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Review
. 2014 Oct 15;5(5):666-77.
doi: 10.4239/wjd.v5.i5.666.

Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia

Suresh Chandran  1 , Fabian Yap  1 , Khalid Hussain  1
Affiliations
Review

Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia

Suresh Chandran et al. World J Diabetes. .

Abstract

The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors (such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase (GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism.

Keywords: Glutamate dehydrogenase; Glutamine; Hyperinsulinaemic hypoglycaemia; Hyperinsulinism/Hyperammonaemia syndrome; KATP channel; Short-chain-3-hydroxyacyl-CoA dehydrogenase.

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Figures

Figure 1
Figure 1
Glucose and protein mediated insulin secretion in the beta cell of pancreas. GDH: Glutamate dehydrogenase; SCHAD: Short-chain 3-hydroxyacyl- CoA dehydrogenase; GK: Glucokinase; SUR: Sulfonylurea receptor; Kir 6.2: Potassium channel inwardly rectifying; GLUT2: Glucose transporter 2.
Figure 2
Figure 2
Glutamate metabolism. Oxidation of glutamate by glutamate dehydrogenase liberates free ammonia (NH3) and alpha ketoglutarate, which enters tricarboxylic acid cycle cycle and generates ATP. In the liver glutamate also generates N-acetylglutamate (NAG), which in turn allosterically activates carbomyl phosphate synthetase (CPS) to regulate ammonia detoxification into urea. Glutamine provides a substrate for ammonia buffering, by adding ammonia to glutamate to form glutamine. TCA: Tricarboxylic acid cycle; GDH: Glutamate dehydrogenase.
Figure 3
Figure 3
Glutamate and alanine as insulin secretagogues. Protein induced hyperinsulinaemic hypoglycaemia due to loss of function mutation in HADH gene (SCHAD). Alanine is deaminated to pyruvate and pyruvate dehydrogenase (PDH) converts it to acetyl CoA, which can enter TCA cycle to generate ATP for closing KATP channel. TCA: Tricarboxylic acid cycle; α-KG: Alpha ketoglutarate; GDH: Glutamate dehydrogenase; OAA: Oxaloacetic acid.
Figure 4
Figure 4
β-oxidation of fatty acids. Acyl-CoA is converted to acetyl-CoA through dehydrogenation, hydration, oxidation and thiolysis. Acetyl-CoA can enter the Krebs cycle or can lead to ketogenesis. CPT-1: Carnitine palmitoyltransferase-1; SCHAD: 3-hydroxyacyl CoA dehydrogenase.
Figure 5
Figure 5
Protein Induced Hypoglycaemia due to defects in KATP channel genes. GDH: Glutamate dehydrogenase; GK: Glucokinase.
See this image and copyright information in PMC

References

    1. Newsholme P, Brennan L, Rubi B, Maechler P. New insights into amino acid metabolism, beta-cell function and diabetes. Clin Sci (Lond) 2005;108:185–194. - PubMed
    1. Maechler P, Carobbio S, Rubi B. In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol. 2006;38:696–709. - PubMed
    1. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, De Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed. 2000;82:F98–F107. - PMC - PubMed
    1. James C, Kapoor RR, Ismail D, Hussain K. The genetic basis of congenital hyperinsulinism. J Med Genet. 2009;46:289–299. - PubMed
    1. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995;268:426–429. - PubMed