally defined as glucose ≤2.5 mmol/L, and levels ≤2.8 mmol/L among neonates raise concerns of neuroglycopenia, often prompting immediate clinical action., However, glucose levels of 1.4–1.7 mmol/L in well term infants in the first 2 h of life represents a physiological nadir that does not require medical intervention. Navigating through this critical transition period requires enteral feeding and appreciation of the nadir because it is unknown how parenteral glucose during a glucose nadir would influence β-cell function.
Infants at-risk of hypoglycemia include infants born to diabetic mothers (IDM), large for gestational age (LGA), small for gestational age (SGA), preterm (PT), and infants born to overweight mothers (IOM). Mechanism of hypoglycemia in IDM, LGA, and IOM is related to inappropriate insulin levels that cause HH. In SGA and PT infants, reasons for hypoglycemia are multifactorial but primarily related to substrate deficiency. The at-risk infants comprise approximately one-third of newborns and may require intervention that includes early parenteral dextrose. As parenteral glucose exerts a direct effect on the β-cell, while gut peptide hormones and first-pass through the liver modulate β-cell responses to enteral feeds, it is not unreasonable to expect transient dysregulation of β-cell function among infants who receive early parenteral glucose.
Although there is complexity in the hypoglycemia management framework that begins in the first hours to days of life, a more gentle, physiological, and phased approach can lead to better outcomes in the management of infants at-risk for hypoglycemia. This review article describes a stepwise, practical workflow on the management of these at-risk infants that is based on the physiology of fetal and neonatal glucose homeostasis.
Glucose homeostasis and insulin secretion in fetus and newborn
Fuel for fetal metabolism is generated mostly by oxidation of glucose. Maternal plasma glucose (PG) levels maintain continuous glucose supply to the fetus, exposing the fetal brain to PG concentration only slightly below that of maternal plasma with fetomaternal PG difference of 0.5 mmol/L. During the umbilical to enteral transition at birth, in well-term infants, the PG levels drop to a nadir of 1.4–1.7 mmol/L by 1 h of age and then steadily rise to 3–3.3 mmol/L by 2 h of age and continue to rise and maintain PG in the range of 3.9–5.9 mmol/L. Transitional hypoglycemia in newborn infants is expected to resolve within 48 h of life. In the immediate neonatal period, hepatic glycogenolysis provides glucose, whereas β-oxidation of fatty acids and lactate generation due to proteolysis provide substrate for gluconeogenesis.
Effect of PG on insulin secretion by β-cells of pancreas is the key factor in understanding the medical management of HH. Glucose, amino acid, and fatty acid metabolism results in the production of adenosine triphosphate (ATP), which controls the stimulus response-coupling action of the ATP-sensitive potassium channels in the β-cells of the pancreas regulating insulin release precisely to keep the fasting PG concentrations between 3.5 and 5.9 mmol/L [Figure 1]., Following raised PG level, glucose enters the β-cells through facilitative glucose transporter (GLUT 2) and is converted to glucose-6-phosphate by the enzyme glucokinase. Glycolysis results in the generation of high-energy molecules such as ATP leading to a rise in the ATP: ADP ratio. Functional integrity of the pancreatic ATP-sensitive potassium (KATP) channel depends on the interactions between the pore-forming inward rectifier potassium channel subunit (Kir6.2) and the regulatory sulfonylurea receptor 1 (SUR1), encoded by KCNJ11 and ABCC8 genes, respectively. The increase in the cytosolic ATP: ADP ratio leads to activation of plasma membrane SUR1 and closure of KATP channel causing depolarization of cell membrane allowing influx of calcium. This leads to release of insulin by exocytosis from storage granules.
|Figure 1: Glucose and protein mediated insulin secretion from β-cells of pancreas. SUR1 – Sulfonylurea receptor; Kir6.2 – Potassium channel inwardly rectifier; GLUT2 – Glucose transporter 2; G-6-P – Glucose 6 phosphate; GDH – Glutamate dehydrogenase; SCHAD – short-chain 3-hydroxyacyl-CoA dehydrogenase; HADH-L3 – Hydroxyl acyl-Coenzyme A dehydrogenase; GK – Glucokinase|
Click here to view
The gut also regulates glucose homeostasis. Glucagon-like peptide 1 (GLP1) is secreted from the L-cells of the small intestine, which binds to the GLP1 receptors in pancreatic β-cells, thereby stimulating the secretion of insulin.,
Definition of hypoglycemia in at-risk infants
After the first 72 h life, normal fasting blood glucose concentrations in term well infants are maintained within a narrow physiological range of 3.5–5.5 mmol/L. However, recommended target levels are currently variable in infants at-risk of hypoglycemia. The American Academy of Pediatrics (AAP) 2011 clinical guidelines recommend target PG levels ranges from 1.4 to 2.2 mmol/L in asymptomatic infants <4 h of age and 1.9–2.5 mmol/L in those who are 4–24 h of life. More recently in 2015, the Pediatric Endocrine Society (PES) recommended target PG concentration of >2.8 mmol/L for those aged <48 h, >3.3 mmol/L in high-risk neonates without a suspected congenital hypoglycemia disorder aged >48 h of life, and >3.9 mmol/L when there is suspicion of genetic form of HH.,
Given the importance of navigating the physiological nadir  and the risks of neuroglycopenia among at-risk infants, we adopted the AAP guidelines for the first 4 h of life and the PES guidelines after 4 h of life.
