Hyperinsulinaemic hypoglycaemia in children and adults

Review

Hyperinsulinaemic hypoglycaemia in children and adults Pratik Shah, Sofia A Rahman, Huseyin Demirbilek, Maria Güemes, Khalid Hussain

Pancreatic β cells are functionally programmed to release insulin in response to changes in plasma glucose concentration. Insulin secretion is precisely regulated so that, under normal physiological conditions, fasting plasma glucose concentrations are kept within a narrow range of 3·5–5·5 mmol/L. In hyperinsulinaemic hypoglycaemia, insulin secretion becomes dysregulated (ie, uncoupled from glucose metabolism) so that insulin secretion persists in the presence of low plasma glucose concentrations. Hyperinsulinaemic hypoglycaemia is the most common cause of severe and persistent hypoglycaemia in neonates and children. At a molecular level, mutations in nine different genes can lead to the dysregulation of insulin secretion and cause this disorder. In adults, hyperinsulinaemic hypoglycaemia accounts for 0·5–5·0% of cases of hypoglycaemia and can be due either to β-cell tumours (insulinomas) or β-cell hyperplasia. Rapid diagnosis and prompt management of hyperinsulinaemic hypoglycaemia is essential to avoid hypoglycaemic brain injury, especially in the vulnerable neonatal and childhood periods. Advances in the field of hyperinsulinaemic hypoglycaemia include use of rapid molecular genetic testing for the disease, application of novel imaging techniques (6-[fluoride-18]fluoro-levodopa [¹⁸F-DOPA] PET-CT and glucagon-like peptide 1 (GLP-1) receptor imaging), and development of novel medical treatments (eg, long-acting octreotide formulations, mTOR inhibitors, and GLP-1 receptor antagonists) and surgical therapies (eg, laparoscopic surgery).

Introduction Glucose is the key metabolic substrate for cellular energy metabolism. Under normal physiological conditions, plasma glucose concentration is maintained within a narrow (3·5–5·5 mmol/L) range. Insulin is the primary hormone that lowers plasma glucose concentration; under normal physiological conditions, secretion of insulin from the β cell is precisely regulated to prevent hypoglycaemia or hyperglycaemia. Glucose is the main regulator of insulin secretion; pancreatic β cells act as glucose sensors, coupling changes in glucose metabolism to rate of insulin secretion.1 This coupling is the key role of β-cell ATP-sensitive potassium (KATP) channels. These channels are composed of four sulfonylurea receptor 1 (SUR1) subunits, encoded by ABCC8, and four inward-rectifier potassium channel Kir6.2 subunits, encoded by KCNJ11.2 After a meal, when the plasma glucose concentration increases, glucose enters the β cell via glucose transporter 2 (GLUT-2). Glucose is phosphorylated by glucokinase and is then metabolised via the glycolytic pathway (figure 1). This process results in an increase in the ATP:ADP ratio which causes the KATP channels to close, thus depolarising the β-cell membrane. Depolarisation of the cell membrane causes voltage-gated calcium channels to open, leading to insulin exocytosis. In hyperinsulinaemic hypoglycaemia, insulin secretion becomes dysregulated and uncoupled from glucose and fuel metabolism so that insulin secretion persists despite hypoglycaemia.3 Unregulated insulin secretion reduces glucose production through inhibition of glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Hyperinsulinaemic hypoglycaemia is, therefore, associated with a paucity of alternative cellular energy sources, principally ketone bodies, when blood glucose concentrations are low. Hence children, especially newborn babies and infants, are at high risk of developing hypoglycaemic brain injury—such as epilepsy, cerebral

palsy, or neurological impairment—if hyperinsulinaemic hypoglycaemia is not promptly diagnosed and managed. Most neonatal hypoglycaemia is transient, and does not have a genetic cause. However, hyperinsulinaemic hypoglycaemia is the most frequent cause of persistent and severe hypoglycaemia in neonates,4 and genetic abnormalities in nine different genes have been associated with unregulated insulin secretion.5 Insulinomas are the most common functional neuroendocrine tumours that lead to hyperinsulinaemic hypoglycaemia in adults. This Review summarises the latest advances in the field of hyperinsulinaemic hypoglycaemia, with particular emphasis on molecular mechanisms, diagnosis, and management in children and adults.

Lancet Diabetes Endocrinol 2016 Published Online November 30, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30323-0 Department of Pediatric Medicine, Sidra Medical & Research Center, Outpatient Clinic, Doha, Qatar (Prof K Hussain MD); Genetics and Genomic Medicine Programme, University College London (UCL) Institute of Child Health, London, UK(P Shah MD, S A Rahman PhD, M Güemes MD); Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK (P Shah, M Güemes); and Department of Paediatric Endocrinology, Hacettepe University, Ankara, Turkey (H Demirbilek MD) Correspondence to: Prof Khalid Hussain, Department of Pediatric Medicine, Sidra Medical & Research Center, Outpatient Clinic, Doha, Qatar [email protected]

Clinical presentation and biochemical diagnosis Hyperinsulinaemic hypoglycaemia presents as hypoglycaemia during fasting, exercise, or the postprandial period. These symptoms are either adrenergic (eg, sweating, tremor, palpitations, tachycardia, agitation, or hunger) or neuroglycopenic (eg, impaired consciousness, speech, memory, or blurred vision; seizures; ataxia; or loss of consciousness). In newborn babies and young infants, the clinical presentation might be with non-specific hypoglycaemic symptoms such as poor feeding, lethargy, jitteriness, and irritability. On clinical examination, some newborn babies with hyperinsulinaemic hypoglycaemia have macrosomic features, cardiomyopathy, and hepatomegaly (due to increased storage of glycogen). In adults, the Endocrine Society recommends6 evaluation and management of hypoglycaemia only in patients in whom Whipple’s triad is seen: symptoms, signs, or both consistent with hypoglycaemia; a low plasma glucose concentration; and resolution of those symptoms or signs after the plasma glucose concentration is raised. In neonates and infants, the definition of hypoglycaemia and the threshold for treatment and continued

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

1

Review

correlation between the serum insulin concentration and the severity of hypoglycaemia exists.12 Sometimes hypoglycaemia is mild and provoked by meals (postprandial or protein-sensitive hypoglycaemia) or exercise (panel 1).

Calcium K+

Membrane depolarisation Voltage-gated calcium channel

Kir6.2 SUR1 Ca2+

Ca2+

Overview Insulin release

UCP2

TCA cycle

Lactate

Genetic causes

Insulin

ATP or ADP closes KATP channel

Ca2+

MCT 1 HADH

Lactate

2+

Ca

Ca2+ Pyruvate

α-ketoglutarate +NH3 Glucose

Glycolysis

Nucleus Pi GDH

Glucokinase Glucose

Transcription factors (HNF1A and HNF4A)

Glutamate GLUT-2

Glucose

Figure 1: Regulation of insulin release from pancreatic β cell G6P=glucose 6 phosphate. GDH=glutamate dehydrogenase. GLUT-2=glucose transporter 2. HADH=hydroxyacyl-CoA dehydrogenase. Kir6.2=inward rectifier potassium channel Kir6.2. MCT1=monocarboxylate transporter 1. NH3=ammonia. Pi=inorganic phosphate. SUR1=sulfonylurea receptor 1. TCA=tricarboxylic acid. UCP2=mitochondrial uncoupling protein 2.

management remain controversial. The Pediatric Endocrine Society has published new recommendations7,8 regarding the management of hypoglycaemia in newborn babies and children. Recommendations for the neonate were written to help clinicians to distinguish between infants with low, but physiologically normal, plasma glucose concentrations in the first 48 h after birth, and infants who might be at risk of persistent hypoglycaemia. These recommendations were formulated so that patients with hyperinsulinaemic hypoglycaemia could be diagnosed before being discharged from hospital, with the aim of preventing neurological injury in children with persistent disease. Diagnosis of hyperinsulinaemic hypoglycaemia (panel 1) is based on the clinical presentation and biochemical profile (hypoketonaemic, hypofattyacidaemic) of hypoglycaemia that arises from the anabolic effects of increased serum insulin concentration. Since circulating insulin has a short half-life (approximately 6 min) and secretion is pulsatile in some patients, the serum insulin concentration measured at the time of hypoglycaemia might not be raised.11 However, the C-peptide concentration is almost always elevated at the time of hypoglycaemia and this surrogate marker could be a better indication of dysregulated insulin secretion than serum insulin itself. Patients require a rate of intravenous glucose infusion higher than 8 mg/kg per min (normal infusion is 4–6 mg/kg per min) to maintain normoglycaemia.4 No 2

Hyperinsulinaemic hypoglycaemia can be due to many different transient and persistent causes in both children and adults (panel 2). The underlying molecular mechanisms in transient cases are not known, but some cases could be due to mutations in HNF4A and HNF1A, which encode transcription factors. The severe and persistent forms of hyperinsulinaemic hypoglycaemia can present in the newborn period as well as in infancy and childhood, and in about 50% of patients, a known underlying genetic basis can explain the molecular mechanism for dysregulated insulin secretion. Genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, and UCP2) have been described so far that lead to unregulated insulin secretion and hyperinsulinaemic hypoglycaemia. In adults and older children, an insulinoma is the most common cause of hyperinsulinaemic hypoglycaemia.

