Glycemic Control and Hypoglycemia

G lycemic control remains a delicate balancing act. The diabetic patient is tasked with maintaining euglycemic blood glucose levels, a goal requiring education, decision strategies, volitional control, and the wisdom to avoid hyperand hypoglycemia, with the latter defined as plasma glucose less than 60 mg/dl. Glucose levels must be controlled continuously and without holidays. Failure to maintain euglycemia results from biological factors and psychosocial factors including overmedication and/or inappropriate choices regarding food, drink, and, in certain cases, exercise. Diabetic patients, especially those treated with insulin, are at risk for developing hypoglycemia. Treatment, even with oral agents such as sulfonylureas, increases this risk. Asymptomatic episodes of hypoglycemia may constitute up to 10% of a 24-h period in diabetic patients (1,2). Individuals with type 1 diabetes average 43 symptomatic episodes annually; insulin-treated individuals with type 2 diabetes average 16 episodes (3). As for severe hypoglycemic episodes, patients with type 1 diabetes experience up to two episodes annually, whereas patients with type 2 diabetes experience about one episode over 5 years. The risk increases with a history of hypoglycemia and an increased number of years of insulin treatment (3,4). Hypoglycemia deprives the brain of the constant supply of glucose needed for energy. Such low levels of blood glucose are sensed by the ventromedial hypothalamus (5). In turn, a counterregulatory hormonal cascade is activated to rapidly restore euglycemia that begins with inhibition of insulin secretion. Thereafter, the release of glucagon and epinephrine elevates endogenous glucose production through increased hepatic glycogenolysis and gluconeogenesis, as well as renal gluconeogenesis. Growth hormone and cortisol are slow-acting adjustments to prolonged hypoglycemia (6). Hypoglycemia may promote oxidative stress and neuronal cell death, primarily as a consequence of neuronal NADPH oxidase activation and extracellular zinc release during glucose reperfusion. Thus, heightened glucose concentrations during reperfusion can lead to cell death (7). Counterregulatory responses also stimulate the sympathetic autonomic nervous system, resulting in symptoms of sweating, trembling, anxiety, hunger, and nervousness. Deprivation of glucose triggers neuroglycopenic symptoms, including confusion and irritability (8). Severe hypoglycemic episodes often occur during sleep, when the intensity and recognizability of counterregulatory responses tend to be diminished, thereby depriving individuals of the adequate stimulus to counteract hypoglycemia (9). These episodes, termed nocturnal hypoglycemia (NH), may result in part from insufficient food intake and/or inappropriate insulin dosage the previous evening. Asymptomatic NH is a relatively common phenomenon affecting up to 50% of adults and 78% of children and lasting as long as several hours (10). Moreover, NH is suspected to contribute to the “dead-in-bed syndrome” that leads to the mortality of 6% of type 1 diabetic individuals below the age of 40 years (11). In addition to NH, individuals may also fail to recognize hypoglycemic episodes during the day. Such desensitization is due to decreased neuroendocrine responses to hypoglycemia that dampen symptomatic responses (12). Men are more prone to desensitization, whereas women inherently exhibit decreased counterregulatory responses to hypoglycemia (13). Thus, in both sexes, the warning signs and symptoms of hypoglycemia are typically not exhibited until blood glucose drops to dangerously low levels. Even two episodes of moderate hypoglycemia are sufficient to decrease counterregulatory hormonal responses to hypoglycemia (14). Hence, as has been said, hypoglycemia begets hypoglycemia (15). Hypoglycemia-associated autonomic failure may also result from intense physical activity. Exercise-induced hypoglycemia occurs up to 17 h after cessation of physical activity and can result from increased insulin sensitivity and glucose utilization. Furthermore, counterregulatory responses may be reduced by 50% during hypoglycemia following moderately intense exercise (16). From a practical perspective, a 10-s “sprint” of maximal effort immediately before or after moderately intense physical activity may reduce the rapid fall in glucose level associated with exercise. The sprint stabilizes glycemia in the period of early recovery from exercise, possibly by facilitating the release of counterregulatory response hormones (17,18).