Glucose Sensing During Hypoglycemia: Lessons From the Lab

Shortly after the introduction of insulin in the management of type 1 diabetes, clinicians became aware of the potential for insulin therapy to induce iatrogenic hypoglycemia. Hypoglycemia remains the major adverse effect of insulin therapy and has emerged as a significant limitation to achieving near-normal glucose control, which is required to reduce the risk of microvascular complications. The average individual with type 1 diabetes experiences around two episodes of symptomatic hypoglycemia per week. In the recent U.K. Hypoglycemia Study (1), the incidence of severe hypoglycemia (requiring external assistance) was 110 episodes per 100 patient-years in subjects with duration of diabetes <5 years and 320 episodes per 100 patient-years in subjects with duration of diabetes >15 years. Thus, despite the introduction of insulin analogues and improved delivery systems, hypoglycemia remains a major concern for individuals with type 1 and long-duration type 2 diabetes as well as their caregivers.

When glucose levels fall, a sequence of counterregulatory responses is triggered, which mainly involves the suppression of endogenous insulin secretion and the release of counterregulatory hormones that act rapidly to promote endogenous glucose production and limit peripheral glucose utilization. As glucose levels fall further, subjective awareness of hypoglycemia results in behavioral changes that ordinarily lead an individual to seek food. In healthy individuals, this homeostatic mechanism works well and hypoglycemia is rare, but for individuals with type 1 diabetes, these compensatory systems are disrupted at every level. First, for most individuals insulin delivery to the systemic circulation following a subcutaneous injection will continue despite the development of hypoglycemia. Second, almost all individuals with type 1 diabetes will over time develop defects in the hormonal counterregulatory defense against hypoglycemia. Within 5 years of diagnosis of type 1 diabetes, hypoglycemia fails to stimulate release of the major counterregulatory hormone glucagon (2). As a result, individuals …