Diabetes Metab J.  2013 Jun;37(3):157-164. 10.4093/dmj.2013.37.3.157.

Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor

• Proks P

• KMID: 2174288
• DOI: http://doi.org/10.4093/dmj.2013.37.3.157

Abstract

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic beta-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.

Keyword

ABC transporter; Insulin secretion; KATP channels; Kir6.2; Neonatal diabetes; Pancreatic beta-cell; Sulphonylurea receptor; Sulphonylureas

MeSH Terms

Adenosine Triphosphate
Glucose
Homeostasis
Insulin
KATP Channels
Polyphosphates
Potassium
Adenosine Triphosphate
Glucose
Insulin
KATP Channels
Polyphosphates
Potassium

Figure

• 

  Fig. 1 Stimulus-secretion coupling in pancreatic β-cells. (A) When extracellular glucose, and thus pancreatic β-cell metabolism, is low, adenosine triphosphate (ATP)-sensitive potassium (KATP) channels are open. As a result, the cell membrane is hyperpolarised. This keeps voltage-gated Ca2+ channels closed, so that Ca2+ influx remains low and no insulin is released. (B) When extracellular glucose concentration rises, glucose is taken up by the β-cell and metabolised. Metabolism generates ATP at the expense of magnesium adenosine diphosphate (MgADP), thereby closing KATP channels. This causes membrane depolarization, opening of voltage-gated Ca2+ channels, Ca2+ influx and insulin secretion.

• 

  Fig. 2 Location of neonatal diabetes mutations in the sulphonylurea receptor. Membrane topology of the sulphonylurea receptor with schematic representation of mutations which cause neonatal diabetes. Mutations showed in red and orange represent neonatal diabetes with developmental delay and epilepsy (DEND) and intermediate DEND syndrome respectively and grey colored mutations in italics transient neonatal diabetes; the rest of the mutations cause permanent neonatal diabetes. TMD, transmembrane domain; NBD, nucleotide binding domain.

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