Diagnosis of hyperinsulinemic hypoglycemia
A diagnosis of HH is made when serum insulin/C-peptide is detectable in the presence of hypoglycemia in infants >48 h of life receiving a glucose infusion rate (GIR) of >8 mg/kg/min concurrently with hypoketonemia, hypofattyacidemia, and a positive glycemic response to glucagon [Table 1].
HH in infants can be transient, prolonged, or persistent (congenital). Transient HH may be observed in IDM, IOM, SGA, LGA, infants with perinatal asphyxia, or Rh isoimmunization and even in those without risk factors. Although no clear definition is given for the duration of transient hypoglycemia, resolution occurs within days following increment of feeds or short-term glucose infusion. Prolonged HH may be observed in SGA infants who require high GIR and demonstrate diazoxide responsiveness where resolution is observed in weeks to months. Persistent HH, seen in CHI, may have more severe phenotypes with mutations in at least 12 genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PMM2) that alter β-cell function have been reported. In addition, genetic mutations have also been reported which cause syndromic diseases with HH. Histologically, genetic forms of HH can be focal, diffuse, or atypical.,,,
Genetics of hyperinsulinemic hypoglycemia
Channelopathies: KATP channel defects
Mutations in ABCC8 and KCNJ11 genes encoding KATP channel proteins are the most common cause of severe CHI. Medically unresponsive HH is mainly caused by recessive inactivating loss-of-function mutations, while milder forms of CHI are caused by autosomal dominant mutations in these genes. Mutations in the KATP channel regulating genes cause CHI that is unresponsive to diazoxide.
- Hyperinsulinemia–hyperammonemia (HI/HA) syndrome: GLUD1 gene encodes for the mitochondrial enzyme GDH, which catalyzes the oxidative deamination of glutamate to α-ketoglutarate and ammonia. GDH is allosterically activated by leucine and inhibited by guanosine-5-triphosphate (GTP). In HI/HA syndrome, mutations in GLUD1 gene decreases the sensitivity of inhibitor GTP, causing gain-of-function of GDH, resulting in activation of insulin secretion by leucine. They present with leucine sensitive symptomatic hypoglycemia and hyperammonemia. HI/HA cases respond well to diazoxide ,
- L-3-Hydroxyacyl-Coenzyme A Dehydrogenase (HADH) gene mutations: Short-chain 3-hydroxy acyl-CoA dehydrogenase, encoded by the gene HADH, is an enzyme that catalyzes the penultimate step of mitochondrial fatty acid oxidation. HADH gene is expressed in β-cells and has an inhibitory effect on GDH. Autosomal recessive loss-of-function mutations lead to rise in intracellular ATP and inappropriate leucine-sensitive HH. The serum ammonia level is normal. HH is protein-induced, can be mild to severe in infants, and is diazoxide responsive [Figure 1],
- HNF4A, HNF1A, and GCK mutations: HNF4A and HNF1A genes encode for hepatocyte nuclear factor (HNF) 1-α and 4-α proteins, which are transcription factors expressed in β-cells. Heterozygous loss-of-function mutations in HNF4A and HNF1A have biphasic phenotype: HH in newborn infants and maturity-onset diabetes in young adults. The transient-to-severe HH due to these gene mutations are diazoxide-responsive ,,
- Heterozygous-activating mutations of GCK gene, which encodes for glucokinase enzyme, raise the ATP/ADP ratio, leading to inappropriate secretion of insulin. Affected patients can be symptomatic in infancy with fasting hypoglycemia and are diazoxide responsive ,
- Exercise-induced CHI: Monocarboxylase transporter1 protein (MCT1) is involved in the transport of pyruvate and lactate across the β-cell. MCT1, encoded by SLC16A1 gene, is normally silenced in β-cells, preventing lactate and pyruvate from stimulating insulin release. Dominant gain-of-function SLC16A1 mutations lead to exercise-induced CHI due to release of inhibition by the mutated gene. This form of HH is characterized by inappropriate insulin secretion that is exaggerated following exercise. Most of these patients are diazoxide responsive and are advised to avoid strenuous exercises ,
- Recently reported gene mutations causing CHI include HK1, PGM1, PMM2, FOXA2, and CACNA1D,,,,
- Syndromic infants having CHI include Beckwith-Wiedemann, Kabuki, Sotos, Usher, Timothy, and Costello syndrome 
- Metabolic causes of HH include congenital disorders of glycosylation Type 1a, 1b and 1d and tyrosinemia Type 1.,
Infants at-risk of hypoglycemia are screened 2 h after birth till prefeed PG levels remain stable on feeds. Even though most infants with HH present with hypoglycemia during the first 48 h of life, SGA infants may present later., Symptoms of hypoglycemia are often nonspecific and include jitteriness, lethargy, apnea, irritability, poor feeding, seizure, coma, and even sudden death. Presence of hepatomegaly may point to a diagnosis of glycogen storage disorder in the presence of hypoglycemia.
