Mechanisms of Hypoglycemia Associated Autonomic Dysfunction, Differing Levels of Hypoglycemia

Recent large randomized multicenter trials have investigated the effects of lowering blood glucose levels towards normal in both inpatient and ambulatory care/community settings. All studies have reported increasing prevalence and incidence of hypoglycemia as glucose levels approach normal. In fact, the occurrence of hypoglycemia was so problematic that some hospital based studies were halted and the target recommendations for glucose levels in critically unwell patients have been increased. Similarly three recent large glucose control and complications trials in type 2 diabetes mellitus (DM) have reported significantly high rates of hypoglycemia in intensively treated type 2 DM individuals. In two of these studies (VADT, ADVANCE) there was a highly significant association between severe hypoglycemia (glucose low enough to cause neurologic impairment) and serious cardiac events and increased death. Furthermore, in two studies performed in the USA (VADT, ACCORD), severe hypoglycemia occurring in the standard/conventionally treated group produced even more serious adverse cardiac effects as compared to the intensively treated group. The in-vivo mechanism(s) responsible for the above findings could not be identified from the above studies. Surprisingly there is very limited data available regarding the effects of hypoglycemia on in-vivo vascular biology. Previously, in vitro work has determined that epinephrine, norepinephrine, growth hormone, glucagon, and corticosteroids (all counterregulatory hormones) can have vascular biologic effects (platelet aggregation, fibrinolytic balance, increases in pro-inflammatory markers and changes in endothelial function). Three recent studies from my own and other laboratories performed in healthy volunteers and type 1 DM have demonstrated that hypoglycemia can produce a spectrum of pro-inflammatory and pro-atherothrombotic changes. Novel preliminary data from my lab has also demonstrated that hypoglycemia can impair endothelial function, reduce fibrinolytic balance (increase plasminogen activator inhibitor-1) and produce pro-atherothrombotic (increase platelet aggregation, thrombin anti-thrombin complexes, vascular adhesion molecules) changes in type 2 DM. Additionally, preliminary data presented below will demonstrate that a 90 minute episode of hypoglycemia (50 mg/dl) produces similar pro-atherothrombotic changes as compared to 4 hours of hyperglycemia (200 mg/dl). However, as investigators are just beginning to realize the effects of hypoglycemia on vascular biology, there remain many unanswered questions. For example, in the vulnerable type 2 DM population what is the dose response of different levels of hypoglycemia with attendant ANS activation on endothelial function and atherothrombotic balance? How does level of glycemic control affect ANS and vascular biologic responses to hypoglycemia in type 2 DM? Proposed studies in this protocol will provide novel information answering the clinically important question regarding the effects of mild to moderate hypoglycemia on vascular biologic mechanisms in a healthy population.