Familial hyperinsulinemic hypoglycemia

Secondary hyperammonemia [DS:H01400]

Familial hyperinsulinemic hypoglycemia (HHF) is the most common cause of persistent hypoglycemia in infancy. Recent studies on the molecular basis of the disease have disclosed specific genetic defects in the regulation of insulin secretion. Seven different loci have been associated with hyperinsulinism: ABCC8, KCNJ11, HADHSC, GCK, GLUD1, SLC16A1, and INSR. Mutations of these loci have significant differences in phenotype and inheritance pattern. The most common genes associated with hyperinsulinism, involve the ABCC8 and KCNJ11 genes that encode the two subunits of the beta-cell ATP-dependent potassium channel. Recessive mutations of these genes cause a severe form of neonatal hypoglycemia that frequently requires near-total pancreatectomy. Diazoxide, a drug that acts as an agonist of the ATP-dependent potassium channel to suppress insulin secretion, is effective in defects associated with mutations of GLUD1 and HADHSC. Diazoxide is often ineffective in mutations of the ATP- dependent potassium channel and may not adequately control hypoglycemia in GCK or SLC16A1 mutations.

Inherited metabolic disease

(HHF1/ LIH) ABCC8 [HSA:6833] [KO:K05032]
(HHF2) KCNJ11 [HSA:3767] [KO:K05004]
(HHF3) GCK [HSA:2645] [KO:K12407]
(HHF4) HADHSC [HSA:3033] [KO:K00022]
(HHF5) INSR [HSA:3643] [KO:K04527]
(HHF6) GLUD1 [HSA:2746] [KO:K00261]
(HHF7) SLC16A1 [HSA:6566] [KO:K08179]

Diazoxide [DR:D00294]

Leucine-induced hypoglycemia (LIH)

PMID:16357843 (HHF1/2)

Suchi M, MacMullen CM, Thornton PS, Adzick NS, Ganguly A, Ruchelli ED, Stanley CA

Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism.

Mod Pathol 19:122-9 (2006)
DOI:10.1038/modpathol.3800497

PMID:9435328 (HHF3)

Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC

Familial hyperinsulinism caused by an activating glucokinase mutation.

N Engl J Med 338:226-30 (1998)
DOI:10.1056/NEJM199801223380404

PMID:11489939 (HHF4)

Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE

Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion.

J Clin Invest 108:457-65 (2001)
DOI:10.1172/JCI11294

PMID:15161766 (HHF5)

Hojlund K, Hansen T, Lajer M, Henriksen JE, Levin K, Lindholm J, Pedersen O, Beck-Nielsen H

A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.

Diabetes 53:1592-8 (2004)
DOI:10.2337/diabetes.53.6.1592

PMID:9571255 (HHF6)

Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M

Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene.

N Engl J Med 338:1352-7 (1998)
DOI:10.1056/NEJM199805073381904

PMID:17701893 (HHF7)

Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipila I, Mayatepek E, Meissner T, Halestrap AP, Rutter GA, Kere J

Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells.

Am J Hum Genet 81:467-74 (2007)
DOI:10.1086/520960

PMID:16356235 (Drug)

Lheureux PE, Zahir S, Penaloza A, Gris M

Bench-to-bedside review: Antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide.

Crit Care 9:543-9 (2005)
DOI:10.1186/cc3807

PMID:21378225 (Description)

Palladino AA, Stanley CA

Nesidioblastosis no longer! It's all about genetics.

J Clin Endocrinol Metab 96:617-9 (2011)
DOI:10.1210/jc.2011-0164

PMID:15356046 (LIH)

Magge SN, Shyng SL, MacMullen C, Steinkrauss L, Ganguly A, Katz LE, Stanley CA

Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor.

J Clin Endocrinol Metab 89:4450-6 (2004)
DOI:10.1210/jc.2004-0441