Theophylline Improves Hypoglycemia Unawareness in Type 1 Diabetes
- Bastiaan E. de Galan1,
- Cees J. Tack1,
- Jacques W. Lenders1,
- Jaco W. Pasman2,
- Lammy D. Elving1,
- Frans G. Russel3,
- Jos A. Lutterman1 and
- Paul Smits13
- 1Department of Medicine, University Medical Center, Nijmegen, the Netherlands
- 2Department of Clinical Neurophysiology, University Medical Center, Nijmegen, the Netherlands
- 3Department of Pharmacology-Toxicology, University Medical Center, Nijmegen, the Netherlands
Iatrogenic hypoglycemias and the subsequent occurrence of hypoglycemia unawareness are well-known complications of intensive insulin therapy in type 1 diabetic patients that limit glycemic management. From a pharmacological point of view, the adenosine-receptor antagonist theophylline might be beneficial in the management of hypoglycemia unawareness. Theophylline stimulates the release of catecholamines and reduces cerebral blood flow, thereby facilitating stronger metabolic responses to and a prompter perception of decreasing glucose levels. To test the effect of theophylline on responses to hypoglycemia, we performed paired hyperinsulinemic-hypoglycemic clamp studies in 15 diabetic patients with hypoglycemia unawareness and 15 matched healthy control subjects. In random order, we concurrently infused either theophylline or placebo. Measurements included counterregulatory hormones, symptoms, hemodynamic parameters, and sweat detection using a dew-point electrode. Additionally, middle cerebral artery velocities (VMCA) using transcranial Doppler were monitored as an estimate of cerebral blood flow. When compared with placebo, theophylline significantly enhanced responses of plasma epinephrine, norepinephrine, and cortisol levels in both diabetic patients and control subjects. Because of the theophylline, sweat production started at ∼0.3 mmol/l higher glucose levels in both groups (P < 0.01), and symptom scores in diabetic patients approached those in control subjects. Theophylline decreased VMCA in both groups (P < 0.001), but significantly greater in diabetic patients (P < 0.01), and prevented the hypoglycemia-induced increase of VMCA that occurred during the placebo studies. We conclude that theophylline improves counterregulatory responses to and perception of hypoglycemia in diabetic patients with impaired awareness of hypoglycemia.
Address correspondence and reprint requests to Paul Smits, MD, PhD, Professor of Pharmacology, Department of Pharmacology-Toxicology, 233 University Medical Center, Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail:.
Received for publication 16 March 2001 and accepted in revised form 11 December 2001.
CBF, cerebral blood flow; CV, coefficient of variation; GH, growth hormone; GIR, glucose infusion rate; HPLC, high performance liquid chromatography; RIA, radioimmunoassay.