Defects in pancreatic β-cell KATP channels KATP channels are located in the β-cell membrane and transduce the metabolic signals generated by glucoseinduced metabolism to regulate insulin secretion. KCNJ11 and ABCC8 are localised on chromosome 11p15.1 and encode the Kir6.2 and SUR1 subunits of the KATP channel. Mutations in these genes are the most common cause of severe hyperinsulinaemic hypoglycaemia.16,17 The most common mutations in ABCC8 and KCNJ11 are recessive (loss-of-function),16 usually resulting in medically unresponsive hyperinsulinaemic hypoglycaemia. These mutations affect either trafficking of channel proteins to the plasma membrane or channel regulation in response to changes in nucleotide concentrations.18 However, milder forms of congenital hyperinsulinaemic hypoglycaemia are seen with dominant inactivating mutations in ABCC8 and KCNJ11,19 although there have also been reports of medically unresponsive forms.20

Abnormalities in glutamate dehydrogenase expression Glutamate dehydrogenase is a homohexameric enzyme that catalyses the reversible oxidative deamination of L-glutamate to 2-oxoglutarate. 2-oxoglutarate is shunted into the citric acid cycle to generate ATP. Glutamate dehydrogenase is allosterically regulated by major activators like ADP and leucine, and by inhibitors such as GTP, palmitoyl-CoA, and ATP.21 Hyperinsulinismhyperammonaemia syndrome is caused by spontaneous and dominantly inherited missense activating mutations in the GTP inhibitory site of this enzyme.22 These patients typically present with prandial hypoglycaemia

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

Review

in response to protein ingestion. Milder phenotypes can be difficult to recognise in the first year of life.23 The typical biochemical picture is hyperammonaemia (usually two-to-three-times the upper limit of normal) with hyperinsulinaemic hypoglycaemia. However, there are reports of children with leucine hypersensitivity who have normal serum ammonia concentrations.23 The concentration of urinary α-ketoglutarate is increased in patients with hyperinsulinism-hyperammonaemia syndrome.24 Diazoxide is the mainstay of therapy for patients with this syndrome, and dietary protein restriction might be required in some patients.

Mutations in the gene encoding L-3-hydroxyacyl-CoA dehydrogenase The enzyme L-3-hydroxyacyl-CoA dehydrogenase (HADH) is involved in the penultimate step of the β-oxidation pathway and is encoded by the mitochondrial HADH gene.25 Enzyme activity is highest in the pancreatic islets of Langerhans, although it is expressed in most tissues. HADH gene mutations are a rare cause of hyperinsulinaemic insulinaemia, leading to either severe neonatal hyperinsulinaemic insulinaemia or to mild lateonset hyperinsulinaemic hypoglycaemia26,27 that is responsive to diazoxide. Patients with mutations in HADH present with protein (predominantly leucine)-induced hyperinsulinaemic hypoglycaemia. The molecular basis of disease observed in patients with HADH mutations involves a loss of the protein–protein interaction between HADH and glutamate dehydrogenase, which causes an overstimulation of glutamate dehydrogenase and a rise in cellular ATP and upregulated insulin secretion.28 These observations suggest that glutamate dehydrogenase plays a pivotal role in fatty acid and aminoacid metabolism to control insulin secretion. Some patients with HADH mutations have increased plasma concentrations of 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutaric acids;26 however, the role of these metabolites (if any) in the pathogenesis of hyperinsulinaemic hypoglycaemia in these patients is not clear. Adult patients with HADH mutations can also present with protein-induced hyperinsulinaemic hypoglycaemia.29

Hepatic nuclear transcription factors HNF4A is a transcription factor that controls the expression of genes involved in glucose-stimulated insulin secretion30 and regulates the function of β cells. It is encoded by HNF4A and heterozygous mutations in this gene can cause transient hyperinsulinaemic hypoglycaemia in neonates.31 However, in later life the same mutation leads to progressive β-cell dysfunction and causes maturity-onset diabetes of the young type 1.32 Affected neonates presenting with hyperinsulinaemic hypoglycaemia within the first week of life are usually macrosomic. The duration of diazoxide therapy can range from 3 months to 8 years in these children.32 Few children with a missense mutation in HNF1A have also

Panel 1: Diagnostic criteria for patients with hyperinsulinaemic hypoglycaemia9 Diagnostic criteria Plasma glucose <3 mmol/L with: • Detectable serum insulin • Detectable C-peptide (in endogenous hyperinsulinaemic hypoglycaemia) • Suppressed or low serum ketone bodies (3-β-hydroxybutyrate <2 mmol/L) • Suppressed or low serum concentrations of free fatty acids (<1·5 mmol/L) Supportive evidence (when diagnosis is in doubt or difficult) • Glucose infusion rate >8 mg/kg per min required to maintain normoglycaemia • Positive glycaemic (>1·5 mmol/L or 27 mg/dL) response to intramuscular or intravenous glucagon10 • Positive glycaemic response (>1·5 mmol/L or 27 mg/dL) to a subcutaneous dose of octreotide • Low serum concentrations of IGFBP-1 (insulin negatively regulates the expression of IGFBP-1) • Suppressed branched chain (leucine, isoleucine, and valine) aminoacids • Provocation tests (leucine loading or exercise testing) might be needed in some patients • A proinsulin concentration of >20 pmol/L • Absence of plasma and urine toxic screening including sulfonylureas and their metabolites • Normal plasma hydroxybutyrylcarnitine* • Normal ammonia concentration† • Elevated concentrations of counter-regulatory hormones‡ (cortisol >20 μg/dL [500 nmol/L]; growth hormone >7 ng/mL) *Raised in hyperinsulinaemic hypoglycaemia because of a mutation in the HADH gene (patient also has raised urinary 3-hydroxyglutarate). †Raised in hyperinsulinism-hyperammonaemia syndrome because of a mutation in the GDH gene. ‡Counter-regulatory hormone response can be blunted in spontaneous, particularly recurring, hypoglycaemia.

presented with hyperinsulinaemic hypoglycaemia. However, in a 2015 study, HNF1A mutations were the second most frequent genetic cause of congenital hyperinsulinism of infancy in the Czech Republic.33

SLC16A1 and exercise-induced hyperinsulinaemic hypoglycaemia Pyruvate and lactate are involved in regulating insulin secretion in response to glucose stimulation, and their transport into β cells involves monocarboxylate transporter 1, which is encoded by the SLC16A1 gene. Since both pyruvate and lactate are insulin secretagogues, under normal physiological conditions SLC16A1 is not expressed in the β cell, thus preventing pyruvate and lactate from stimulating insulin secretion. Exercise-induced hyperinsulinaemic hypoglycaemia is an autosomal dominant disorder characterised by inappropriate insulin secretion in response to vigorous physical exercise.34 Activating mutations in the promoter region of SLC16A1 have been linked to exercise-induced hyperinsulinaemic insulinaemia.35 These mutations lead to increased expression of the pyruvate transporter, increased pyruvate accumulation in the β cell, and increased insulin secretion. Avoidance of vigorous exercise will help prevent hypoglycaemic episodes in these patients, and they respond to therapy with diazoxide.34

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

3

Review

Panel 2: Causes of hyperinsulinaemic hypoglycaemia with onset in childhood, or at any age Childhood onset: transient hyperinsulinaemic hypoglycaemia • Mother with diabetes (before and during gestation) • Maternal use of sulfonylureas or intrapartum intravenous glucose infusion • Intrauterine growth restriction • Perinatal asphyxia • Rhesus haemolytic disease • Erythroblastosis fetalis • HNF4A, HNF1A mutation

Other causes: • Congenital central hypoventilation syndrome • Adenosine kinase deficiency14 • TRMT10A mutations15

Childhood onset: persistent hyperinsulinaemic hypoglycaemia • Congenital hyperinsulinism (genetic hyperinsulinaemic hypoglycaemia—ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, or UCP2 mutation) • Insulinoma

Adult onset: non-insulinoma pancreatogenous hypoglycaemia • Postprandial hypoglycaemia with morphological changes in pancreas similar to diffuse hyperinsulinaemic hypoglycaemia of infants

