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The Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia.

Roženková K, Güemes M, Shah P, Hussain K - J Clin Res Pediatr Endocrinol (2015)

Bottom Line: Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage.Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children.The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

View Article: PubMed Central - PubMed

Affiliation: Great Ormond Street Hospital for Children, UCL Institute of Child Health, Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, London, UK Phone: +44 2079052128 E-mail: khalid.hussain@ucl.ac.uk.

ABSTRACT
Insulin secretion from pancreatic β-cells is tightly regulated to keep fasting blood glucose concentrations within the normal range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is a heterozygous condition in which insulin secretion becomes unregulated and its production persists despite low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. The most severe and permanent forms are due to congenital hyperinsulinism (CHI). Recent advances in genetics have linked CHI to mutations in 9 genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A). Histologically, CHI can be divided into 3 types; diffuse, focal and atypical. Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage. Therefore, it is essential to diagnose and treat HH promptly. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children. This review provides an overview of the genetic and molecular mechanisms leading to development of HH in children. The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

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Genetic defects associated with CHI: (1) SUR1 subunit of the KATP channel encoded by ABCC8 gene; (2) Kir6.2 subunit of the KATP channel encoded by KCNJ11 gene; (3) Glutamate dehydrogenase (GDH) encoded by GLUD1 gene; (4) Glucokinase (GCK) encoded by GCK gene; (5) L-3-hydroxyacyl-coenzyme A dehydrogenase (HADH) encoded by HADH gene; (6) Monocarboxylate transporter (MCT1) encoded by SLC16A1 gene; (7) Uncoupling protein 2 (UCP2) encoded by UCP2 gene; (8) Hepatocyte nuclear factor 4α (HNF4α) encoded by HNF4A gene; (9) Hepatocyte nuclear factor 1α (HNF1α) encoded by HNF1A gene
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f1: Genetic defects associated with CHI: (1) SUR1 subunit of the KATP channel encoded by ABCC8 gene; (2) Kir6.2 subunit of the KATP channel encoded by KCNJ11 gene; (3) Glutamate dehydrogenase (GDH) encoded by GLUD1 gene; (4) Glucokinase (GCK) encoded by GCK gene; (5) L-3-hydroxyacyl-coenzyme A dehydrogenase (HADH) encoded by HADH gene; (6) Monocarboxylate transporter (MCT1) encoded by SLC16A1 gene; (7) Uncoupling protein 2 (UCP2) encoded by UCP2 gene; (8) Hepatocyte nuclear factor 4α (HNF4α) encoded by HNF4A gene; (9) Hepatocyte nuclear factor 1α (HNF1α) encoded by HNF1A gene

Mentions: CHI occurs due to mutations in key genes which play a role in insulin secretion from pancreatic β-cells. Currently mutations have been identified in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A) that lead to dysregulated secretion of insulin (5,7,8). The most common cause for CHI are mutations in the genes ABCC8 and KCNJ11 (both autosomal recessive and dominant) that encode the SUR1 and Kir6.2 subunits of the pancreatic β-cell KATP channel, respectively (9,10,11,12,13,14). The genetic defects associated with CHI are summarized in Figure 1.


The Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia.

Roženková K, Güemes M, Shah P, Hussain K - J Clin Res Pediatr Endocrinol (2015)

Genetic defects associated with CHI: (1) SUR1 subunit of the KATP channel encoded by ABCC8 gene; (2) Kir6.2 subunit of the KATP channel encoded by KCNJ11 gene; (3) Glutamate dehydrogenase (GDH) encoded by GLUD1 gene; (4) Glucokinase (GCK) encoded by GCK gene; (5) L-3-hydroxyacyl-coenzyme A dehydrogenase (HADH) encoded by HADH gene; (6) Monocarboxylate transporter (MCT1) encoded by SLC16A1 gene; (7) Uncoupling protein 2 (UCP2) encoded by UCP2 gene; (8) Hepatocyte nuclear factor 4α (HNF4α) encoded by HNF4A gene; (9) Hepatocyte nuclear factor 1α (HNF1α) encoded by HNF1A gene
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563192&req=5

f1: Genetic defects associated with CHI: (1) SUR1 subunit of the KATP channel encoded by ABCC8 gene; (2) Kir6.2 subunit of the KATP channel encoded by KCNJ11 gene; (3) Glutamate dehydrogenase (GDH) encoded by GLUD1 gene; (4) Glucokinase (GCK) encoded by GCK gene; (5) L-3-hydroxyacyl-coenzyme A dehydrogenase (HADH) encoded by HADH gene; (6) Monocarboxylate transporter (MCT1) encoded by SLC16A1 gene; (7) Uncoupling protein 2 (UCP2) encoded by UCP2 gene; (8) Hepatocyte nuclear factor 4α (HNF4α) encoded by HNF4A gene; (9) Hepatocyte nuclear factor 1α (HNF1α) encoded by HNF1A gene
Mentions: CHI occurs due to mutations in key genes which play a role in insulin secretion from pancreatic β-cells. Currently mutations have been identified in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A) that lead to dysregulated secretion of insulin (5,7,8). The most common cause for CHI are mutations in the genes ABCC8 and KCNJ11 (both autosomal recessive and dominant) that encode the SUR1 and Kir6.2 subunits of the pancreatic β-cell KATP channel, respectively (9,10,11,12,13,14). The genetic defects associated with CHI are summarized in Figure 1.

Bottom Line: Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage.Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children.The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

View Article: PubMed Central - PubMed

Affiliation: Great Ormond Street Hospital for Children, UCL Institute of Child Health, Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, London, UK Phone: +44 2079052128 E-mail: khalid.hussain@ucl.ac.uk.

ABSTRACT
Insulin secretion from pancreatic β-cells is tightly regulated to keep fasting blood glucose concentrations within the normal range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is a heterozygous condition in which insulin secretion becomes unregulated and its production persists despite low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. The most severe and permanent forms are due to congenital hyperinsulinism (CHI). Recent advances in genetics have linked CHI to mutations in 9 genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A). Histologically, CHI can be divided into 3 types; diffuse, focal and atypical. Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage. Therefore, it is essential to diagnose and treat HH promptly. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children. This review provides an overview of the genetic and molecular mechanisms leading to development of HH in children. The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

Show MeSH
Related in: MedlinePlus