Management of infant's at-risk of hypoglycemia
Infants at-risk of hypoglycemia should be monitored for hypoglycemia from birth. Asymptomatic high-risk neonates should be given a feed (breast or formula milk) during the phase of glucose nadir at 1 h of life and glucose levels checked at 2 h of age., Parental history of consanguinity, family history of early-onset diabetes, a sibling with a history of seizures/sudden collapse (inborn error of metabolism) may point to an inherited cause for hypoglycemia. History of maternal diabetes, obesity, perinatal asphyxia, gestational age, and birth weight (SGA/LGA) might indicate the etiology of hypoglycemia., Physical examination may reveal syndromes associated with HH.
In asymptomatic infants, the mainstay of medical treatment of hypoglycemia is to provide adequate carbohydrate to maintain PG levels in the normoglycemic range. Sometimes, to ensure regular frequent feeds, feeding via nasogastric tube may be needed. Oral buccal glucose gel (Rapilose, Penlan Healthcare, UK) is useful in the initial management of these infants with hypoglycemic episodes. Administer 0.5 ml/kg of glucose gel to the buccal mucosa in infants >35 weeks gestation, and follow with a feed. Parenteral glucose infusion is indicated if 2h PG level <1.4mmol/L or if there is no rise in PG level following glucose gel administration and top up feeds. Avoid intravenous mini-boluses in asymptomatic hypoglycemic infants and use intravenous dextrose infusion to avoid increased glucose variability and the rapidity with which low glucose concentrations are corrected. Beyond 48 h of life, any infant with persistence or recurrence of hypoglycemia is an indication for investigations and specific therapy.
Neonates presenting with symptomatic hypoglycemia, especially seizures, are treated with “mini-bolus” of intravenous 10% dextrose at 2 ml/kg over 3 min, followed by glucose infusion targeting GIR of 4–7 mg/kg/min and titrating up as needed., Consider HH if the GIR is >8 mg/kg/min. Babies with confirmed HH should be managed at specialized centers as they will need central venous access. For confirmation of HH, infants may need to undergo controlled GIR reduction to induce hypoglycemia to collect critical blood samples. In infants with suspected amino acid-induced HH, protein-loading test is indicated.
Once the diagnosis of HH is confirmed, attempts should be made to wean dextrose infusion as tolerated because transient forms may resolve within 5–7 days. Instead, if GIR is rising even after a week of parenteral glucose ± feeds, a trial of diazoxide therapy (3 mg for SGA and 5 mg/kg/day for AGA infants) with thiazide diuretics is initiated. If unable to achieve desired glucose levels, increment in the dosage of diazoxide can be made by 2.5 mg/kg up to a maximum dosage of 15 mg/kg/day. If the patient is diazoxide responsive, gradually wean GIR until full oral feeds are established.,, Around 50% of infants with CHI have feeding problems which are independent of neurodevelopmental delay or mode of treatment.,
While on full feeds if prefeed PG levels are stable, age-appropriate safety fast study (SFS) (6-h) is done to confirm the infant's ability to maintain normoglycemia during an inadvertent fast at home. If PG levels are maintained during the SFS and biochemical response is appropriate, the patient can be discharged with home glucose monitoring. If a baby develops hypoglycemia or becomes symptomatic during SFS, the study is abandoned, parenteral “mini glucose” bolus therapy is given, and dose of diazoxide is increased. Once PG remains stable, the SFS is repeated before discharge. Home glucose monitoring continues and on follow up plan to stop diazoxide when the dose of diazoxide is “self-weaned” with stable PG levels. Consider withdrawal of diazoxide if the daily dose required (3–5 mg/kg/day) “self-weans” to half the initial dose (1.5–2.5 mg/kg/day). In others on higher initial dose >5 mg/kg/day, discontinuation should be considered when the dose has self-weaned to <2.5 mg/kg/day. After 3 days of discontinuation of diazoxide, while on home glucose monitoring, infant is admitted to the hospital for resolution fast study (RFS). RFS should be done for 8–18 h (shorter for infants below 6 months). The infant passes the RFS if he maintains normal PG levels and adequate biochemical responses until the end of the fast. If the infant pass RFS, neurodevelopmental assessment follow-up is given.,