Childhood onset: syndromic or metabolic causes of hyperinsulinism13 Prenatal and postnatal overgrowth syndromes: • Beckwith-Wiedemann syndrome • Soto’s syndrome • Simpson-Golabi-Behmel syndrome • Perlman syndrome Chromosomal abnormality syndromes: • Trisomy 13 (Patau syndrome) • Mosaic Turner syndrome Postnatal growth failure syndromes: • Kabuki syndrome • Costello syndrome Contiguous gene deletion affecting the ABCC8 gene: • Usher syndrome Syndromes leading to abnormalities in calcium homoeostasis: • Timothy syndrome Insulin receptor mutation: • Insulin resistance syndrome (leprechaunism) Congenital disorders of glycosylation: • Types 1a, 1b, and 1d

Activating mutations in the gene encoding glucokinase Glucokinase is a key regulatory enzyme in the pancreatic β cell. It plays a crucial part in the regulation of insulin secretion and has been called the glucose sensor of pancreatic β cells.36 Given its important role in regulating glucose-induced insulin secretion, mutations in the gene encoding glucokinase (GCK) can cause both hyperglycaemia and hypoglycaemia. Glucokinase phosphorylates glucose to produce glucose-6-phosphate in the pancreatic β cell. Heterozygous activating GCK mutations increase the ATP:ADP ratio, leading to closure of the KATP channel, which then causes unregulated 4

Adult onset: postsurgical hyperinsulinaemic hypoglycaemia • After gastric bypass surgery Adult onset: non-islet cell tumour • Paraneoplastic syndrome due to tumours of mesenchymal or epithelial origin

Any age onset: postprandial hyperinsulinism • Dumping syndrome • Accelerated gastric emptying • Protein sensitivity • Insulin resistance syndromes • Insulin autoantibody syndrome • Congenital portosystemic shunt • Idiopathic or isolated postprandial hyperinsulinaemic hypoglycaemia Any age onset: insulinoma • Benign or malignant • Mutations in MEN1 gene • Mutations in YY1 gene Any age onset: factitious hyperinsulinaemic hypoglycaemia • Munchausen syndrome by proxy • Factitious disorder imposed on self Any age onset: drug-induced hyperinsulinism • Sulfonylureas • Glinides • Insulin Any age onset (mostly adult): autoimmune-induced hyperinsulinism • Autoantibodies against insulin

insulin secretion.37 Mutations in GCK can be inherited in an autosomal dominant manner or can occur spontaneously, with the severity of symptoms varying markedly within and between families.38 Most patients will respond to therapy with diazoxide, but some patients with severe diazoxide-unresponsive hyperinsulinaemic hypoglycaemia require a near-total pancreatectomy.39

Abnormalities in the expression of uncoupling protein 2 Uncoupling proteins (UCPs) regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is proposed to catalyse a mitochondrial

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

Review

Interpretation

Type of hypoglycaemia or hyperinsulinaemic hypoglycaemia

Fast stimulation test

Hypoglycaemic samples taken once blood glucose is <3·0 mmol/L (see panel 1 for expected results in hyperinsulinaemic hypoglycaemia)

To differentiate hyperinsulinaemic hypoglycaemia from other causes of hypoglycaemia

Glucagon administration (intramuscular or intravenous) at the time of hypoglycaemia10

Positive glycaemic response (>1·5 mmol/L or 27 mg/dL) indicates an insulin-mediated cause

All forms of hyperinsulinaemic hypoglycaemia Insulinomas: insulin values often > 160 μU/mL within 15–30 min, although some patients do not hypersecrete insulin after glucagon injection Non-islet cell tumours also present a positive glycaemic response

Octreotide administration (subcutaneous or intravenous) at the time of hypoglycaemia

Positive glycaemic response (>1·5 mmol/L or 27 mg/dL) indicates an insulin-mediated cause

All forms of hyperinsulinaemic hypoglycaemia

Protein load (containing leucine)54

Detectable insulin concentrations at a glucose concentration <3·0 mmol/L and compatible clinical symptomatology indicate an insulin-mediated cause that is triggered by aminoacids

Protein-sensitive hyperinsulinaemic hypoglycaemia

Exercise and pyruvate load34

Detectable insulin concentrations at a glucose concentration <3·0 mmol/L and compatible clinical symptomatology indicate pyruvate-stimulated and lactate-stimulated insulin release during exertion

Exercise-induced hyperinsulinaemic hypoglycaemia

Oral glucose tolerance (3 h or 5 h prolonged); Detectable insulin concentrations at a glucose concentration mixed meal (3 h or 5 h prolonged); <3·0 mmol/L and compatible clinical symptomatology indicate a meal standardised hyperglucidic breakfast55 component triggering insulin release (via incretin mediation)

Postprandial forms of hyperinsulinaemic hypoglycaemia

C-peptide suppression by intravenous insulin An abnormal result is a lower percentage decrease of C-peptide at 60 min Insulinoma administration56 compared with normative data, appropriately adjusted for the patient’s BMI and age Stimulation tests for diagnostic purposes need to be done while the patient is not taking medication that interferes with insulin production or action. These tests can also be employed for medication management.

Table 1: Stimulation tests for the diagnosis and differential diagnosis of hyperinsulinaemic hypoglycaemia

inner-membrane hydrogen leak that bypasses ATP synthase, thereby reducing cellular ATP content.40 It is highly expressed in islet β cells and its induction reduces glucose-stimulated insulin secretion by lowering the efficiency of oxidative phosphorylation in the β cell. As a result, loss of function in UCP2 enhances ATP synthesis and glucose-sensitive insulin secretion, leading to hyperinsulinaemia. UCP2-knockout mice exhibit biochemical evidence of hyperinsulinaemic hypoglycaemia, suggesting involvement of UCP2 in insulin secretion.41 Two unrelated children with hyperinsulinaemic hypoglycaemia were found to be heterozygous for mutated forms of the gene encoding UCP2; they had both inherited these gene variants from a parent.42 Functional assays in yeast and in cultured insulinsecreting cells revealed impaired activity of the UCP2 protein encoded by the mutated genes carried by these children, suggesting that these variants might lead to unregulated insulin secretion.42 However, the role of UCP2 in patients with hyperinsulinaemic hypoglycaemia is still unclear and further studies are required.

Somatic overexpression of hexokinase 1 Hexokinase catalyses the first step in glucose metabolism and uses ATP for the phosphorylation of glucose to glucose-6-phosphate. Four different forms of hexokinase, HK I, HK II, HK III, and HK IV, are encoded by different genes and are expressed in mammalian tissues. Among these, HK I is the predominant glucose-phosphorylating enzyme. In one large family with dominant hyperinsulinaemic hypoglycaemia, linkage analysis mapped the responsible locus to chromosome 10q21-22, a region

containing 48 genes.43 Three novel non-coding variants were found in the gene encoding HK I, raising the possibility of a mutation that interferes with the normal suppression of HK1 in β cells. Further evidence to support the role of HK I in the pathophysiology of hyperinsulinaemic hypoglycaemia comes from studying a subset of patients with hyperinsulinaemic hypoglycaemia in whom the pancreatic histology was atypical, with hyperfunctional islets confined to a few lobules and hypofunctional islets present throughout the rest of the pancreas.44 Studies of insulin secretion in these patients showed marked increases in insulin secretion in response to suboptimal glucose levels (1 mmol/L) and immunohistochemistry showed increased expression of the enzyme HK I.

Postprandial hyperinsulinaemic hypoglycaemia Development of hypoglycaemia within a few hours of meal ingestion is termed postprandial hyperinsulinaemic hypoglycaemia. One of the most common causes of this disorder is so-called dumping syndrome after a Nissen’s fundoplication or gastric bypass surgery.45 Children with postprandial hyperinsulinaemic hypoglycaemia after Nissen’s fundoplication can have abnormally exaggerated secretion of glucagon-like peptide 1 (GLP-1), which subsequently leads to excessive insulin secretion and hypoglycaemia.46 Dumping syndrome is usually noted soon after the surgery, but hyperinsulinaemic hypoglycaemia can present after several months to years (usually >1 year) of gastric bypass surgery.47 Other causes of postprandial hyperinsulinaemic hypoglycaemia include sensitivity to protein in the meal

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

5

Review

(linked to mutations in KCNJ11, ABCC8, HADH, and GLUD1 genes),9 accelerated gastric emptying,48 insulin resistance syndrome, and insulin autoimmune syndrome49 (ie, insulin autoantibodies in people not previously exposed to exogenous insulin). An exceptionally rare case of postprandial hyperinsulinaemic hypoglycaemia due to a congenital portosystemic shunt was reported in an infant.50 Not uncommonly, postprandial hyperinsulinaemic hypoglycaemia presents in people after all these causes have been excluded. This disease is then classified as idiopathic, isolated, or even so-called reactive hypoglycaemia, although the latter term remains controversial.48 The postulated underlying mechanisms involve hyperinsulinaemia stimulated by GLP-151 and abnormal sensitivity to the actions of insulin, glucagon,52 and β-adrenergic drugs.53 The diagnostic tests for postprandial hyperinsulinaemic hypoglycaemia are presented in table 1.

