Systemic insulin‐like growth factor‐I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats

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Abstract
Diabetic patients have impaired learning/memory, brain atrophy, and two‐fold increased risk of dementia. The cause of cognitive disturbances that progress to dementia is unknown. Because neurotrophic insulin‐like growth factor (IGF) levels are reduced in diabetic patients and rodents, and IGF can cross the blood‐central nervous system barrier (B‐CNS‐B), the hypothesis was tested that IGF administered systemically can prevent cognitive disturbances, independently of hyperglycemia and a generalized catabolic state. Latency to escape to a hidden platform in the Morris Water Maze is used widely to test spatial memory, a hippocampus‐dependent task. Adult rats were rendered diabetic with streptozotocin and implanted 4 weeks later with subcutaneous pumps that released either vehicle (D + Veh) or 20 μg/day IGF‐I (D + IGF). Latency to escape to the hidden platform was prolonged in (D + Veh) versus non‐diabetic rats (P < 0.003) 10.5 weeks after the onset of diabetes. Such prolongation was prevented in (D + IGF) versus (D + Veh) rats (P < 0.03). The data show that IGF‐I can act across the B‐CNS‐B to prevent loss of cognition‐related performance in the water maze independently of ongoing hyperglycemia and reduction in brain (P < 0.001) and whole body weight (P < 0.001) in diabetic rats. The hypothesis that brain IGF contributes to learning/memory was tested. An anti‐IGF antibody, or preimmune serum, was infused into the lateral ventricles in non‐diabetic rats. Learning in a passive avoidance task was impaired significantly in the IGF antibody versus preimmune serum‐treated groups on test Days 1, 2, and 3 (P = 0.04, 0.02 and 0.004, respectively). The data together are consistent with a model in which brain IGF is essential for learning/memory, and a loss of IGF activity due to diabetes may contribute to cognitive disturbances.

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