Diazoxide, at the maximum dose of 15 mg/kg/day should be tried before considering genetic testing. If the GIR cannot be weaned on maximum doses of diazoxide, infants are considered as diazoxide-unresponsive, and octreotide therapy is indicated. Responsiveness to diazoxide is a standard means of distinguishing KATP channel mutations from others. Since octreotide is unable to perform this differentiating role, it is not a primary modality of treatment in HH. DNA of the infant and parents is collected for molecular testing for mutations in genes causing CHI. In diazoxide-unresponsive HH, in addition to octreotide, some of these infants may need glucagon infusion to transition from diazoxide to octreotide. Successful glycemic control using continuous glucagon infusion in genetic forms of HH has been reported. Nifedipine is currently not recommended in the treatment of CHI, even though some case reports of HH without genetic study claims treatment response. Other medications, including sirolimus, GLP1 receptor antagonist, and ketogenic diet, are still being evaluated for efficacy and safety in infants and are not routinely recommended. Genetic mutations in KATP channel regulating genes are more often detected. Homozygous and compound heterozygous mutations in ABCC8 and KCNJ11 genes usually cause diffuse disease and paternally inherited mutations in these two genes result in focal disease. Once genetic study suggests focal disease, imaging using 18 F-DOPA-PET-CT scan has to be done to localize, facilitating precise surgical excision and cure., The therapeutic approach to the management of diffuse forms of CHI is much more challenging, and a trial of medical therapy using octreotide/lanreotide and sirolimus may be attempted before resorting to surgical options. [Figure 2] outlines the practical workflow.
|Figure 2: Proposed algorithm for management of transitional and perisitent hyperinsulinemic hypoglycemia. GIR – Glucose infusion rate; IDM – Infant of diabetic mother; SGA – Small for gestational age; LGA – Large for gestational age; IOM – Infant of obese mother|
Click here to view
Infants on and after medical treatment for CHI should have long-term follow-up due to high-risk of neurodevelopmental delay, cerebral palsy, and epilepsy., All the familial forms of CHI should be offered genetic counseling [Figure 3].
|Figure 3: Phased-approach to managing newborns at-risk of hyperinsulinemic hypoglycemia. HH – Hyperinsulinemic hypoglycemia; GIR – Glucose infusion rate; DZX – Diazoxide|
Click here to view
Medical treatment of hyperinsulinemic hypoglycemia [Table 2]
|Table 2: Drugs used in medical management of hyperinsulinemic hypoglycemia|
Click here to view
Diazoxide remains the first-line medical therapy for HH. Diazoxide acts on the SUR1 subunit of the KATP channel, preventing cell membrane depolarization, and thereby inhibiting insulin secretion. It is effective for a variety of HH subtypes such as syndromic forms and “metabolopathies” since KATP channels are functional in these patients. However, it is generally ineffective for the most severe, recessive, and focal forms due to inactivating mutations in ABCC8 or KCNJ11 genes.
Diazoxide is used orally at the dose of 5–15 mg/kg/day in three divided doses. Diazoxide is metabolized in the liver and excreted by kidneys, warranting close monitoring of hepatic and renal functions. When using diazoxide in infants having hepatic dysfunction or hypoalbuminemia, it is initiated at lower doses of 3 mg/kg/day as diazoxide is 90% protein bound. Oral diazoxide is available in suspension (Proglycem, Teva Pharmaceuticals, USA) form and desired dosage of diazoxide can be achieved precisely with suspension.
Tolerance to diazoxide is usually good. Hypertrichosis occurs in most patients but is reversible on discontinuation. Others include tachycardia, neutropenia, thrombocytopenia, and hyperuricemia. Pulmonary hypertension (PH) was reported with a frequency of 2.4%, especially in infants who had PH risk factors; respiratory failure and structural heart disease. Fluid retention side effect of diazoxide can cause serious complications such as pericardial effusion warranting use of thiazide diuretics., As SGA infants are very sensitive to diazoxide, it is safer to start diazoxide at 3 mg/kg/day.