Other causes of hyperinsulinaemic hypoglycaemia Insulinoma Insulinoma is a rare cause of fasting or postprandial hyperinsulinaemic hypoglycaemia, but should be considered in the differential diagnosis, especially in older children, adolescents, or adults presenting with hyperinsulinaemic hypoglycaemia.57 Insulinomas are usually solitary, benign, and occur sporadically. Family history is very important to the diagnosis of familial cases of multiple endocrine neoplasia type 1 because insulinoma can be involved in 8% of cases.58 Recurrent somatic T372R mutations in YY1 have been found by whole exome sequencing of ten sporadic insulinomas.59 In some patients, insulinomas show distinct defects in insulin secretion that are attributed to the undue expression of HK I.60 Although malignant insulinoma is rare (6–10% of all cases), insulinomas in multiple endocrine neoplasia type 1 are more likely to be multifocal and malignant than those that occur sporadically.58 Given the different management strategies, differentiation of malignant and benign insulinoma is crucial. However, differentiation of a malignant insulinoma from a benign one on the basis of clinical or histological characteristics is difficult. Metastasis is generally considered the most reliable and definitive criterion.61 The other criteria are tumour size, growth, and vascular invasion; the percentage of mitoses; and proliferative index.61

Munchausen syndrome by proxy Factitious or induced hyperinsulinaemic hypoglycaemia should be considered as a differential diagnosis in cases when no clear explanation of hypoglycaemia exists. Induced hyperinsulinaemic hypoglycaemia is caused by exogenous administration of insulin or oral anti-diabetic drugs (sulfonylureas). Reports of patients that have been misdiagnosed and undergone pancreatectomy exist.62 6

Post-gastric bypass surgery A common complication of gastric bypass surgery is socalled dumping syndrome, whereby food moves too quickly from the stomach to the small bowel. Dumping syndrome is a form of postprandial hyperinsulinaemic hypoglycaemia observed in children who typically undergo a Nissen’s fundoplication. However, postprandial hyperinsulinaemic hypoglycaemia can occur in patients who have undergone Roux-en-Y gastric bypass for extreme obesity.63 There is no clear underlying mechanism for this disorder, but one of the proposed mechanisms involves enlargement of pancreatic islet cells, budding of β cells from ductal epithelium, and development of islets in apposition to ducts after surgery.64 Non-insulinoma pancreatogenous hypoglycaemia syndrome leads to postprandial hypoglycaemia in patients without a previous gastric bypass procedure, and is histologically characterised by pancreatic islet hyperplasia.63 The syndrome is characterised by neuroglycopenic episodes of hyperinsulinaemic hypoglycaemia, usually within 4 h of meal ingestion and negative 72 h fasts. These patients show positive selective arterial calcium stimulation tests indicative of pancreatic β-cell hyperfunction.65

Syndromes associated with hyperinsulinaemic hypoglycaemia Hyperinsulinaemic hypoglycaemia has been reported in a large number of syndromes (panel 2). The most common syndrome causing hyperinsulinaemic hypoglycaemia in childhood is Beckwith-Wiedemann syndrome. Almost half of all children with BeckwithWiedemann syndrome will develop hyperinsulinaemic hypoglycaemia. In most of these cases, hyperinsulinaemic hypoglycaemia will be transient; however, in approximately 5% of them, it will be severe, medically unresponsive, and might require a near-total pancreatectomy.66

Histological subtypes of hyperinsulinaemic hypoglycaemia and imaging studies Overview The congenital forms of hyperinsulinaemic hypoglycaemia are classified histologically into two major subgroups, namely diffuse and focal disease (figure 2). The diffuse form is typically characterised by hyperchromatic β-cell enlargement and hyperplasia. By contrast, in the focal form there is nodular hyperplasia with acinar-ductular complexes confined to a single region of the pancreas, with normal surrounding pancreas. Diffuse hyperinsulinaemic hypoglycaemia occurs in about 40–50% of patients and is due to biallelic recessive or dominant mutations in the genes ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, and UCP2. The focal form is found in approximately 50% of patients with hyperinsulinaemic hypoglycaemia. The focal form has a unique cause and involves two independent events—the inheritance of a

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

Review

paternal mutation in ABCC8 or KCNJ11 (located in the 11p15.1 region), and somatic loss of the maternal 11p15 allele including the ABCC8 or KCNJ11 region within the focal lesion.67 The maternal loss of heterozygosity leads to imbalance between the maternally expressed tumour suppressor genes H19 and CDKN1C, and the paternally expressed growth factor IGF2.68 Hence maternal loss of heterozygosity as a result of paternal uniparental disomy will lead to the unmasking of the paternally inherited KATP channel mutation. It is important to differentiate between diffuse and focal disease before surgery. Localisation of focal lesions by MRI and CT scans has not been possible. Because of recent advances in the management of hyperinsulinaemic hypoglycaemia, including rapid genetic mutation analysis in ABCC8 and KCNJ11, and 6-[fluoride-18]fluoro-levodopa (¹⁸F-DOPA)-PET-CT scanning, it is now possible to discriminate between focal and diffuse disease with high sensitivity and specificity.69–72 Genetic mutation analysis will help to predict focal and diffuse disease. However, imaging with the ¹⁸F-DOPA-PET-CT scan should be performed in all patients (including patients with medically unresponsive disease without a mutation) who are thought to have a focal lesion, to identify its precise location before surgery. In patients with biallelic recessive or dominant ABCC8 or KCNJ11 mutations, there is no need to do scanning with ¹⁸F-DOPA-PET-CT, since this genotype is consistent with diffuse histology.

A

B

C

D

E

F

G

H

I

J

K

Insulinoma İnsulinomas are usually small (<2 cm in diameter), intrapancreatic, and solitary, with equal distribution throughout the pancreas (figure 2).73 A few tumours associated with multiple endocrine neoplasia type 1 can be multifocal.58 Preoperative localisation of an insulinoma is recommended before any planned surgical procedure. Evolving techniques in CT, MRI, endoscopic ultrasonography, and nuclear medicine, such as dualenergy CT, diffusion-weighted MRI, liver-specific magnetic resonance contrast agents, and new nuclear medicine agents (GLP-1 receptor imaging), offer new ways to visualise, and ultimately manage, these tumours.74 Transabdominal ultrasonography is easily applicable and widely available. However, insulinomas are usually small neuroendocrine tumours and the sensitivity of ultrasonography to localise them is frequently unsatisfactory. The reported values range from 9% to 64%.75 Therefore, it is not recommended as a first-line imaging method. To increase the sensitivity of ultrasonography, an invasive method called endoscopic ultrasonography has been used. Sensitivity of endoscopic ultrasonography has been reported to be up to 94% (range 57–94%).76 Abdominal CT is the first-line option to visualise an insulinoma. Despite being able to perform it easily and safely, its diagnostic sensitivity is poor, ranging from 33% to 64%.77 New advanced techniques have improved

Figure 2: Imaging of congenital hyperinsulinaemic hypoglycaemia and insulinoma Representative images of the PET-CT scans for (A–B) focal area(s) in congenital hyperinsulinism of infancy. There is increased tracer uptake in the head of the pancreas, highlighting a focal lesion (arrows: standard uptake value— max 7·9). A slightly less intense uptake is also seen in the uncinate process (standard uptake value—max 5) with low-grade activity in the body (standard uptake value—max 3·6). Tracer distribution elsewhere is unremarkable. Conclusion: persistent focal uptake in the head and uncinate process of the pancreas. (C–D) Diffuse disease in congenital hyperinsulinism of infancy (arrows show uptake of levodopa). (E–F) Representative MRI scan images of an insulinoma (arrows) within the symphysis of the pancreas. Representative pancreatic tissue sections from a (G) focal lesion, (H) diffuse disease, and (I) insulinoma section, 10× magnification. All tissue sections were stained with haematoxylin and eosin and imaged using a high-powered microscope. Schematic appearance of (J) focal and (K) diffuse β-cell hyperplasia. Focal lesions can be superficial, deep parenchymal, or tentacled (star shape, J).

