Diseases of Insulin Secretion

The ATP-sensitive K+ (KATP) channel plays a key role in glucose-stimulated insulin secretion. It is therefore not surprising that mutations in the genes that encode KATP channel subunits, or that encode proteins involved in the regulation of KATP channel activity, affect insulin secretion. Fig. 8.14 illustrates our current model of insulin secretion. When plasma glucose levels rise, glucose uptake and metabolism by the pancreatic ^-cell is enhanced, producing an increase in intracellular ATP and a concomitant fall in intracellular MgADP. These changes act synergistically to close KATP channels in the cell membrane because ATP inhibits, whereas MgADP activates, channel activity. Since KATP channel activity determines the ^-cell resting potential, its closure causes a membrane depolarisation that activates voltage-gated Ca2+ channels, increases Ca2+ influx and so stimulates insulin release. Two classes of therapeutic drugs modulate insulin secretion by interacting with the SUR1 subunit of the KATP channel. Sulphonylureas, such as glibenclamide,

Glucose

Diazoxide Sulphonylureas \0

f 1 granules ^

Depolarisation ~ ~ """

FIGURE 8.14 Katp CHANNELS PLAY A KEY ROLE IN INSULIN SECRETION

At low extracellular glucose levels (<3mM), KATP channels are open and their activity sets the resting potential of the pancreatic ^-cell at a hyperpo-larised level. When blood glucose rises, the uptake and metabolism of the sugar is increased. Some product of this metabolism, possibly changes in the intracellular concentration of adenine nucleotides, causes the KATP channels to close. This results in membrane depolarization, activation of voltage-gated Ca2+ channels and an increase in cytosolic Ca2+ that triggers the exocytosis of insulin-containing secretory granules.

inhibit channel activity and are used to enhance insulin secretion in patients with type-2 diabetes mellitus. By contrast, K-channel openers (e.g., diazoxide) activate KATP channels, hyperpolarizing the fi-cell and preventing insulin release. It is clear from this model, that a reduction in KATP channel activity will enhance insulin secretion and cause hypoglycaemia (low blood glucose), whereas an increase in channel activity may be expected to decrease insulin release and produce hyperglycaemia. Both may occur in man.

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