Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism

Abstract

Purpose of review: To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes.

Recent findings: Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of 'genetic testing negative' HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68 Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18 F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal.

Summary: Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.

Fig 1.

Management Algorithm for Congenital Hyperinsulinism. After the diagnosis of hyperinsulinism has been made, the next step is to assess whether diazoxide is effective treatment. Responsiveness to diazoxide is established by showing that the cardinal feature of HI, hypoketotic hypoglycemia, has been reversed. In practice, this means demonstrating the ability to fast and generate hyperketonemia (beta-hydroxybutyrate >1.8 mmol/L) prior to developing hypoglycemia (plasma glucose <50-60 mg/dL). If responsive, diazoxide treatment is continued and comprehensive genetic testing is obtained. For patients unresponsive to diazoxide, expedited genetic testing is obtained to differentiate diffuse and focal forms of HI. ¹⁸F-DOPA PET/CT is performed when genetic testing is suggestive of possible focal disease, to localize the focal lesion preoperatively. For patients with diffuse, diazoxide-unresponsive disease, intensive medical therapy is initiated, with near-total pancreatectomy reserved for medically unresponsive cases. ¹⁸F-DOPA PET/CT 6-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography/computed tomography, BWS Beckwith-Wiedemann syndrome, HI hyperinsulinism, VUS variant of uncertain significance Source: Original

Fig 2.

Diagram of the beta-cell insulin secretion pathway, highlighting genetic causes of congenital hyperinsulinism and therapeutic targets. Glucose enters the beta-cell via glucose transporters, predominantly glucose transporter 1 (GLUT-1), and is phosphorylated by glucokinase (GCK), the glucose sensor of the beta-cell. Hexokinase 1 (HXK1) has a higher affinity for glucose than glucokinase and is not normally expressed in the beta-cell. Further metabolism of glucose-6-phosphate leads to an increase in the ATP-to-ADP ratio, closure of the K_ATP channel beta-cell membrane depolarization, opening of voltage-dependent calcium channels, calcium influx, and insulin secretion. Amino acids stimulate insulin secretion through glutamine-mediated amplification of glucagon-like peptide 1 receptor (GLP-1R) signaling. In addition, leucine stimulates insulin secretion by activating glutamate dehydrogenase (GDH), increasing the oxidation of glutamate to alpha-ketoglutarate, thereby increasing the ATP-to-ADP ratio, triggering insulin secretion. GDH is allosterically inhibited by guanine triphosphate and short-chain 3-OH acyl-CoA dehydrogenase (SCHAD). Monocarboxylate transporter 1 (MCT1) is not normally present on the beta-cell. Known sites of defects associated with congenital hyperinsulinism are highlighted in bold and include the K_ATP channel subunits, SUR1 (sulfonylurea receptor) and Kir6.2 (inwardly rectifying potassium channel), GCK, HK1, GDH, SCHAD, PNC2 (pyrimidine nucleotide carrier 2), HNF4a (hepatic nuclear transcription factor 4 alpha), HNF1a (hepatic nuclear transcription factor 1 alpha), FOXA2 (forkhead box A2), MCT1, and UCP2 (uncoupling protein 2). Therapeutic agents currently used to treat hyperinsulinism are underlined and therapies under investigation are italicized. Diazoxide suppresses insulin secretion by activating the K_ATP channel. Somatostatin suppresses insulin secretion downstream of calcium entry. ATP, adenosine triphosphate; ADP, adenosine diphosphate; Ca, calcium; cAMP, cyclic adenosine monophosphate; G6P, glucose-6-phosphate Source: Original