the sensitivity and specificity of CT, and have enabled visualisation of 95% of insulinomas.78 For example, thin-section helical CT scanning is superior to conventional methods in the detection of insulinomas.78,79 A combination of endoscopic ultrasonography and biphasic thin-section helical CT can improve the overall diagnostic sensitivity of the detection of pancreatic head and body lesions by up to 100%, and by 37–60% for pancreatic tail lesions.76 Abdominal MRI is a safe, non-invasive, and rapid method to detect an insulinoma. Although it is still

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

7

Review

accepted as a second-line method to localise an insulinoma following CT, advances that increase the quality of imaging, thereby providing diagnostic sensitivity up to 95%, suggest that MRI is more reliable than CT for the detection of small insulinomas.80 Studies show that MRI enables preoperative localisation of small pancreatic insulinomas and determination of metastasis better than other preoperative imaging techniques.81 Small insulinomas can be quite difficult to localise. Insulinomas exhibit a very high density of GLP-1 receptor expression in vitro, and this has been used as a specific target for in-vivo receptor radiolabelling. GLP-1 receptor imaging has now been successfully reported for the localisation of small insulinomas,82 and thus represents an innovative, non-invasive diagnostic approach that successfully localises small insulinomas, which can be difficult to localise with conventional imaging. Despite the use of these imaging techniques, there are some insulinomas that will still not be detected. In these cases, it is recommended that patients undergo selective

Route

intra-arterial calcium stimulation with hepatic venous sampling. This is an accurate and safe method for the preoperative localisation of insulinomas.83,84

Management Overview There are specific tests for the differential diagnosis of hyperinsulinaemic hypoglycaemia (table 1). Table 2 highlights the therapies used in the management of hyperinsulinaemic hypoglycaemia, which include both medical and surgical therapies. The aim of treatment is to attain normal blood glucose concentration (>3·5 mmol/L) either by increasing glucose intake (via intravenous or oral high calorie carbohydrate diet) or by augmenting endogenous glucose production by administering hormones such as glucagon. Normoglycaemia is also achieved by suppressing insulin production from β cells by using drugs (diazoxide, octreotide, and others), or by doing a pancreatectomy. For postprandial hyperinsulinaemic hypoglycaemia, dietary modification is the

Dose

Mechanism of action

Side-effects

Conventional drugs Diazoxide

Oral

5–20 mg/kg per day, in three divided doses

Binds SUR1 subunit of KATP channels, opens the channels, and inhibits insulin secretion; needs intact KATP channel activity to work

Common: water and salt retention, hypertrichosis, loss of appetite; rare: cardiac failure, hyperuricaemia, blood dyscrasias (eg, bone marrow suppression, anaemia, eosinophilia), paradoxical hypoglycaemia

Chlorothiazide

Oral

7–10 mg/kg per day, in two divided doses

Prevents fluid retention, synergistic effects with diazoxide on KATP channels to inhibit insulin secretion

Hyponatraemia, hypokalaemia

Nifedipine

Oral

0·25–2·5 mg/kg per day, in two to three divided doses

Inhibits calcium channels in the β-cell membrane

Hypotension

Acarbose

Oral

6·25–300 mg/day, in three divided doses

Intestinal α-glucosidase inhibitor; inhibits intestinal cleavage of complex carbohydrate to glucose, thereby lowers absorption rate of glucose; effective in postprandial hyperinsulinaemic hypoglycaemia

Flatulence, diarrhoea, intestinal discomfort, elevated liver enzyme concentrations

Octreotide

Subcutaenous

5–35 μg/kg per day, in three to four divided doses, or continuous subcutaneous infusion

Activation of somatostatin receptor-2 and somatostatin receptor-5 inhibits calcium mobilisation and acetylcholine activity, decreases insulin gene promoter activity, and reduces insulin biosynthesis and secretion

Acute: anorexia, nausea, abdominal discomfort, diarrhoea, hepatitis, elevated liver enzyme concentrations, long QT syndrome, tachyphylaxis, necrotising enterocolitis; long-term: decreased intestinal motility, bile sludge and gallstones, suppressed pituitary hormones (growth hormone, thyroid-stimulating hormone)

Glucagon

Subcutaneous or intramuscular bolus, or subcutaneous or intravenous infusion

0·02 mg/kg per dose or infusion of 5–10 μg/kg per h

G-protein-coupled activation of adenylate cyclase increases cyclic AMP, and induces glycogenolysis and gluconeogenesis

Nausea, vomiting, skin rash, and rebound hypoglycaemia in high doses (>20 μg/kg per h) due to paradoxical activation of insulin secretion

Sirolimus (rapamycin, everolimus)

Oral

Starting dose of 1 mg/m² per day, and dose adjusted to blood concentration (usually to keep between 5 and 15 ng/mL); dose adjusted according to blood concentration, usually to keep between 5 and 15 ng/mL

mTOR inhibitor; inhibits insulin release Immune suppression, mucositis, hyperlipidaemia, elevation of and β-cell proliferation through different liver enzyme concentrations, thrombocytosis, impaired mechanisms, which have not been immune response to BCG vaccine clarified

Long-acting octreotide or lanreotide

Deep intramuscular or subcutaneous

Doses given once every 4 weeks or 15–60 mg every 4 weeks

Long-acting somatostatin analogues with similar effects to daily multiple-dose octreotide

New drugs

Similar to daily multiple injection octreotide; however, long-term follow-up is not known

SUR1=sulfonylurea receptor 1. KATP=ATP-sensitive potassium channel.

Table 2: Drugs for medical therapy of hyperinsulinaemic hypoglycaemia

8

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

Review

first step of management, which includes frequent feeding of a low carbohydrate (avoiding short-acting carbohydrates), high-protein diet, and addition of fibre and fat emulsions.52 Panel 3 summarises the different treatment strategies and follow-up for patients with hyperinsulinaemic hypoglycaemia.

Emergency management of hypoglycaemia Prompt treatment with 1–2 mL/kg of 10% glucose can be life-saving in patients presenting with symptomatic (eg, seizure) hypoglycaemia, or who are unable to achieve normoglycaemia by oral feeds or by oral glucose gel. Subsequently, to maintain blood glucose greater than 3·5 mmol/L, intravenous glucose infusion (glucose rate of over 6–8 mg/kg per min) should be initiated. Central venous line insertion might be required to administer a high concentration glucose solution while investigating and planning long-term management. Intramuscular glucagon increases the blood glucose concentration within a few minutes and can be life-

saving in emergency situations such as symptomatic hypoglycaemia, hypoglycaemic seizures, or difficult intravenous access.85 Glucagon immediately releases hepatic glucose stores by induction of glycogenolysis and stimulates gluconeogenesis, ketogenesis, and lipolysis. Subcutaneous infusion of glucagon has been used as a long-term therapy in hyperinsulinaemic hypoglycaemia,86 but practical issues exist with delivering subcutaneous infusion of glucagon at home.

Medical therapy for long-term management The first-line treatment for hyperinsulinaemic hypoglycaemia is with oral diazoxide (at 5–20 mg/kg per day), which activates KATP channels. The side-effects associated with diazoxide include hypotension, tachycardia, and sodium and fluid retention. Since diazoxide has an antidiuretic action it can be combined with a diuretic to reduce the side-effect of fluid retention, which is a commonly observed feature in patients with hyperinsulinaemic hypoglycaemia who are receiving large volumes of intravenous

Panel 3: Summary of treatment strategies and follow-up for patients with hyperinsulinaemic hypoglycaemia Emergency treatment • Intravenous glucose infusion (can require central venous catheterisation) • Glucagon injection • Frequent feeding Long-term medical treatment • Diazoxide with or without chlorothiazide • Nifedipine • Octreotide • Acarbose • New drugs: long-acting octreotide and long-acting somatostatin analogue (lanreotide); mTOR inhibitors (sirolimus, everolimus); GLP-1 antagonists—eg, exendin-(9-39) Dietary adjustments • Individualised feeding plan adjusted by fasting tolerance • Assessment of protein intake and modify protein in diet if required • Feeding with high calorie and carbohydrate solutions (eg, Vitajoule, Vitflo Ltd) • Overnight continuous or bolus intra-gastric feeding • Cornstarch (1–2 g/kg per dose; usually overnight) Surgical management • Differentiation of histological subtype • Lesionectomy for focal disease (laparoscopy or laparotomy) • Pancreatectomy for diffuse disease (laparoscopic or open) • Partial pancreatectomy with medical therapy • Subtotal pancreatectomy (removal of up to 95% of pancreas) • Near-total pancreatectomy (removal of 95–98% of pancreas)

