Joseph C. Koster, Ph.D.

Research

The ATP-sensitive K+-channel, or KATP, represents a critical link in coupling electrical activity with insulin secretion in pancreatic ?-cells. When glucose metabolism is elevated in the ?-cell, a the rise in the [ATP]/[ADP] ratio serves to inhibit KATP channel activity leading to membrane depolarization, an increase in [Ca2+]i, and insulin secretion. Conversely, a falling [ATP]/[ADP] ratio restores channel activity and suppresses depolarization-dependent insulin secretion. Thus, according to this model gain-of-function mutations in KATP, as would occur if the mutant channels had reduced sensitivity to inhibitory ATP, should lead to suppressed insulin release and contribute to a diabetic phenotype. My previous work has confirmed this critical prediction by demonstrating a profound neonatal diabetes and a nearly complete neonatal lethality in transgenic mice expressing ‘overactive’ mutant KATP channels in pancreatic ?-cells (Figure 1: KATP [?N30] Tg. versus wild-type). More importantly, this transgenic mouse model has correctly predicted that similar gain of function mutations in KATP should give rise to neonatal diabetes in humans. Recent reports now provide compelling evidence that activating mutations in KATP underlie permanent neonatal diabetes in humans and suggests that these patients may benefit from treatment with the KATP inhibitory drugs alone.

My current efforts involve developing additional mouse models of KATP-induced diabetes with the expectation that less ‘overactive’ KATP channel activity will result in a milder and later-onset diabetic phenotype. In addition, in a clinical collaboration my colleagues and I are attempting to identify and functionally characterize novel mutation in KATP which are associated with human neonatal diabetes.