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ABCC8-associated hyperinsulinism
Monday 25 January 2010
Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11, respectively.
Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI).
The beta-cell ATP-sensitive potassium (K(ATP)) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability.
Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes.
Epidemiology
The minimum birth prevalence of ABCC8-CHI in Norway to 1:70,000. (19475716)
By mutations
ABCC8-E1506K
- Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the ABCC8-E1506K inactivating mutation. (20042013)
ABCC8-W231R
ABCC8-C267X
ABCC8-IVS6-3C>G
ABCC8-I462V
ABCC8-Q917X
ABCC8-T1531A
ABCC8-IVS10+1G>T
ABCC8-R1493W
ABCC8-V21D
ABCC8-R74W (19151370)
- ABCC8-R74W reduces channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. (19151370)
ABCC8-E128K (19151370) - ABCC8-E128K reduces channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes.
- Under normal conditions, ABCC8-R74W and ABCC8-E128K mutant channels show poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital hyperinsulinism patients. (19151370)
- This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for K(ATP) channels.
- The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively.
- Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2.
- In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation.
- Sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants.
References
Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation. Vieira TC, Bergamin CS, Gurgel LC, Moisés RS. Pediatr Diabetes. 2009 Dec 23. PMID: 20042013
The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Søvik O, Njølstad PR, Molven A. Clin Genet. 2009 May;75(5):440-8. PMID: 19475716
Sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure. Pratt EB, Yan FF, Gay JW, Stanley CA, Shyng SL. J Biol Chem. 2009 Mar 20;284(12):7951-9. PMID: 19151370
Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Flanagan SE, Clauin S, Bellanné-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, Ellard S. Hum Mutat. 2009 Feb;30(2):170-80. PMID: 18767144