• Surgery for insulinoma (laparoscopic or open) • Enucleation • Resection • Metastatectomy • Adjunctive therapies for malignant insulinoma • Hepatic arterial embolisation • Chemoembolisation • Local destruction • Systemic chemotherapy • Correction of gastric bypass that caused dumping syndrome and postprandial hyperinsulinaemic hypoglycaemia • Assessment of postsurgical complications and their management • Insulin therapy for diabetes • Replacement of pancreatic enzymes for exocrine pancreatic insufficiency Other surgical interventions (if required) • Surgery for gastro-oesophageal reflux • Percutaneous endoscopic gastrostomy Follow-up • Growth • Neurological outcome • Drug side-effects • Fasting tolerance and adjustment of drug doses • Postsurgical complications (diabetes and exocrine pancreas insufficiency) • Recurring or relapsing malignant insulinomas (assessment and imaging)

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

9

Review

fluids to control their hypoglycaemia. Diazoxide treatment has also been associated with the development of pulmonary hypertension, especially in the newborn period.87 Nifedipine has been used to treat hyperinsulinaemic hypoglycaemia88 and is known to specifically inhibit the activity of L-type voltage-gated calcium channels. At least 11 case reports of nifedipine to treat hyperinsulinaemic hypoglycaemia, either alone or in combination with feeds or octreotide, exist. Müller and colleagues89 specifically addressed the question of whether nifedipine should be used to treat hyperinsulinaemic hypoglycaemia, and concluded that it should be used before any planned pancreatic surgery. However, a large, multicentre, randomised clinical trial is required to fully elucidate the effectiveness and safety of nifedipine for the treatment of hyperinsulinaemic hypoglycaemia, and this has yet to be done. Somatostatin analogues are used in diazoxide-unresponsive hyperinsuliaemic hypoglycaemia.90 The halflife of natural somatostatin is only 2–3 min. Octreotide is an eight aminoacid analogue polypeptide of somatostatin, and it has a substantially longer half-life than somatostatin (113 min vs 2–3 min). After subcutaneous administration of octreotide, the serum concentration is reached within 30 min.91 Patients with hyperinsulinaemic hypoglycaemia usually require high doses of octreotide (5–35 μg/kg per day) and they could become insensitive to the drug. The mechanism of action for octreotide is based on its binding to G-protein-coupled somatostatin receptor type-2 and somatostatin receptor type-5 located on pancreatic β cells; this binding in turn prevents the influx of calcium through the voltage-gated calcium channels. The inhibition of calcium entry prevents the release of insulin. Octreotide has the potential to become ineffective over time because of internalisation of the somatostatin receptors, which results in the patients gradually becoming desensitised to the drug.92 Acarbose inhibits intestinal α-glucosidase enzymes, delaying the absorption of glucose into the bloodstream and therefore limiting the postprandial glucose and insulin surge. It is used in postprandial hyperinsulinaemic hypoglycaemia as the first pharmacological step.93

Potential new therapies Lanreotide and long-acting octreotide have been developed with longer activity than octreotide, and have the potential to be better than the current drugs for hyperinsulinaemic hypoglycaemia. In a series of case reports published on the use of long-acting octreotide94 and lanreotide95 in hyperinsulinaemic hypoglycaemia, patients required one injection every 28 days. Moreover, Kühnen and colleagues96 have reported the use of lanreotide treatment in six children with the disorder. The dose used in this group was 90–120 mg every 4 weeks in children aged 7 months to 4·5 years. All children had a significant reduction in hypoglycaemic episodes, indicating that the effect on glycaemic control was improved. 10

mTOR is a serine/threonine kinase that regulates cellular functions such as protein synthesis, transcription, and growth. The mTOR pathway has been implicated in β-cell growth and abnormal secretion of insulin in patients with insulinoma.97,98 Hence, mTOR inhibitors are widely used to treat neoplasms. β-cell hyperplasia in diffuse hyperinsulinaemic hypoglycaemia can result from activation of the mTOR pathway.99 Particularly, mTOR complex 1 can promote glucose uptake and metabolism via hypoxia-inducible factor-1-α.100 Treatment with mTOR inhibitors has been shown to reduce β-cell proliferation and insulin production. The effectiveness of the mTOR inhibitor sirolimus was assessed in one study101 in which four patients with severe diffuse hyperinsulinaemic hypoglycaemia were treated. All four patients had improved glycaemic responses and fasting tolerance, in all patients a near total pancreatectomy was avoided, and there were no major side-effects. Since the original study, several more case reports have shown the effectiveness of sirolimus treatment in newborn babies with hyperinsulinaemic hypoglycaemia.102,103 Sirolimus has also been used to treat an 8-year-old boy affected by a severe form of hyperinsulinaemic hypoglycaemia due to a biallelic heterozygous ABCC8 mutation. There was a pronounced improvement in his regulation of blood glucose concentration and quality of life, with no serious adverse events after 6 months of follow-up.104 The possible molecular mechanisms of sirolimus action in patients with hyperinsulinaemic hypoglycaemia is not clear, but might include inhibition of β-cell proliferation, inhibition of insulin production,105 and induction of peripheral insulin resistance.97 GLP-1 is an incretin hormone released postprandially to induce insulinotropic effects.106 GLP-1 functions by binding to its receptor to promote glucose-dependent insulin secretion, β-cell proliferation, and increased insulin synthesis and secretion, both via and independently of cyclic AMP and protein kinase A activation.107 GLP-1 receptor agonists are used for the treatment of type 2 diabetes.108 Studies in SUR1 knockout mice have shown that the GLP-1 receptor is constitutively active in β cells and that cyclic AMP plays a key role in KATP-independent insulin secretion.109 SUR1 knockout mice treated with a GLP-1 receptor antagonist (exendin-[9–39]) had significantly higher blood glucose concentrations than did mice treated with placebo.109 In β cells from these mice, exendin-(9–39) blocked amino acid-stimulated insulin secretion by lowering the concentration of cyclic AMP. The observation that antagonism of the GLP-1 receptor with exendin-(9–39) can raise blood glucose concentrations in mice has important implications for managing patients with hyperinsulinaemic hypoglycaemia due to defects in KATP channel genes. Calabria and colleagues110 examined the effects of exendin-(9–39) infusion on fasting blood glucose in nine adult patients with KATP channel defects. In all patients, the mean nadir blood glucose and glucose area

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

Review

under the curve were significantly increased by the infusion. These observations suggest that the GLP-1 receptor plays a key part in regulating fasting blood glucose levels in patients with KATP channel defects.

Surgical therapy and preoperative investigations Surgical management of congenital hyperinsulinaemic hypoglycaemia Once the focal lesion is completely excised, cure is achieved in most patients without development of postoperative complications such as diabetes and exocrine pancreatic insufficiency. A multidisciplinary team (endocrinology, radiology, and histopathology) should be involved in managing patients with focal and diffuse disease.111 Complete excision of the focal lesion requires intraoperative biopsies to look for abnormal cells at the lesion margin. Large focal lesions in the pancreatic head might not be cured with local resection alone, and could need pancreatic head resection with Roux-en-Y pancreaticojejunostomy.112 However, patients with a focal lesion in the head of the pancreas have been treated by local resection of the pancreatic head and preservation of the main pancreatic duct to avoid pancreaticojejunostomy.113 Near-total pancreatectomy (95–98% of the pancreas) is required in children who do not respond to medical therapy for diffuse hyperinsulinaemic hypoglycaemia. A small amount of pancreatic tissue is left between the duodenum and the common bile duct. A few studies have shown that up to 50% of patients continue to have hypoglycaemia after surgery or develop postoperative diabetes and exocrine pancreatic insufficiency.114,115 Laparoscopic pancreatectomy is now a preferred option for surgical treatment in management of children with hyperinsulinaemic hypoglycaemia.116,117

Surgery for insulinoma in adults Surgical removal of the tumour is the mainstay of therapy for childhood and adult insulinoma, and the overall cure rate is up to 98% after surgery.118 Prognosis depends on the tumour stage at the time of presentation and success rate of complete resection. The mode of surgery depends on the tumour size, localisation, and metastatic characteristics.119 For small benign tumours with no metastasis that are located at least 2–3 mm from the main pancreatic duct, a limited enucleation should be performed. A tumour that is invading the pancreatic duct or great vessels with a risk of malignancy and lymph node invasion, and that is compressing the distal pancreatic duct, might require a more extensive surgical resection. The surgical resection procedure depends on the site of the insulinoma and includes either mid-body pancreatectomy, distal pancreatectomy, or pylorus-preserving Whipple procedure.

