Abstract
Type 1 diabetes mellitus is characterized by complete loss of insulin-producing capacity. Patients with type 1 diabetes are dependent on subcutaneous administration of insulin to prevent hyperglycemia. Due to imperfections of therapeutic insulin, diabetic patients are at high risk for hypoglycemia. On average, patients with type 1 diabetes suffer 2-3 hypoglycemic episodes a week and one episode of severe, at least temporarily disabling, hypoglycemia per year. This high frequency is for a large part due to defective hormonal counterregulation and loss of hypoglycemic symptoms (hypoglycemia unawareness), which interfere with prevention and correction of falling blood glucose levels. In this thesis, we addressed the pathophysiology of hypoglycemia unawareness and explored the validity of a pharmacological approach to improve glucose counterregulation. Concerning its pathophysiology, we found that the impaired response of the counterregulatory hormone adrenaline in patients with hypoglycemia unawareness is partly the result of reduced adrenomedullary capacity to synthesize adrenaline and not only the result of adrenal insensitivity to the prevailing glucose level. We also found that an elevated adrenaline level may act suppressively on the responsiveness to counterregulatory hormones during subsequent hypoglycemia, suggesting a mediating role for adrenaline (albeit small) in the pathogenesis of hypoglycemia unawareness. In the second part of this thesis, we tested the validity of a pharmacological approach for the treatment of hypoglycemia unawareness. We found that the methylxanthine derivative theophylline stimulated counterregulatory hormone responses to and symptomatic awareness of experimental hypoglycemia in diabetic patients with hypoglycemia unawareness. During long-term use the effect of theophylline persisted under hypoglycemic conditions, thus providing a rationale for the use of theophylline in the management of hypoglycemia unawareness. In a related experiment, we found that another methylxanthine derivative, caffeine, decreased insulin sensitivity, which may be important because reduced insulin sensitivity is a risk factor for cardiovascular disease
