Hypoglycemia—The Major Barrier to Good Glycemic Control

Stephen N Davis, Julia P Dunn
US Endocrinology, 2006;(1):2-9
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Approximately 20.8 million Americans (14.6 million diagnosed and 6.2 million undiagnosed) have diabetes mellitus (DM) and in 2002 it was the sixth leading cause of death, emphasizing the need for improved treatment.1 However, iatrogenic hypoglycemia precludes reaching and maintaining euglycemia. During the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), outcomes of diabetes improved while hypoglycemia worsened with intensive therapy. The consequence was that hypoglycemia became the major obstacle to achieving the stated glycemic targets in these studies.2,3 As a result, hypoglycemia becomes a major barrier in improving outcomes in type 1 and type 2 DM. This has considerable financial implications as at least US$40 billion is spent each year in the US on complications of diabetes. Understanding the mechanisms and impact of hypoglycemia in diabetes is vital so that it can be addressed clinically. Furthermore, newer pharmacologic agents offer the clinician options to reduce iatrogenic hypoglycemia.

Risk factors have been identified for iatrogenic hypoglycemia, and physiologic studies have revealed the mechanisms of many of these risk factors. Predictors of severe (requiring assistance) hypoglycemia identified through the DCCT include prior history of severe hypoglycemia, longer duration of diabetes, higher baseline glycosylated hemoglobin (HbA1c), and lower treatment HbA1c4 in type 1 DM. The strongest predictor of future episodes of hypoglycemia was the number of prior episodes.5 In type 2 DM, the risk of hypoglycemia increases with disease duration and duration of insulin therapy.6,7 Counter-regulatory responses to hypoglycemia are the physiologic changes that occur to increase blood glucose and protect the body and brain from severe hypoglycemia. These responses become altered in diabetics and the pathophysiologic changes add to the above identified risk factors.

The characteristic physiologic counter-regulatory response to hypoglycemia has been described in detail elsewhere8,9 and will be briefly explained here. Hypoglycemia occurs when an imbalance of insulin and energy consumption and output (exercise) exists. As plasma glucose (pg) declines, the first counter-regulatory response is for insulin secretion to decrease. As pg continues to decline, glucagon, epinephrine, cortisol, norepinephrine and growth hormone secretion increases. Epinephrine and glucagon are the two primary counter-regulatory hormones, and their metabolic effects are seen within minutes, increasing available glucose, decreasing glucose utilization and contributing to suppression of insulin secretion. Cortisol, norepinephrine and growth hormone do not play a role in the acute defense against hypoglycemia. These later hormones only have metabolic effects during very prolonged hypoglycemia (hours) and then only one-quarter to one-fifth of the counter-regulatory actions of epinephrine and glucagon.

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