Conclusion The accessibility of rapid molecular genetics testing for hyperinsulinaemic hypoglycaemia, the application of

Search strategy and selection criteria We identified references for this Review using Pubmed and MEDLINE (OVID), and selected all resources for articles published between Jan 1, 1980, and June 30, 2016. We used the MeSH (Medical Subject Heading) terms “congenital hyperinsulinism”, “persistent hyperinsulinemic hypoglycaemia of infancy”, “hyperinsulinemic hypoglycaemia in children”, and “hyperinsulinemic hypoglycaemia in adults”. These terms were then combined and either of these terms used in any articles were included. Subsequent MeSH terms we included were “genetics”, “pathophysiology”, “treatment”, "children and adults", and "hyperinsulinism". Articles published in English were included.

novel imaging techniques, the use of novel medical therapies, and advances in laparoscopic surgery have radically changed the clinical approach to patients with hyperinsulinaemic hypoglycaemia. Despite these advances, the molecular basis of hyperinsulinaemic hypoglycaemia is still unclear in 50% of patients. Imaging with ¹⁸F-DOPA-PET-CT of focal hyperinsulinaemic hypoglycaemia is not easily available in all centres, and patients with diffuse hyperinsulinaemic hypoglycaemia who do not respond to any drugs exist. Using state-of-the-art techniques in genomics, proteomics, and metabolomics, future research needs to focus on understanding the genetic basis of hyperinsulinaemic hypoglycaemia in the remaining 50% of patients, developing highly sensitive and easily accessible imaging techniques for localising focal forms of hyperinsulinaemic hypoglycaemia and insulinoma, and developing new medical therapies for patients with diffuse hyperinsulinaemic hypoglycaemia, so that a neartotal pancreatectomy can be avoided. Contributors All authors were involved in the literature review. PS wrote sections on clinical presentation, diagnosis, and management, and helped to sort the references. SAR wrote sections on postprandial hypoglycaemia and helped with figure creation. HD and MG wrote the introduction, helped to write about the molecular mechanisms, and contributed to the creation of some of the figures. KH conceptualised the Review, helped write all of the sections, and revised the manuscript. Declaration of interests We declare no competing interests. References 1 Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 1984; 312: 446–48. 2 Aguilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268: 423–26. 3 Dunne MJ, Kane C, Shepherd RM, et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997; 336: 703–76. 4 Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000; 82: F98–107. 5 Rahman SA, Nessa A, Hussain K. Molecular mechanisms of congenital hyperinsulinism. J Mol Endocrinol 2015; 54: R119–29.

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

11

Review

6

7

8

9

10

11

12

13 14

15

16

17

18

19

20

21

22

23

24

25

26

27

12

Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94: 709–28. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management. J Pediatr 2015; 166: 1520–25. Thornton PS, Stanley CA, De Leon DD, 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. Senniappan S, Shanti B, James C, Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis 2012; 35: 589–601. Finegold DN, Stanley CA, Baker L. Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 1980; 96: 257–59. De León DD, Stanley CA. Determination of insulin for the diagnosis of hyperinsulinemic hypoglycemia. Best Pract Res Clin Endocrinol Metab 2013; 27: 763–69. Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin Chem 2008; 54: 256–63. Kapoor RR, James C, Hussain K. Hyperinsulinism in developmental syndromes. Endocr Dev 2009; 14: 95–113. Staufner C, Lindner M, Dionisi-Vici C, et al. Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options. J Inherit Metab Dis 2016; 39: 273–83. Gillis D, Krishnamohan A, Yaacov B, Shaag A, Jackman JE, Elpeleg O. TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly. J Med Genet 2014; 51: 581–86. Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995; 268: 426–29. Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996; 5: 1809–12. Aguilar-Bryan L, Bryan J. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 1999; 20: 101–35. Pinney SE, MacMullen C, Becker S, et al. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 2008; 118: 2877–86. Flanagan SE, Kapoor RR, Banerjee I, et al. Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. Clin Genet 2011; 79: 582–87. Li M, Li C, Allen A, Stanley CA, Smith TJ. Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis. Neurochem Res 2014; 39: 433–45. Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998; 338: 1352–57. Kapoor RR, Flanagan SE, Fulton P, et al. Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations. Eur J Endocrinol 2009; 161: 731–35. Meissner T, Mayatepek E, Kinner M, Santer R. Urinary alpha-ketoglutarate is elevated in patients with hyperinsulinism-hyperammonemia syndrome. Clin Chim Acta 2004; 341: 23–26. Vredendaal PJ, van den Berg IE, Malingré HE, Stroobants AK, Olde Weghuis DE, Berger R. Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence. Biochem Biophys Res Commun 1996; 223: 718–23. Clayton PT, Eaton S, Aynsley-Green A, et al. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 2001; 108: 457–65. Molven A, Matre GE, Duran M, et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 2004; 53: 221–27.

28

29

30

31

32

33

34

35

36 37

38

39

40

41

42

43

44

45

46

47

48

49

Li C, Chen P, Palladino A, et al. Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem 2010; 285: 31806–18. Babiker O, Flanagan SE, Ellard S, Al Girim H, Hussain K, Senniappan S. Protein-induced hyperinsulinaemic hypoglycaemia due to a homozygous HADH mutation in three siblings of a Saudi family. J Pediatr Endocrinol Metab 2015; 28: 1073–77. Gupta RK, Vatamaniuk MZ, Lee CS, et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 2005; 115: 1006–15. Pearson ER, Boj SF, Steele AM, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007; 4: e118. Kapoor RR, Locke J, Colclough K, et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes 2008; 57: 1659–63. Rozenkova K, Malikova J, Nessa A, et al. High incidence of heterozygous ABCC8 and HNF1A mutations in Czech patients with congenital hyperinsulinism. J Clin Endocrinol Metab 2015; 100: E1540–49. Otonkoski T, Kaminen N, Ustinov J, et al. Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 2003; 52: 199–204. Otonkoski T, Jiao H, Kaminen-Ahola N, et al. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet 2007; 81: 467–74. Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes 2002; 51 (suppl 3): S394–404. Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998; 338: 226–30. Wabitsch M, Lahr G, Van de Bunt M, et al. Heterogeneity in disease severity in a family with a novel G68V GCK activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy. Diabet Med 2007; 24: 1393–99. Cuesta-Muñoz AL, Huopio H, Otonkoski T, et al. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 2004; 53: 2164–68. Chan CB, De Leo D, Joseph JW, et al. Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 2001; 50: 1302–10. Zhang CY, Baffy G, Perret P, et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 2001; 105: 745–55. González-Barroso MM, Giurgea I, Bouillaud F, et al. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLoS One 2008; 3: e3850. Pinney SE, Ganapathy K, Bradfield J, et al. Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr 2013; 80: 18–27. Henquin JC, Sempoux C, Marchandise J, et al. Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of β-cells. Diabetes 2013; 62: 1689–96. Bufler P, Ehringhaus C, Koletzko S. Dumping syndrome: a common problem following Nissen fundoplication in young children. Pediatr Surg Int 2001; 17: 351–55. Palladino AA, Sayed S, Levitt Katz LE, Gallagher PR, De León DD. Increased glucagon-like peptide-1 secretion and postprandial hypoglycemia in children after Nissen fundoplication. J Clin Endocrinol Metab 2009; 94: 39–44. Foster-Schubert KE. Hypoglycemia complicating bariatric surgery: incidence and mechanisms. Curr Opin Endocrinol Diabetes Obes 2011; 18: 129–33. Middleton SJ, Balan K. Idiopathic accelerated gastric emptying presenting in adults with post-prandial diarrhea and reactive hypoglycemia: a case series. J Med Case Rep 2012; 6: 132. Lupsa BC, Chong AY, Cochran EK, Soos MA, Semple RK, Gorden P. Autoimmune forms of hypoglycemia. Medicine (Baltimore) 2009; 88: 141–53.

