OBJECTIVE-The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin.RESEARCH DESIGN AND METHODS-Ten normal, nondiabetic subjects (six men, age 36Ϯ7 years, and BMI 22.9Ϯ2.6 kg/m 2 ) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps).RESULTS-Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 Ϯ 7.7 mg/dl) versus human insulin (56 Ϯ 7.8 mg/dl) (P ϭ 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 Ϯ 2.5 vs. 2.4 Ϯ 1.8) and neuroglycopenic (4 Ϯ 3.9 vs. 2.7Ϯ2.5) symptoms (score, P Ͻ 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 Ϯ 8.1 vs. 47 Ϯ 3.6 mg/dl, P ϭ 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P Ͻ 0.05).
CONCLUSIONS-Compared with human insulin, responses tohypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes. Diabetes 57:746-756, 2008 T he physiology of glucose counterregulation to hypoglycemia in humans has been extensively studied (1). A progressive decline in plasma glucose induced by insulin triggers a well-established sequence of hierarchic responses that occur at specific glycemic thresholds (2-4).It is important that new insulin formulations and/or insulin analogs available for treatment of diabetes are compared with the reference human insulin for thresholds of responses and overall responses to hypoglycemia to exclude additional risks of inducing hypoglycemia unawareness. The rapid-acting insulin analogs lispro (5) and aspart (6) and the long-acting analog glargine (7) have been shown to be no different in terms of responses to hypoglycemia versus human insulin. Regarding the longacting insulin analog detemir, there are no systematic observations with the exception of two preliminary studies-one in normal, nondiabetic subjects (8) and the other in subjects with type 1 diabetes (9)-with conflicting results.Insulin detemir is a long-acting soluble insulin analog with a 14 C fatty acid chain conferring lipophility, associated with free fatty acid (FFA) binding sites on albumin (10). Because of these characteristics, the responses of insulin detemir to hypoglycemi...