© 2004 Prime Health Consultants, Inc.
Lupien et al tested the following hypotheses: (1) IGF treatment can prevent brain disturbances that contribute to impaired spatial learning/memory; (2) IGF-I can support cognitive function across the blood-brain barrier; (3) IGF can preserve brain function in diabetes independently of hyperglycemia; and (4) brain IGF contributes to hippocampal-based cognitive functions.
The first three hypotheses were tested by comparing normal rats versus streptozocin (STZ) diabetic rats. Four weeks after STZ, minipumps were implanted to deliver continuous infusions of 20 ?g/day IGF-I or vehicle (10 mM acetic acid, pH 6.0) for 7.5 weeks. (For reference, daily IGF-I production by the adult rat liver is about 31 ?g/day.) The hidden platform or “place” test was performed to assess spatial learning and memory; the “probe” test to examine memory; and the “cued” test to detect sensorimotor deficits. Following these tests, the mean blood glucose levels were 125.0 + 11 mg/dl in the non-diabetic rats versus 515 + 73 in the STZ + vehicle and 495 + 99 in the STZ + IGF rats. Body weights of both STZ groups were about half that of the non-diabetic rats.
All 3 groups decreased their latency times to escape the hidden platform, but there was a 3-day lag before latencies began to decline in the STZ + vehicle group. STZ + IGF performed similarly to the non-diabetic rats, and both groups decreased their latencies by shortening their search paths. The STZ + vehicle group decreased their latencies by increasing their swim velocity; their paths did not shorten. The average latency was more prolonged in the STZ + vehicle, than in the STZ + IGF rats. The STZ + vehicle rats also swam the furthest distance; STZ + IGF were again like the non-diabetics. Swim velocities were not significantly different, thus motor or proprioceptive disturbances were not the cause of the poorer performance of the STZ + vehicle rats. IGF infusion improved learning/memory performance without ameliorating the hyperglycemia or the catabolism of the STZ rats. Total brain weight and hippocampal weight were significantly reduced in the STZ rats, and these were not attenuated by IGF infusion.
The second experimental design tested IGF's contribution to normal learning/memory by passive avoidance of electric shocks, after two-weeks of continuous infusion into the lateral ventricle of either 40% anti-IGF-II antiserum or 40% preimmune serum. Whereas the latencies of the preimmune serum rats increased, those of the IGF-II antiserum rats were significantly diminished. The authors concluded that IGF treatment can prevent brain disturbances that contribute to impaired spatial learning/memory in experimental diabetes in rats.
Editor's Comment: The authors integrated their results into a review of prior studies of the effects of diabetes and IGF on neurologic function. Experimentation in rats allowed controlled manipulations that cannot be made in humans, like the examination of brain tissues and the continuous intraventricular infusion of IGF antiserum. These data add to the evidence supporting IGF benefits for neurologic function. Aleman and colleagues demonstrate significant associations between circulating IGF-I concentrations and performance on perceptual-motor performance and mental processing speed in healthy men aged 65-76 years.1 Although it is tempting to attribute the better performance to the higher IGF-I levels, associations are NEVER sufficient to prove causation and require corroborative evidence.
While the associations between high circulating IGF-I concentrations and increased cancer risk have garnered a lot of attention, the neurologic effects of IGF should be considered, particularly pertaining to diabetes-induced learning/memory impairments and increased risk of dementia. Gasparini and Xu recently reviewed IGF-I and insulin as it related to the pathophysiology of Alzheimer's disease.2 It appears that there may also be risks to having low IGF-I levels; IGF-I does more than promote somatic growth.
Adda Grimberg, MD
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