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 (V(MCA)) 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 approximately 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 V(MCA) in both groups (P < 0.001), but significantly greater in diabetic patients (P < 0.01), and prevented the
hypoglycemia-induced increase of V(MCA) 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.