Portal vein hypoglycemia sensor: Elucidating metabolic signaling and pathogenesis of hypoglycemia-associated sympathoadrenal failure

In insulin-dependent diabetes mellitus exposure to antecedent hypoglycemia impairs the sympathoadrenal response to subsequent hypoglycemia, plausibly by diminishing hypoglycemia sensing. We have repeatedly shown that portal vein glucose sensors mediate the sympathoadrenal response to hypoglycemia under variety of physiological conditions. However the mechanism of glycemic detection at the portal vein remains unknown. Thus this dissertation (1) attempted to delineate cellular mechanism(s) of hypoglycemic detection at the portal vein, and (2) to determine whether local portal vein antecedent hypoglycemia leads to the genesis of hypoglycemia-associated sympathoadrenal failure.;To gain insight into the mechanisms underlying glucose sensing at the portal vein, I employed a well-known strategy of testing the responses of glucosensors to substrates other than glucose. Specifically, chronically cannulated Male Wistar rats were exposed to a hyperinsulinemic-hypoglycemic clamp with concomitant elevation of portal vein lactate, pyruvate or beta-hydroxybutyrate concentrations and catecholamine response was assessed at basal and during sustained hypoglycemia. The data demonstrates that selective elevation of portal vein lactate or pyruvate concentration resulted in a 64--80% suppression of the sympathoadrenal response to whole body insulin-induced hypoglycemia. In contrast, local portal vein hyperketonemia failed to impact on the epinephrine and the norepinephrine responses to insulin-hypoglycemia. Therefore, since only glycolytic metabolites such as glucose, lactate and pyruvate were able to impact upon the portal vein sensor and beta-hydroxybutyrate failed to demonstrate an effect, these findings suggest that both acetyl CoA production and anaplerotic input into the citric acid cycle are two critical events mediating the glycemic detection at the portal vein.;To ascertain whether antecedent hypoglycemia local to the portal vein is essential for subsequent sympathoadrenal failure, I compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the sympathoadrenal response to a subsequent bout of hypoglycemia. Normalization of portal glycemia during day 1 hypoglycemia fully prevented the blunting of the epinephrine response to day next day hypoglycemia. The data therefore suggest that hypoglycemia-associated sympathoadrenal failure can be attributed to impaired portal vein glucose sensing.