Nicole Rockweiler
Chronic Effects of K_ATP Channel Blockers on Pancreatic ß-Cell Function
Mentor:  Dr. Colin Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine

ATP-sensitive potassium channels (K_ATP channels) play a critical role in the regulation of insulin secretion in pancreatic ß-cells by linking glucose metabolism to electrical activity of the plasma membrane.  During glucose-stimulated insulin secretion, K_ATP channels close, and the ß-cell membrane depolarizes.  Voltage-gated Ca²⁺ channels open, and the influx of Ca²⁺ triggers insulin secretion.  Glibenclamide, a type of sulfonylurea, is an anti-diabetic drug which inhibits K_ATP channels and consequently, stimulates insulin secretion.  In this study, the chronic effects of high doses of glibenclamide on insulin release and glucose content in wild type C57/Bl6 mice were investigated.

Glibenclamide pellets (2.5mg) were implanted into 12-week old mice (WT+glib).  Blood glucose was taken daily in fed or fasting conditions and assayed for glucose content using a blood glucose meter.  Blood for insulin was taken from fed mice, and plasma insulin levels were assayed using the Rat Insulin Elisa Kit.  Glucose tolerance was tested at 2 days, 1 week, and 1 month after implantation by injecting mice with glucose and measuring their blood glucose content with a blood glucose meter at 0, 15, 30, 45, 60, and 120 minutes after injection.  Mice were euthanized after 1 month.  Glucose-stimulated insulin secretion was measured by incubating groups of 10 islets in 1, 23, and 23mM glucose + 1mM glibenclamide solutions at 37°C for 1 hr.  Glucose content was analyzed by radioimmunoassay.

WT+glib mice showed impaired glucose tolerance compared to WT control mice.  WT+glib mice had consistent elevated levels of glucose in fed and fasting conditions and showed reduced insulin secretion.  These results suggest that chronic high-doses of glibenclamide in mice secondarily activate pathways that lead to impaired glucose tolerance with a reduction of b-cell insulin secretion from isolated islets.