Hyperinsulinism in Infancy: From Basic Science to Clinical Disease

Abstract

Dunne, Mark J., Karen E. Cosgrove, Ruth M. Shepherd, Albert Aynsley-Green, and Keith J. Lindley. Hyperinsulinism in Infancy: From Basic Science to Clinical Disease. Physiol Rev 84: 239–275, 2004; 10.1152/physrev.00022.2003.—Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+ channel. From gene defects in ion channel subunits to defects in β-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.

Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis

“…3, immunoreactivity for Kir6.2 (43 kDa) antibody was detected principally (>90% of total immunoreactivity) on insulin-and Golgi marker-containing fractions (8)(9)(10)(11)(12), with an overall distribution similar to that of endogenous phogrin (calculated peak at fraction 9.6±0.16). Kir6.2 positivity was also detected in ER and plasma membrane fractions (2 and 6, respectively) but at low levels, likely to have resulted from contamination with vesicles, in a mitochondrial marker-enriched fraction (14).…”

“…Closure of K ATP channels is pivotal to the actions of both nutrient secretagogues and sulfonylureas; changes in the activity of either subunit leads to defective insulin secretion and glucose homeostasis in rodents [5][6][7]. Moreover, mutations in either subunit are a common cause of hyperinsulinism in infancy [8,9], whilst polymorphisms in the KCNJ11 gene, which generate a form (E23K) of Kir6.2 with decreased activity, are linked to type 2 diabetes in human populations [10][11][12]. Moreover, mutations in the KCNJ11 gene are responsible for ∼50% of cases of permanent neonatal diabetes mellitus [13][14][15].…”

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

“…However, they have also been reported in other regions of SUR1, including TMD0 (AbdulhadiAtwan et al 2008): one can speculate that these mutations either affect coupling to Kir6.2, or interfere with MgATP binding/hydrolysis allosterically. In general, this class of mutations result in a less severe phenotype due to a partial response to Mg-nucleotides, and some patients can be treated by the K-channel opener diazoxide (Dunne et al 2004). …”

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

“…protein kinases, lipids) has been extensively studied (1,5,6). By comparison, little is known about how the number of channels at the plasma membrane of the cell is controlled, although there is growing evidence that changes in the membrane density of the channel underlie disease states (7,8).Structurally, K ATP channels exist as octamers formed from four subunits of the inwardly rectifying potassium channel Kir6.1 or Kir6.2, together with four sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits (5, 9 -11). The pancreatic K ATP channel comprises Kir6.2 and SUR1 subunits, which are encoded by the genes KCNJ11 and ABCC8, respectively (5, 6, 10, 11).…”

“…Studies have shown that although some mutations affect the nucleotide regulation of the channel (12-14), others alter the density of the channels at the cell surface by affecting trafficking (15)(16)(17)(18)(19). Recent large scale genome-wide studies have established a strong link between the KCNJ11 gene and type 2 diabetes (20); however, the underlying mechanisms are unknown.The genetic and cell biological evidence that changes in cell surface density of K ATP channels can have profound effects on insulin secretion raises the possibility that changes in the surface density could play a role in the regulation of insulin secretion in normal ␤-cells (7,17,18,21). Although there are no data for ␤-cells, studies of cardiac and neuronal cells have demonstrated that activation of PKC 3 down-regulates K ATP channels (22).…”