A Role for Uncoupling Proteins in Neuroprotection Following Recurrent Hypoglycemia?

Mccrimmon, Rory; Andrews, Zane; Coppola, Anna; Cheng, Haiying; Sherwin, Robert; Diano, Sabrina

Recurrent hypoglycemia has emerged as a significant limitation to the widespread implementation of intensive insulin therapy in type 1 diabetes. Key to developing therapies designed to reduce the frequency of hypoglycemia is a greater understanding of the adaptive changes that occur at a molecular level in response to recurrent hypoglycemic stress. Acute hypoglycemia is a cellular stress that induces Reactive Oxygen Species (ROS) formation. Uncoupling proteins (in particular, UCP-2, UCP-4 and BMCP-1) in addition to their roles in mitochondrial respiration play a major role in regulating calcium flux and free radical production and are thought to have a role to play in neuroprotection. In this study we examine the impact of recurrent hypoglycemia on uncoupling protein (UCP) gene expression and function in two different brain regions; hypothalamus and hippocampus. Chronically catheterized male Sprague-Dawley rats underwent 4 consecutive, once-daily, 3-hr episodes of intra-peritoneal (IP) insulin-induced hypoglycemia (n=18), or IP Saline (Euglycemic control; n=18) after which they were fed ad libitum. On the fourth day, having fed overnight, they were rapidly sacrificed and whole hypothalamus or hippocampus removed for later analysis. Within whole hypothalamus recurrent hypoglycemia significantly increased gene expression of uncoupling proteins UCP-2 (45-75%), UCP-4 (14-23%) and BMCP-1 (28-43%), but no changes were seen in gene expression in the hippocampus. In the hypothalamus, but not in hippocampus, the Respiratory Control Ratio (RCR) was decreased following recurrent hypoglycemia [5.0(0.2) vs. 5.5(0.2); p<.05] indicating higher mitochondrial uncoupling, and fatty acid dependent uncoupled respiration was also significantly increased [69.3 (1.8) vs. 59.4 (1.9); p<.01). Recurrent hypoglycemia (n=8 in each group) was found to reduce basal levels of ROS production by hypothalamic [18.0(3.0) vs. 29.6(2.8); p<.05], but not hippocampal tissue [30.6(4.4) vs. 32.5(4.7); p=ns]. Conclusion: Recurrent hypoglycemia in a rodent model results in regional changes in the expression and function of uncoupling proteins. This is associated with a reduction in basal ROS production and may represent a response to local hypothalamic oxidative stress, designed to protect neurons from subsequent hypoglycemia-induced ROS formation.

HYPOGLYCEMIA; INSULIN therapy; TREATMENT of diabetes; NERVE tissue proteins; REACTIVE oxygen species; GENE expression; HYPOTHALAMUS; HIPPOCAMPUS (Brain)

Diabetes, 2007, Vol 56, pA166

0012-1797

Academic Journal