Glycemic control, a worthwhile goal for people with diabetes, is limited by the barrier of iatro-genic hypoglycemia (1). Iatrogenic hypoglycemia 1) causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal, 2) compromises physiological and behavioral defenses against subsequent falling plasma glucose concentrations and thus causes a vicious cycle of recurrent hypoglycemia, and 3) precludes maintenance of euglycemia over a lifetime of diabetes and therefore full realization of the vascular benefits of glycemic control. The premise of this “Perspective in Diabetes” is that insight into the pathophysiology of glucose counterregulation in diabetes leads to understanding of the frequency and impact of, risk factors for, and prevention of iatrogenic hypoglycemia.

Partial glycemic control reduces, but does not eliminate, the development of microvascular complications of diabetes (retinopathy, nephropathy, and neuropathy) in type 1 (2) and type 2 (3, 4) diabetes. Extrapolation of the Diabetes Control and Complications Trial (DCCT) retinopathy data suggests that long-term maintenance of euglycemia might eliminate those complications (5). Follow-up of the DCCT patients seemingly indicates that a period of earlier partial glycemic control reduces the development of macrovascular complications in type 1 diabetes (6). Aside from the metformin subset of the UK Prospective Diabetes Study (4), randomized controlled trials of intensive glycemic therapy have not documented a cardiovascular mortality benefit in type 2 diabetes (3, 7, 8). However, those trials do not exclude a cardiovascular benefit if glycemic control, or even partial glycemic control, could be maintained over a longer period of time. In any event, given its documented microvascular benefit, maintenance of euglycemia over a lifetime of diabetes would be in the best interest of people with diabetes if that could be accomplished safely. Unfortunately, maintenance of euglycemia over a lifetime of diabetes cannot be accomplished safely with currently available treatment methods because of the barrier of hypoglycemia (1). Even if they are effective initially, medications that should not, and probably do not, cause hypoglycemia (a biguanide [metformin], thiazolidinediones,-glucosidase inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl dipeptidase-IV