Hypoglycemia: The Limiting Factor
Comprehensive treatment, including glycemic control, makes a difference for people with diabetes. Glycemic control prevents or delays the microvascular complications - retinopathy, nephropathy and neuropathy - of both type 1 diabetes (1) and type 2 diabetes (2); it may also reduce macrovascular events (3,4).  However,  because of the imperfections of all current treatment regimens, iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (5). Were it not for the potentially devastating effects of hypoglycemia on the brain - which requires a continuous supply of glucose from the circulation - diabetes would be rather easy to treat.  Enough insulin,  or any effective drug,  to lower plasma glucose concentrations to or below the normal range would eliminate the symptoms of hyperglycemia, prevent acute hyperglycemic complications (ketoacidosis, hyperosmolar syndrome), almost assuredly prevent the long-term microvascular complications (1,2)  and likely reduce atherosclerotic risk to baseline (3,4). But the effects of hypoglycemia on the brain are real, and the glycemic management of diabetes is therefore complex.

Iatrogenic hypoglycemia is, in fact, the limiting factor in the glycemic management of diabetes (5). It causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and is sometimes fatal. In addition, even asymptomatic episodes compromise defenses against subsequent hypoglycemia by causing hypoglycemia-associated autonomic failure (HAAF) - the syndromes of defective glucose counterregulation and hypoglycemia unawareness - and thus a vicious cycle of recurrent hypoglycemia.  Finally,  the barrier of hypoglycemia precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the vascular benefits of glycemic control.

For example, in the Diabetes Control and Complications Trial in type 1 diabetes, retinopathy developed or progressed in 14% of the patients treated intensively (compared with 32% in those treated conventionally) (1). In the UK Prospective Diabetes Study (UKPDS) in type 2 diabetes, any microvascular endpoint was reached in 8%  of the patients treated intensively (compared with 11%  of those treated conventionally) (2). Similarly, there is a direct relationship between atherosclerotic events and mean glycemia. However, it appears that lower plasma glucose concentrations over time are required to reduce macrovascular complications than to reduce microvascular complications (Fig. 1) (4).

The topic of hypoglycemia, including hypoglycemia in diabetes, has been reviewed in detail (5,6). The focus in this section is on iatrogenic hypoglycemia in type 2 diabetes in the context of the larger body of knowledge concerning hypoglycemia in type 1 diabetes.

Philip E. Cryer
Washington University School of Medicine, St. Louis, Missouri, U.S.A.

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