Somatostatin is secreted by δ-cells of the pancreatic islets and inhibits both insulin and glucagon secretions. The mechanisms leading to decrease in the insulin secretion is mediated through inhibition of the intracellular mobilization of calcium as well as decrease in the insulin gene promoter activity., Octreotide has short half-life requiring its administration either by multiple subcutaneous injections every 6–8 hourly or by continuous infusion. Recommended dose of octreotide is 5–35 μg/kg/day and it is used as the second line of medical therapy for children with diazoxide-unresponsive HH.
Two long-acting somatostatin analogs, long-acting release octreotide and the lanreotide acetate, have been introduced and can be administered every 28 days. They are safe and effective alternative to octreotide pump therapy in patients with CHI, offering better compliance and an improved quality of life.
Side effects of octreotide include vomiting, diarrhea, abdominal distension and fatal necrotizing enterocolitis in neonates.,,
Pancreatic α-cells secrete glucagon as a counter-regulatory hormone of insulin. It can be administered by intravenous, subcutaneous, or intramuscular route and has been used at doses of 1–20 μg/kg/h mainly for short-term control of diazoxide-unresponsive HH patients. In symptomatic hypoglycemic LGA infants, intramuscular administration of glucagon may be used as a single dose between 0.5 and 1 mg. Side effects of glucagon include feed intolerance and erythema necrolyticum. Glucagon being an insulin secretagog in high doses, long-term use is recommended only with somatostatin analogs.,
Evidence for the use of corticosteroid in the management of hypoglycemia is limited. Glucocorticoids reduce insulin secretion and enhance glycogenolysis and gluconeogenesis. Current recommendations support the use of glucocorticoids when there is documented hypocortisolism while hypoglycemic or when there is proven adrenal insufficiency via a Synacthen test.
Nifedipine, an L-type calcium channel blocker, has been used at a dose of 0.25–2.5 mg/kg/day as a therapeutic option in patients for whom diazoxide therapy was unsuccessful. The clinical response to this drug is highly variable. Response to nifedipine in patients with HH have been reported, but they all lack genetic study, fasting tolerance, and follow-up. Güemes et al. reported 11 patients who had ABCC8 gene mutation who were treated with nifedipine either as monotherapy or in combination but with no response on glycemic profile. Common side effects with the use of nifedipine include flushing, feed intolerance, and hypotension.,,
Mammalian target of rapamycin inhibitor: Sirolimus
Mammalian target of rapamycin (mTOR) is a member of the serine/threonine kinase family. A possible mechanism of hyperinsulinism and β-cell hyperplasia in diffuse HH involves the constitutive activation of the mTOR pathway, which causes increased glucose uptake and glycolysis. The use of the mTOR inhibitor, sirolimus, helps in both the reduction of beta-cell proliferation and the inhibition of insulin production.,
Sirolimus is started at an initial dose of 0.5 mg/m 2 of body surface area/day. The dose is titrated up targeting a serum trough level of 5–15 ng/ml with stable PG levels. Adverse effects of mTOR inhibitors include stomatitis, increased risk of infection, and pneumonitis. The successful use of sirolimus, either alone or as an adjuvant therapy with octreotide, for patients with diffuse HH may be a feasible potential alternative to pancreatectomy [Table 2].
Glucagon-like peptide 1 receptor antagonist
Incretin hormone, GLP1, amplifies postprandial insulin secretion. GLP1 receptor antagonist, exendin-9-39, by decreasing cAMP levels and thereby inhibiting insulin secretion, is effective for the treatment of CHI. However, further clinical studies are needed to assess its pharmacokinetics, effectiveness, and safety.,
In CHI, there is shortage of cerebral energy fuels and can lead to severe neurological sequelae. By reproducing a fasting-like condition in which energy is mainly derived from beta-oxidation, ketogenic diet provides alternative energy source to neurons. There are reports showing clinical improvement and seizure free periods when ketogenic diet is used. However, additional studies are needed to confirm the efficacy of this novel therapeutic approach for its neuroprotective effect in CHI.,
| Conclusion|| |
The management of infants at-risk of hypoglycemia, which begins in the first hours to days of life with the potential to lead to a diagnosis of HH, is of fundamental interest to doctors looking after newborn babies. Although there is complexity in the overall framework of care, the critical checkpoints in the pathway are upstream and include recognizing and navigating the glucose nadir, choosing the appropriate form of therapy during hypoglycemia, and ensuring a precise diagnosis of HH. The middle of the process involves the assessment of Diazoxide responsiveness, which takes center stage and determines treatment and prognosis. Further downstream, the safety and resolution fasting studies play important roles in the transition from hospital to home care.
We express our gratitude to Dr. Shrenik Vora, Staff Physician, Department of Neonatology, KK Women's and Children's Hospital, Singapore, for helping with the preparation of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, De Lonlay-Debeney P, et al.
Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98-107.
Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes 2010;17:20-4.
