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Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

From the Department of Internal Medicine, Endocrinology, and Metabolism, University of Perugia, Perugia, Italy

Address correspondence and reprint requests to Prof. Geremia B. Bolli, Department of Internal Medicine, Endocrinology, and Metabolism, University of Perugia, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: bolli{at}unipg.it, gbolli{at}libero.it

Abbreviations: AUC, area under the curve; FFA, free fatty acid; GIR, glucose infusion rate; PASAT, paced auditorial serial addition test

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 36±7 years, and BMI 22.9±2.6 kg/m²) 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 ± 7.7 mg/dl) versus human insulin (56 ± 7.8 mg/dl) (P = 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 ± 2.5 vs. 2.4 ± 1.8) and neuroglycopenic (4 ± 3.9 vs. 2.7±2.5) symptoms (score, P < 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 ± 8.1 vs. 47 ± 3.6 mg/dl, P = 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P < 0.05).

CONCLUSIONS—Compared with human insulin, responses to hypoglycemia 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.

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