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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
References - (linked to  )
- Aleman A, et al. J Clin Endocrinol Metab 1999; 84:471-475.
- Gasparini L and Xu H. Trends Neurosci 2003;26:404-406.
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Current GGH - Vol. 24 No. 1
Lupien SB et al. Systematic insulin-like growth factor-I administration prevents cognitive impairment
in diabetic rats, and brain IGF regulates learning/memory in normal adult rats. J Neurosci Res
2003;74:512-523.
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