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.


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 x kg(-1) x min(-1)) severe hypoglycemic ( approximately 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.
Puente
Erwin C
EC
Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri, USA.
Silverstein
Julie
J
Bree
Adam J
AJ
Musikantow
Daniel R
DR
Wozniak
David F
DF
Maloney
Susan
S
Daphna-Iken
Dorit
D
Fisher
Simon J
SJ
D000818:Animals; D001926:Brain Death / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000209:etiology* / Q000473:pathology / Q000523:psychology; D003072:Cognition Disorders / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D007003:Hypoglycemia / Q000150:complications / Q000503:physiopathology* / Q000523:psychology; D008297:Male; D018782:Maze Learning; D008568:Memory; D009043:Motor Activity; D009474:Neurons / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012640:Seizures / Q000209:etiology; D012720:Severity of Illness Index; D013028:Space Perception / Q000502:physiology