Menni F, de Lonlay P, Sevin C, Touati G, Peigné C, Barbier V, et al.
Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476-9.
Hussain K, Aynsley-Green A. Hyperinsulinism in infancy: Understanding the pathophysiology. Int J Biochem Cell Biol 2003;35:1312-7.
Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ 1988;297:1304-8.
Stanley CA, Rozance PJ, Thornton PS, De Leon DD, Harris D, Haymond MW, et al.
Re-evaluating “transitional neonatal hypoglycemia”: Mechanism and implications for management. J Pediatr 2015;166:1520-50.
Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lilien LD. Plasma glucose values in normal neonates: A new look. J Pediatr 1986;109:114-7.
García-Patterson A, Aulinas A, María MÁ, Ubeda J, Orellana I, Ginovart G, et al.
Maternal body mass index is a predictor of neonatal hypoglycemia in gestational diabetes mellitus. J Clin Endocrinol Metab 2012;97:1623-8.
Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest 2007;117:24-32.
Marconi AM, Paolini C, Buscaglia M, Zerbe G, Battaglia FC, Pardi G. The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference. Obstet Gynecol 1996;87:937-42.
Malaisse WJ, Sener A, Herchuelz A, Hutton JC. Insulin release: The fuel hypothesis. Metabolism 1979;28:373-86.
Zhang T, Li C. Mechanisms of amino acid-stimulated insulin secretion in congenital hyperinsulinism. Acta Biochim Biophys Sin (Shanghai) 2013;45:36-43.
Johnson JH, Newgard CB, Milburn JL, Lodish HF, Thorens B. The high Km glucose transporter of islets of langerhans is functionally similar to the low affinity transporter of liver and has an identical primary sequence. J Biol Chem 1990;265:6548-51.
Inagaki N, Gonoi T, Clement JP 4th
, Namba N, Inazawa J, Gonzalez G, et al.
Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor. Science 1995;270:1166-70.
De León DD, Crutchlow MF, Ham JY, Stoffers DA. Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus. Int J Biochem Cell Biol 2006;38:845-59.
Nelson RL. Oral glucose tolerance test: Indications and limitations. Mayo Clin Proc 1988;63:263-9.
Güemes M, Rahman SA, Hussain K. What is a normal blood glucose? Arch Dis Child 2016;101:569-74.
Committee on Fetus and Newborn, Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575-9.
Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, et al.
Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr 2015;167:238-45.
Ferrara C, Patel P, Becker S, Stanley CA, Kelly A. Biomarkers of insulin for the diagnosis of hyperinsulinemic hypoglycemia in infants and children. J Pediatr 2016;168:212-9.
Yap F, Högler W, Vora A, Halliday R, Ambler G. Severe transient hyperinsulinaemic hypoglycaemia: Two neonates without predisposing factors and a review of the literature. Eur J Pediatr 2004;163:38-41.
VanHaltren K, Malhotra A. Characteristics of infants at risk of hypoglycaemia secondary to being 'infant of a diabetic mother'. J Pediatr Endocrinol Metab 2013;26:861-5.
Stark J, Simma B, Blassnig-Ezeh A. Incidence of hypoglycemia in newborn infants identified as at risk. J Matern Fetal Neonatal Med 2019. p.1-6. doi: 10.1080/14767058.2019.1568985. [Epub ahead of print].
Chong JH, Chandran S, Agarwal P, Rajadurai VS. Delayed presentation of prolonged hyperinsulinaemic hypoglycaemia in a preterm small-for-gestational age neonate. BMJ Case Rep 2013;2013. pii: bcr2013200920.
Galcheva S, Demirbilek H, Al-Khawaga S, Hussain K. The genetic and molecular mechanisms of congenital hyperinsulinism. Front Endocrinol (Lausanne) 2019;10:111.
Stanley CA, Fang J, Kutyna K, Hsu BY, Ming JE, Glaser B, et al.
Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: Predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA contributing investigators. Diabetes 2000;49:667-73.
Heslegrave AJ, Hussain K. Novel insights into fatty acid oxidation, amino acid metabolism, and insulin secretion from studying patients with loss of function mutations in 3-hydroxyacyl-CoA dehydrogenase. J Clin Endocrinol Metab 2013;98:496-501.
Chandran S, Yap F, Hussain K. Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia. World J Diabetes 2014;5:666-77.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al.
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4:e118.
Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, et al.
Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature 1996;384:458-60.
Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, et al.
Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature 1996;384:455-8.
Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: From basics to therapeutics. Diabetes 2002;51 Suppl 3:S394-404.
Cuesta-Muñoz AL, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Näntö-Salonen K, Rahier J, et al.
