Avoidance of Hypoglycemia Restores Hypoglycemia Awareness by Increasing β-Adrenergic Sensitivity in Type 1 Diabetes

Avoidance of Hypoglycemia Restores Hypoglycemia Awareness by Increasing β-Adrenergic Sensitivity in Type 1 Diabetes

From Medizinische Universitätsklinik Tübingen, Tübingen, Germany; and University of Rochester School of Medicine, Rochester, New York.

Abstract

Background: Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes.

Objective: To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing β-adrenergic sensitivity in patients with type 1 diabetes.

Design: Controlled interventional study.

Setting: Research unit and outpatient diabetes clinic of a university hospital.

Patients: 10 men with type 1 diabetes and hypoglycemia unawareness (mean age [±SD], 46 ± 16 years; mean duration of diabetes, 20 ± 10 years).

Intervention: Strict avoidance of hypoglycemia.

Measurements: β-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia.

Results: After 4 months, the mean (±SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 ± 0.9 to 1.4 ± 0.3 per week (P < 0.001). Hemoglobin A_1c values increased from 0.068 ± 0.003 (6.8% ± 0.3%) to 0.077 ± 0.003 (7.7% ± 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 ± 0.6 to 3.3 ± 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7 ± 0.8) (P > 0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC₂₅) decreased from 1.96 ± 0.43 µg before treatment to 1.09 ± 0.17 µg after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 ± 0.20 µg) (P > 0.2). Improvements in β-adrenergic sensitivity (change in IC₂₅⁻¹) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04).

Conclusions: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing β-adrenergic sensitivity.

Article and Author Information

Acknowledgments: The authors thank Anna Teigeler, Elke Hardt, and Dr. Walter Renn for assistance.
Grant Support: In part by grants 5M01-RR 00044, NIDDK-20411, and 20579 from the National Institute of Health/Division of Research Resources/General Clinical Research Center (Dr. Gerich) and grant DFG #Stu 192-2/1 from Deutsche Forschungsgemeinschaft (Dr. Stumvoll).
Requests for Single Reprints: Michael Stumvoll, MD, Medizinische Universitätsklinik Tübingen, Otfried-Müller-Straβe 10, 72076 Tübingen, Germany.
Current Author Addresses: Drs. Fritsche, Stefan, and Häring: Medizinische Universitätsklinik Tübingen, Otfried-Müller-Straβe 10, 72076 Tübingen, Germany.
Dr. Gerich: University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642.
Author Contributions: Conception and design: A. Fritsche, J. Gerich, M. Stumvoll.
Analysis and interpretation of the data: A. Fritsche, N. Stefan, J. Gerich, M. Stumvoll.
Drafting of the article: A. Fritsche, J. Gerich, M. Stumvoll.
Critical revision of the article for important intellectual content: A. Fritsche, H. Häring, J. Gerich, M. Stumvoll.
Final approval of the article: A. Fritsche, N. Stefan, H. Häring, J. Gerich, M. Stumvoll.
Provision of study materials or patients: A. Fritsche, N. Stefan, M. Stumvoll.
Statistical expertise: A. Fritsche, M. Stumvoll.
Obtaining of funding: J. Gerich, M. Stumvoll.
Administrative, technical, or logistic support: H. Häring, M. Stumvoll.
Collection and assembly of data: A. Fritsche, M. Stumvoll.