Recurrent Moderate Hypoglycemia Ameliorates Brain Damage and Cognitive Dysfunction Induced by Severe Hypoglycemia

OBJECTIVE

Although intensive glycemic control achieved with insulin therapy increases the incidence of both moderate and severe hypoglycemia, clinical reports of cognitive impairment due to severe hypoglycemia have been highly variable. It was hypothesized that recurrent moderate hypoglycemia preconditions the brain and protects against damage caused by severe hypoglycemia.

RESEARCH DESIGN AND METHODS

Nine-week-old male Sprague-Dawley rats were subjected to either 3 consecutive days of recurrent moderate (25–40 mg/dl) hypoglycemia (RH) or saline injections. On the fourth day, rats were subjected to a hyperinsulinemic (0.2 units · kg⁻¹ · min⁻¹) severe hypoglycemic (∼11 mg/dl) clamp for 60 or 90 min. Neuronal damage was subsequently assessed by hematoxylin-eosin and Fluoro-Jade B staining. The functional significance of severe hypoglycemia–induced brain damage was evaluated by motor and cognitive testing.

RESULTS

Severe hypoglycemia induced brain damage and striking deficits in spatial learning and memory. Rats subjected to recurrent moderate hypoglycemia had 62–74% less brain cell death and were protected from most of these cognitive disturbances.

CONCLUSIONS

Antecedent recurrent moderate hypoglycemia preconditioned the brain and markedly limited both the extent of severe hypoglycemia–induced neuronal damage and associated cognitive impairment. In conclusion, changes brought about by recurrent moderate hypoglycemia can be viewed, paradoxically, as providing a beneficial adaptive response in that there is mitigation against severe hypoglycemia–induced brain damage and cognitive dysfunction.Hypoglycemia is the major obstacle in achieving tight glycemic control in people with diabetes (1). Intensive insulin therapy increases the risk of iatrogenic hypoglycemia (2). Episodes of both moderate and severe hypoglycemia have long-term clinical consequences. Recurrent moderate hypoglycemia induces a maladaptive response that limits symptoms of hypoglycemia (hypoglycemia unawareness), limits the counterregulatory response to subsequent hypoglycemia (hypoglycemia-associated autonomic failure), and thus jeopardizes patient safety (1). By depriving the brain of glucose, more severe hypoglycemia causes brain damage in animal studies and leads to long-term impairments in learning and memory (3,4). However, studies examining the effect of severe hypoglycemia in humans are conflicting. Severe hypoglycemia has been shown to alter brain structure (5–7) and cause significant cognitive damage in many (5,7–12) but not all (13–16) studies. Reasons for the discrepancy between human and animal studies are unknown, but a major contributing factor may be the extent of glycemia control (including recurrent hypoglycemia) prior to the episode of severe hypoglycemia.In other models of brain damage, such as ischemic stroke, brief, mild episodes of antecedent brain ischemia has been shown to cause a beneficial adaptation that protects the brain against a subsequent episode of more severe ischemia (a phenomena known as ischemic preconditioning) (17). In a similar fashion, antecedent, recurrent episodes of moderate hypoglycemia were hypothesized to protect the brain against damage caused by a subsequent episode of more severe hypoglycemia.To investigate this hypothesis, recurrent moderately hypoglycemic (25–40 mg/dl) rats (RH rats) and control saline-injected rats (CON rats) were subjected to hyperinsulinemic, severe hypoglycemic clamps (10–15 mg/dl). One group of rats was killed 1 week after severe hypoglycemia to quantify brain damage, while a second group of rats was evaluated by behavioral and cognitive tests 6–8 weeks after the severe hypoglycemia. The results demonstrated that recurrent antecedent moderate hypoglycemia preconditioned the brain and protected it against neurological damage and cognitive defects induced by an episode of severe hypoglycemia.