Severe persistent hyperinsulinemic hypoglycemia due to a de novo
glucokinase mutation. Diabetes 2004;53:2164-8.
Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, et al.
Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 2003;52:199-204.
Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA. Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise. Diabetes 2012;61:1719-25.
Pinney SE, Ganapathy K, Bradfield J, Stokes D, Sasson A, Mackiewicz K, et al.
Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr 2013;80:18-27.
Tegtmeyer LC, Rust S, van Scherpenzeel M, Ng BG, Losfeld ME, Timal S, et al.
Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 2014;370:533-42.
Cabezas OR, Flanagan SE, Stanescu H, García-Martínez E, Caswell R, Lango-Allen H, et al.
Polycystic kidney disease with hyperinsulinemic hypoglycemia caused by a promoter mutation in phosphomannomutase 2. J Am Soc Nephrol 2017;28:2529-39.
Giri D, Vignola ML, Gualtieri A, Scagliotti V, McNamara P, Peak M, et al.
Novel FOXA2 mutation causes hyperinsulinism, hypopituitarism with craniofacial and endoderm-derived organ abnormalities. Hum Mol Genet 2017;26:4315-26.
Flanagan SE, Vairo F, Johnson MB, Caswell R, Laver TW, Lango Allen H, et al.
A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia. Pediatr Diabetes 2017;18:320-3.
Demirbilek H, Hussain K. Congenital hyperinsulinism: Diagnosis and treatment update. J Clin Res Pediatr Endocrinol 2017;9:69-87.
Goreta SS, Dabelic S, Dumic J. Insights into complexity of congenital disorders of glycosylation. Biochem Med (Zagreb) 2012;22:156-70.
Baumann U, Preece MA, Green A, Kelly DA, McKiernan PJ. Hyperinsulinism in tyrosinaemia type I. J Inherit Metab Dis 2005;28:131-5.
Canadian Paediatric Society. Screening guidelines for newborns at risk for low glucose. Paediatr Child Health 2004;9:723-39.
Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol 2013;168:557-64.
Deshpande S, Ward Platt M. The investigation and management of neonatal hypoglycaemia. Semin Fetal Neonatal Med 2005;10:351-61.
Vora S, Chandran S, Rajadurai VS, Hussain K. Hyperinsulinemic hypoglycemia in infancy: Current concepts in diagnosis and management. Indian Pediatr 2015;52:1051-9.
Banerjee I, Forsythe L, Skae M, Avatapalle HB, Rigby L, Bowden LE, et al.
Feeding problems are persistent in children with severe congenital hyperinsulinism. Front Endocrinol (Lausanne) 2016;7:8.
Harris DL, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gel for neonatal hypoglycaemia (the sugar babies study): A randomised, double-blind, placebo-controlled trial. Lancet 2013;382:2077-83.
Hussain K. Diagnosis and management of hyperinsulinaemic hypoglycaemia of infancy. Horm Res 2008;69:2-13.
Rozance PJ, Hay WW Jr. New approaches to management of neonatal hypoglycemia. Matern Health Neonatol Perinatol 2016;2:3.
Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr 2001;138:383-9.
Welters A, Lerch C, Kummer S, Marquard J, Salgin B, Mayatepek E, et al.
Long-term medical treatment in congenital hyperinsulinism: A descriptive analysis in a large cohort of patients from different clinical centers. Orphanet J Rare Dis 2015;10:150.
Tas E, Mahmood B, Garibaldi L, Sperling M. Liver injury may increase the risk of diazoxide toxicity: A case report. Eur J Pediatr 2015;174:403-6.
Al-Shanafey S, Alkhudhur H. Food aversion among patients with persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr Surg 2012;47:895-7.
Yorifuji T, Horikawa R, Hasegawa T, Adachi M, Soneda S, Minagawa M, et al.
Clinical practice guidelines for congenital hyperinsulinism. Clin Pediatr Endocrinol 2017;26:127-52.
De Leon DD, Stanley CA. Congenital hypoglycemia disorders: New aspects of etiology, diagnosis, treatment and outcomes: Highlights of the proceedings of the congenital hypoglycemia disorders symposium, Philadelphia April 2016. Pediatr Diabetes 2017;18:3-9.
Güemes M, Shah P, Silvera S, Morgan K, Gilbert C, Hinchey L, et al.
Assessment of nifedipine therapy in hyperinsulinemic hypoglycemia due to mutations in the ABCC8 gene. J Clin Endocrinol Metab 2017;102:822-30.
Garg PK, Lokitz SJ, Truong L, Putegnat B, Reynolds C, Rodriguez L, et al.
Pancreatic uptake and radiation dosimetry of 6-[18F] fluoro-L-DOPA from PET imaging studies in infants with congenital hyperinsulinism. PLoS One 2017;12:e0186340.
