] i transients to near normal levels. Electrophysiological analysis of the beta cell ion channels revealed that Ca 2؉ currents, delayed rectifier K ؉ currents, and K ؉ ATP channel currents were similar in transgenic and nontransgenic cells, suggesting that these ion channels were able to function normally. However, whereas K ؉ ATP channel currents in control cells were reduced by 50% by the presence of high glucose, those in transgenic cells were unaltered. Addition of tolbutamide inhibited this channel and enhanced the secretion of insulin in response to glucose for both control and transgenic cells. As these observations implicated a metabolic defect, glucose utilization, which is an indicator of glucose metabolism and ATP production in beta cells, was measured and found to be reduced by 40% in the transgenic cells. These data support the contention that excessive levels of calmodulin may compromise the ability of the beta cell to metabolize glucose and to modulate the state of the K ؉ ATP channel, resulting in an inadequate control of the membrane potential, which collectively impair [Ca 2؉ ] i and thus insulin secretion in response to glucose.

A transgenic mouse overexpressing a mutant form of calmodulin (CaM-8) that is selectively targeted to pancreatic beta-cells has an impaired ability to secrete insulin in response to elevated blood glucose.