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

Review

50

51

52 53

54

55

56

57 58

59 60

61

62

63

64

65

66 67

68

69

70

71

72

Senniappan S, Pitt K, Shah P, et al. Postprandial hyperinsulinaemic hypoglycaemia secondary to a congenital portosystemic shunt. Horm Res Paediatr 2015; 83: 217–20. Owada K, Wasada T, Miyazono Y, et al. Highly increased insulin secretion in a patient with postprandial hypoglycemia: role of glucagon-like peptide-1 (7-36) amide. Endocr J 1995; 42: 147–51. Brun JF, Fedou C, Mercier J. Postprandial reactive hypoglycemia. Diabetes Metab 2000; 26: 337–51. Berlin I, Grimaldi A, Landault C, Cesselin F, Puech AJ. Suspected postprandial hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional distress. J Clin Endocrinol Metab 1994; 79: 1428–33. 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: 383–89. Brun JF, Fédou C, Bouix O, Raynaud E, Orsetti A. Evaluation of a standardized hyperglucidic breakfast test in postprandial reactive hypoglycaemia. Diabetologia 1995; 38: 494–501. Service FJ, O’Brien PC, Kao PC, Young WF. C-peptide suppression test: effects of gender, age, and body mass index; implications for the diagnosis of insulinoma. J Clin Endocrinol Metab 1992; 74: 204–10. Shin JJ, Gorden P, Libutti SK. Insulinoma: pathophysiology, localization and management. Future Oncol 2010; 6: 229–37. Niina Y, Fujimori N, Nakamura T, et al. The current strategy for managing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1. Gut Liver 2012; 6: 287–94. Cao Y, Gao Z, Li L, et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun 2013; 4: 2810. Henquin JC, Nenquin M, Guiot Y, Rahier J, Sempoux C. Human insulinomas show distinct patterns of insulin secretion in vitro. Diabetes 2015; 64: 3543–53. Baudin E, Caron P, Lombard-Bohas C, et al. Malignant insulinoma: recommendations for characterisation and treatment. Ann Endocrinol (Paris) 2013; 74: 523–33. Giurgea I, Ulinski T, Touati G, et al. Factitious hyperinsulinism leading to pancreatectomy: severe forms of Munchausen syndrome by proxy. Pediatrics 2005; 116: e145–48. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 2005; 353: 249–54. Patti ME, McMahon G, Mun EC, et al. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia 2005; 48: 2236–40. Service FJ, Natt N, Thompson GB, et al. Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab 1999; 84: 1582–89. DeBaun MR, King AA, White N. Hypoglycemia in Beckwith-Wiedemann syndrome. Semin Perinatol 2000; 24: 164–71. Verkarre V, Fournet JC, de Lonlay P, et al. Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998; 102: 1286–91. Fournet JC, Mayaud C, de Lonlay P, et al. Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Am J Pathol 2001; 158: 2177–84. Otonkoski T, Näntö-Salonen K, Seppänen M, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006; 55: 13–18. Ribeiro MJ, Boddaert N, Delzescaux T, et al. Functional imaging of the pancreas: the role of [18F]fluoro-L-DOPA PET in the diagnosis of hyperinsulinism of infancy. Endocr Dev 2007; 12: 55–66. Barthlen W, Blankenstein O, Mau H, et al. Evaluation of [18F]fluoro-L-DOPA positron emission tomography-computed tomography for surgery in focal congenital hyperinsulinism. J Clin Endocrinol Metab 2008; 93: 869–75. Zani A, Nah SA, Ron O, et al. The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy. J Pediatr Surg 2011; 46: 204–08.

73 74

75 76

77 78

79

80

81 82

83

84

85

86

87

88

89

90

91

92

93 94

95

96

97

Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol 2013; 19: 829–37. Tamm EP, Bhosale P, Lee JH, Rohren EM. State-of-the-art imaging of pancreatic neuroendocrine tumors. Surg Oncol Clin N Am 2016; 25: 375–400. Rockall AG, Reznek RH. Imaging of neuroendocrine tumours (CT/ MR/US). Best Pract Res Clin Endocrinol Metab 2007; 21: 43–68. Gouya H, Vignaux O, Augui J, et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol 2003; 181: 987–92. Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg 2006; 93: 264–75. King AD, Ko GT, Yeung VT, Chow CC, Griffith J, Cockram CS. Dual phase spiral CT in the detection of small insulinomas of the pancreas. Br J Radiol 1998; 71: 20–23. Fidler JL, Fletcher JG, Reading CC, et al. Preoperative detection of pancreatic insulinomas on multiphasic helical CT. AJR Am J Roentgenol 2003; 181: 775–80. Catalano C, Pavone P, Laghi A, et al. Localization of pancreatic insulinomas with MR imaging at 0.5 T. Acta Radiol 1999; 40: 644–48. Matsuki M, Inada Y, Nakai G, et al. Diffusion-weighed MR imaging of pancreatic carcinoma. Abdom Imaging 2007; 32: 481–83. Christ E, Wild D, Ederer S, et al. Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabetes Endocrinol 2013; 1: 115–22. Morera J, Guillaume A, Courtheoux P, et al. Preoperative localization of an insulinoma: selective arterial calcium stimulation test performance. J Endocrinol Invest 2016; 39: 455–63. Sung YM, Do YS, Lee MK, et al. Selective intra-arterial calcium stimulation with hepatic venous sampling for preoperative localization of insulinomas. Korean J Radiol 2003; 4: 101–08. Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis 2011; 6: 63. 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. Nebesio TD, Hoover WC, Caldwell RL, Nitu ME, Eugster EA. Development of pulmonary hypertension in an infant treated with diazoxide. J Pediatr Endocrinol Metab 2007; 20: 939–44. Lindley KJ, Dunne MJ, Kane C, et al. Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade. Arch Dis Child 1996; 74: 373–78. Müller D, Zimmering M, Roehr CC. Should nifedipine be used to counter low blood sugar levels in children with persistent hyperinsulinaemic hypoglycaemia? Arch Dis Child 2004; 89: 83–85. Glaser B, Hirsch HJ, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr 1993; 123: 644–50. Dougherty PP, Klein-Schwartz W. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol 2010; 6: 199–206. Welters A, Lerch C, Kummer S, 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. Salvatore T, Giugliano D. Pharmacokinetic-pharmacodynamic relationships of Acarbose. Clin Pharmacokinet 1996; 30: 94–106. Le Quan Sang KH, Arnoux JB, Mamoune A, et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 2012; 166: 333–39. Modan-Moses D, Koren I, Mazor-Aronovitch K, Pinhas-Hamiel O, Landau H. Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel). J Clin Endocrinol Metab 2011; 96: 2312–17. Kühnen P, Marquard J, Ernert A, et al. Long-term lanreotide treatment in six patients with congenital hyperinsulinism. Horm Res Paediatr 2012; 78: 106–12. Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 2009; 360: 195–97.

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0

13

Review

98

99

100

101

102

103

104

105

106

107

108

14

Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010; 28: 69–76. Alexandrescu S, Tatevian N, Olutoye O, Brown RE. Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. Int J Clin Exp Pathol 2010; 3: 691–705. Düvel K, Yecies JL, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010; 39: 171–83. Senniappan S, Alexandrescu S, Tatevian N, et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014; 370: 1131–37. Shah P, Arya VB, Flanagan SE, et al. Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation. J Pediatr Endocrinol Metab 2015; 28: 695–99. Méder Ü, Bokodi G, Balogh L, et al. Severe hyperinsulinemic hypoglycemia in a neonate: response to sirolimus therapy. Pediatrics 2015; 136: e1369–72. Minute M, Patti G, Tornese G, Faleschini E, Zuiani C, Ventura A. Sirolimus therapy in congenital hyperinsulinism: a successful experience beyond infancy. Pediatrics 2015; 136: e1373–76. Bourcier ME, Sherrod A, DiGuardo M, Vinik AI. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab 2009; 94: 3157–62. Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, Drucker DJ. Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J Clin Invest 2012; 122: 388–402. McClenaghan NH, Flatt PR, Ball AJ. Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide. J Endocrinol 2006; 190: 889–96. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131–57.

109 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. 110 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. 111 Adzick NS, Thornton PS, Stanley CA, Kaye RD, Ruchelli E. A multidisciplinary approach to the focal form of congenital hyperinsulinism leads to successful treatment by partial pancreatectomy. J Pediatr Surg 2004; 39: 270–75. 112 Laje P, Stanley CA, Palladino AA, Becker SA, Adzick NS. Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism. J Pediatr Surg 2012; 47: 130–35. 113 Obatake M, Mochizuki K, Taura Y, et al. Pancreatic head resection preserving the main pancreatic duct for congenital hyperinsulinism of infancy. Pediatr Surg Int 2012; 28: 935–37. 114 Beltrand J, Caquard M, Arnoux JB, et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 2012; 35: 198–203. 115 Ludwig A, Ziegenhorn K, Empting S, et al. Glucose metabolism and neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg 2011; 20: 45–49. 116 Pierro A, Nah SA. Surgical management of congenital hyperinsulinism of infancy. Semin Pediatr Surg 2011; 20: 50–53. 117 Barthlen W, Mohnike W, Mohnike K. Techniques in pediatric surgery: congenital hyperinsulinism. Horm Res Paediatr 2011; 75: 304–10. 118 Iglesias P, Lafuente C, Martín Almendra M, López Guzmán A, Castro JC, Díez JJ. Insulinoma: a multicenter, retrospective analysis of three decades of experience (1983–2014). Endocrinol Nutr 2015; 62: 306–13. 119 Antonakis PT, Ashrafian H, Martinez-Isla A. Pancreatic insulinomas: laparoscopic management. World J Gastrointest Endosc 2015; 7: 1197–207.

www.thelancet.com/diabetes-endocrinology Published online November 30, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30323-0