Hardy OT, Hernandez-Pampaloni M, Saffer JR, Scheuermann JS, Ernst LM, Freifelder R, et al.
Accuracy of [18F] fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab 2007;92:4706-11.
Senniappan S, Alexandrescu S, Tatevian N, Shah P, Arya V, Flanagan S, et al.
Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014;370:1131-7.
Ludwig A, Enke S, Heindorf J, Empting S, Meissner T, Mohnike K. Formal neurocognitive testing in 60 patients with congenital hyperinsulinism. Horm Res Paediatr 2018;89:1-6.
Chandran S, Rajadurai VS, Alim AH, Hussain K. Current perspectives on neonatal hypoglycemia, its management, and cerebral injury risk. Res Rep Neonatol 2015;5:17-30.
Herrera A, Vajravelu ME, Givler S, Mitteer L, Avitabile CM, Lord K, et al.
Prevalence of adverse events in children with congenital hyperinsulinism treated with diazoxide. J Clin Endocrinol Metab 2018;103:4365-72.
Avatapalle B, Banerjee I, Malaiya N, Padidela R. Echocardiography monitoring for diazoxide induced pericardial effusion. BMJ Case Rep 2012;2012. pii: bcr0320126110.
Katz MD, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989;8:255-73.
Doyle ME, Egan JM. Pharmacological agents that directly modulate insulin secretion. Pharmacol Rev 2003;55:105-31.
Le Quan Sang KH, Arnoux JB, Mamoune A, Saint-Martin C, Bellanné-Chantelot C, Valayannopoulos V, et al.
Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 2012;166:333-9.
Shah P, Rahman SA, McElroy S, Gilbert C, Morgan K, Hinchey L, et al.
Use of long-acting somatostatin analogue (Lanreotide) in an adolescent with diazoxide-responsive congenital hyperinsulinism and its psychological impact. Horm Res Paediatr 2015;84:355-60.
Corda H, Kummer S, Welters A, Teig N, Klee D, Mayatepek E, et al.
Treatment with long-acting lanreotide autogel in early infancy in patients with severe neonatal hyperinsulinism. Orphanet J Rare Dis 2017;12:108.
Levy-Khademi F, Irina S, Avnon-Ziv C, Levmore-Tamir M, Leder O. Octreotide-associated cholestasis and hepatitis in an infant with congenital hyperinsulinism. J Pediatr Endocrinol Metab 2015;28:449-51.
Hawkes CP, Adzick NS, Palladino AA, De León DD. Late presentation of fulminant necrotizing enterocolitis in a child with hyperinsulinism on octreotide therapy. Horm Res Paediatr 2016;86:131-6.
Neylon OM, Moran MM, Pellicano A, Nightingale M, O'Connell MA. Successful subcutaneous glucagon use for persistent hypoglycaemia in congenital hyperinsulinism. J Pediatr Endocrinol Metab 2013;26:1157-61.
Mohnike K, Blankenstein O, Pfuetzner A, Pötzsch S, Schober E, Steiner S, et al.
Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon. Horm Res 2008;70:59-64.
Sweet CB, Grayson S, Polak M. Management strategies for neonatal hypoglycemia. J Pediatr Pharmacol Ther 2013;18:199-208.
Mergler S, Singh V, Grötzinger C, Kaczmarek P, Wiedenmann B, Strowski MZ. Characterization of voltage operated R-type Ca2+ channels in modulating somatostatin receptor subtype 2- and 3-dependent inhibition of insulin secretion from INS-1 cells. Cell Signal 2008;20:2286-95.
Eichmann D, Hufnagel M, Quick P, Santer R. Treatment of hyperinsulinaemic hypoglycaemia with nifedipine. Eur J Pediatr 1999;158:204-6.
Yang SB, Lee HY, Young DM, Tien AC, Rowson-Baldwin A, Shu YY, et al.
Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J Mol Med (Berl) 2012;90:575-85.
Leibiger IB, Leibiger B, Moede T, Berggren PO. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol Cell 1998;1:933-8.
De León DD, Li C, Delson MI, Matschinsky FM, Stanley CA, Stoffers DA. Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion. J Biol Chem 2008;283:25786-93.
Calabria AC, Li C, Gallagher PR, Stanley CA, De León DD. GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel. Diabetes 2012;61:2585-91.
Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. Ketogenic diet, amino acid metabolism, and seizure control. J Neurosci Res 2001;66:931-40.
Maiorana A, Manganozzi L, Barbetti F, Bernabei S, Gallo G, Cusmai R, et al.
Ketogenic diet in a patient with congenital hyperinsulinism: A novel approach to prevent brain damage. Orphanet J Rare Dis 2015;10:120.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]