(I-332) The Effect of High Fat Diet on Glucose Tolerance in ATP Sensitive Potassium channels in Dominant Negative Mice

ATP-sensitive K⁺ channels (K_ATP) electrically couple blood glucose to insulin secretion in pancreatic β cells. Gain of function (GOF) mutations, resulting in b cell K_ATP channels that are open more than usual, cause loss of insulin secretion and the development of neonatal diabetes. Loss of function (LOF) mutations, which result in a decreased opening of channels, increase insulin secretion and result in congenital hyperinsulinism. Paradoxically, however, K_ATP knockout (KO) mice, with a complete loss of b cell K_ATP, exhibit a reduction of insulin secretion, and impaired glucose tolerance. The mechanism is still unknown, but the findings suggest a crossover from hypersecretion to under secretion of insulin with progressive loss of K_ATP activity. In vitro, elevated glucose leads to reduced K_ATP channel density suggesting that hyperglycemia in vivo might also result in similar consequences. In this study we used a dominant negative (DN) K_ATP transgene that can be specifically expressed in pancreatic b cells in order to reduce K_ATP density. Since obesity leads to impaired glucose tolerance and hyperglycemia, we utilized a high fat diet (HFD) in these transgenic mice to test the hypothesis that obesity-driven impairment of glucose tolerance and elevated blood glucose might further reduce K_ATP density and induce the crossover phenomenon.

DN expression was driven by PDX-cr We removed the pancreas from anesthetized mice and isolated islets from the pancreas. K_ATP channel activity was assessed using the patch clamp method. e, which was induced with 5 days of tamoxifen treatment. Glucose tolerance was assessed using a glucose tolerance test in which each mouse was given a dose of glucose based off their initial weight, and their blood glucose was measured over a period of two hours.

The patch clamp data demonstrate a reduction in b cell K_ATP channel activity following DN induction. Following HFD there was a further non-significant decrease in K_ATP channel activity. Glucose tolerance tests showed little change in glucose tolerance for DN mice on a chow diet but improved tolerance in HFD, suggesting that these mice had not crossed over and instead that the HFD may be increasing insulin secretion.

Given the incomplete loss of K_ATP activity and the trend towards a slight decrease in HFD, these animals may sit to the left of the secretory peak and the small loss of K_ATP increased insulin secretion, providing new insight into the level of K_ATP loss needed for crossover to occur.

Colin G. Nichols, Nathaniel W. York, Maria S. Remedi; ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes: Inconvenient Paradox or New Paradigm?. Diabetes 1 March 2022; 71 (3): 367–375.