It is not possible to specify a plasma glucose concentration that defines clinical hypoglycemia in people with diabetes because the glycemic thresholds for the manifestations of hypoglycemia shift to higher than normal glucose levels in poorly controlled diabetes and lower than normal glucose levels in well controlled diabetes. The diagnosis is made most convincingly by Whipple’s triad:  symptoms consistent with hypoglycemia,  a low plasma glucose concentration and relief of those symptoms after the plasma glucose concentrations is raised to (or above) normal.

Ideally, suggestive symptoms should prompt a monitor-measured glucose level to confirm that those symptoms are indicative of hypoglycemia.  However, patients often self-treat on the basis of symptoms alone. On the other hand, low self-monitored glucose levels should not be ignored even in the absence of symptoms. The American Diabetes Association Workgroup on Hypoglycemia (11)  recommended that people with diabetes should become concerned, and consider defensive actions, at a plasma glucose concentration ≤ 70 mg/dL (3.9 mmol/L).

Impact of Hypoglycemia
There is little published information about the clinical impact of hypoglycemia in type 2 diabetes. While it is reasonable to extrapolate from the experience in type 1 diabetes, there are obvious differences. As noted earlier, episodes of hypoglycemia become familiar events early in the course of type 1 diabetes.

They are infrequent early in the course of type 2 diabetes, even during treatment with insulin secretagogues or insulin,  but become progressively more frequent as the patient approaches the insulin-deficient end of the spectrum of type 2 diabetes (12,13).

Furthermore, while type 2 diabetes occurs in all age groups including children, most affected people are middle aged and older and,  therefore,  at higher risk of erratic food ingestion and even malnutrition, co-morbid conditions and drug interactions, impaired drug metabolism and renal insufficiency with reduced insulin clearance.  They are also more susceptible to macrovascular events because of underlying cardiovascular disease.

Iatrogenic hypoglycemia causes both physical morbidity (and some mortality)  and psychosocial morbidity (6).

While estimates of hypoglycemic mortality rates in type 2 diabetes are not available, deaths caused by sulfonylurea-induced hypoglycemia (like insulin-induced hypoglycemia)  are well documented (14).  The mortality of a given episode of severe sulfonylurea-induced hypoglycemia has been reported to be as high as 10%  (14,15). 

The physical morbidity of an episode of hypoglycemia ranges from unpleasant neurogenic (autonomic)  symptoms,  such as sweating,  hunger,  palpitations,  tremor and anxiety,  to neuroglycopenic manifestations. The latter range from cognitive impairments and behavioral changes to seizures and coma (and rarely death).

Transient focal neurological deficits occur occasionally. While seemingly complete neurological recovery is the rule following an episode of hypoglycemia, prolonged severe hypoglycemia can cause permanent neurological damage.

The extent to which the latter might be more frequent in older individuals with type 2 diabetes is unknown.

At the very least, an episode of hypoglycemia is a nuisance and a distraction; it can be embarrassing and lead to social ostracism.  The psychological morbidity includes fear of hypoglycemia, guilt about that rational fear, high levels of anxiety and low levels of overall happiness.  Fear of hypoglycemia can be an impediment to glycemic control. 

Thus, hypoglycemia is often a psychological, as well as a pathophysiological, barrier to glycemic control. The performance of critical tasks, such as driving, is measurably impaired during hypoglycemia, as is judgment. Finally, the demands of the management of diabetes, including the prevention of both hyperglycemia and hypoglycemia,  become progressively more obtrusive over time in type 2 diabetes, albeit over a longer time span than in type 1 diabetes.

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

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