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Review
. 2016 Mar 31:7:29.
doi: 10.3389/fendo.2016.00029. eCollection 2016.

Hyperinsulinemic Hypoglycemia - The Molecular Mechanisms

Azizun Nessa  1 , Sofia A Rahman  1 , Khalid Hussain  1
Affiliations
Review

Hyperinsulinemic Hypoglycemia - The Molecular Mechanisms

Azizun Nessa et al. Front Endocrinol (Lausanne). .

Abstract

Under normal physiological conditions, pancreatic β-cells secrete insulin to maintain fasting blood glucose levels in the range 3.5-5.5 mmol/L. In hyperinsulinemic hypoglycemia (HH), this precise regulation of insulin secretion is perturbed so that insulin continues to be secreted in the presence of hypoglycemia. HH may be due to genetic causes (congenital) or secondary to certain risk factors. The molecular mechanisms leading to HH involve defects in the key genes regulating insulin secretion from the β-cells. At this moment, in time genetic abnormalities in nine genes (ABCC8, KCNJ11, GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A, and UCP2) have been described that lead to the congenital forms of HH. Perinatal stress, intrauterine growth retardation, maternal diabetes mellitus, and a large number of developmental syndromes are also associated with HH in the neonatal period. In older children and adult's insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and post bariatric surgery are recognized causes of HH. This review article will focus mainly on describing the molecular mechanisms that lead to unregulated insulin secretion.

Keywords: KATP channels; congenital hyperinsulinism; glucose; hyperinsulinemic hypoglycemia; insulin.

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Figures

Figure 1
Figure 1
KATP channel structure on β-cell membrane. (A) The SUR1 subunit is made up of three transmembrane domains (TMD0, TMD1, and TMD2) and two nucleotide-binding domains (NBD1/NBD2), which face the cytoplasm. The NBD’s harbor the Walker A (WA) and Walker B (WB) motifs. Kir6.2 is the pore-forming subunit, containing two membrane-spanning domains, connected by an extracellular pore-forming region and cytoplasmic –NH2 and –COOH terminal domains. (B) Illustration of the predicted octameric structure of KATP channels, comprising four Kir6.2 and four SUR1 proteins.
Figure 2
Figure 2
Nucleotide regulation of KATP channels. The channel is activated by the presence of PIP2 and the conversion of MgATP to MgADP. High concentrations of ATP block the pore and cause channel closure.
Figure 3
Figure 3
Illustration of KATP channel protein production and regulation. (A) Normal production of KATP channels involves transcription of ABCC8 and KCNJ11 to produce pre-mRNA, this undergoes modification to become mature mRNA. The mRNA exits the nucleus and is translated into a protein on ribosomes embedded on the ER. The polypeptide(s) fold into the tertiary structure and enter the Golgi apparatus for post-translational modifications. Vesicles containing the fully assembled KATP channel proteins are then expressed at the membrane. (B) Mechanisms of CHI include defects in regulation, biogenesis, and trafficking. In these cases, the defective KATP channel may undergo protein degradation in lysosomes.
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References

    1. Güemes M, Rahman SA, Hussain K. What is a normal blood glucose? Arch Dis Child (2015).10.1136/archdischild-2015-308336 - DOI - PubMed
    1. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, De Lonlay-Debeney P, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed (2000) 82(2):F98–107.10.1136/fn.82.2.F98 - DOI - PMC - PubMed
    1. Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L. Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes (2005) 54(10):2946–51.10.2337/diabetes.54.10.2946 - DOI - PubMed
    1. Hussain K, Hindmarsh P, Aynsley-Green A. Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses. J Clin Endocrinol Metab (2003) 88(9):4342–7.10.1210/jc.2003-030135 - DOI - PubMed
    1. Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol (2003) 149(1):43–51.10.1530/eje.0.1490043 - DOI - PubMed

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