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Insulin Resistance: A Common Axis Linking Alzheimer's, Depression and Metabolism?
Our thanks to the Journal of Gerontology for granting permission to post the full text article.
Natalie Rasgon led this live discussion on 6 July 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.  View Transcript of Live Discussion — Posted 28 July 2006
Background
Insulin resistance (IR) is a relatively common metabolic disorder (affecting ~33 percent of the healthy adult population). Insulin is necessary for proper glucose utilization and neuronal survival in the central nervous system, in addition to the peripheral nervous system. Brain glucose deprivation, such as that caused by IR, may underlie the hypometabolic changes observed in crucial brain regions in patients with depression. In those with persistent IR, such changes may progress to more permanent changes characteristic of dementia, especially in those with other risk factors for dementia. We propose that when left undetected and untreated, long-term IR may lead to apoptosis and formation of neuritic plaques and neurofibrillary fibers (NFT), the true hallmark lesions of AD. This is thought to occur via several interactive mechanisms: 1) by affective glucose utilization in insulin-sensitive areas (i.e., limbic structures); 2) by modulating acetylcholine levels in the hippocampus; and 3) by decreasing phosphorylation of the microtubule-associated protein tau (known to play a role in NFT formation). Also, IR furthers cortisol neurotoxicity in the hippocampus, which may be the main mechanism by which changes in endocrine homeostasis affect both mood and cognition.
Read Dr. Rasgon's article in the Journal of Gerontology for details of her intriguing hypothesis. Also of interest is our Live Discussion with Suzanne De la Monte, "Is Alzheimer's a Type 3 Diabetes?."
Topics for discussion:
1) IR in AD and depression
2) IR effects on cognition/memory
3) Potential treatments of AD using insulin-sensitizing medications
Comment by Barry W. Festoff, M.D.—Posted 5 July 2005
My laboratory studied IR in amyotrophic lateral sclerosis (ALS) patients 20 years ago following two decades of anecdotal reports. Using radioactive insulin binding to circulating monocytes and by the euglycemic insulin clamp, we found that insulin receptors were reduced, that a circualting factor, as yet uncharacterized, could account for this reduction and ALS were remarkably insenstive to superphysiologic levels of insulin. These published studies added to other that ultimately resulted in clinical trials using recombinant insulin lije growth factor I (IGF-I) in ALS. A current (third) trial is ongoing.
These studies foreshadowed those seeking to find IR and develop novel treatment approaches in other neurologic diseases.
References:
Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore WV. Insulin resistance in amyotrophic lateral sclerosis. J Neurol Sci. 1984 Mar;63(3):317-24. Abstract
Perurena OH, Festoff BW. Reduction in insulin receptors in amyotrophic lateral sclerosis correlates with reduced insulin sensitivity. Neurology. 1987 Aug;37(8):1375-9. Abstract
Ma J, Yang SX, Ho GJ, Festoff BW. Insulin-like growth factor binding protein-1 at mouse neuromuscular synapses. Synapse. 1994 Aug;17(4):225-9. Abstract
Ma J, Yang SX, Ho GJ, Festoff BW. Insulin-like growth factor binding protein-1 is pre-synaptic at mouse neuromuscular synapses and is transported in nerve.
Neurochem Res. 1994 Nov;19(11):1363-8. Abstract
Festoff BW, Yang SX, Vaught J, Bryan C, Ma JY. The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies. J Neurol Sci. 1995 May;129 Suppl:114-21. Review. Abstract
Hantai D, Akaaboune M, Lagord C, Murawsky M, Houenou LJ, Festoff BW, Vaught JL, Rieger F, Blondet B. Beneficial effects of insulin-like growth factor-I on wobbler mouse motoneuron disease. J Neurol Sci. 1995 May;129 Suppl:122-6. Abstract
Lai EC, Felice KJ, Festoff BW, Gawel MJ, Gelinas DF, Kratz R, Murphy MF, Natter HM, Norris FH, Rudnicki SA. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.
Neurology. 1997 Dec;49(6):1621-30. Abstract
Festoff BW. The preclinical rationale for the use of insulin-like growth factor-I in amyotrophic lateral sclerosis. Drugs Today (Barc). 1998 Jan;34(1):65-77. Abstract
Arnold, P.M., Ma, J.Y., Smirnova, I.V., Zoubine, M.N., Avery, M.E., Huaibo, S., Citron, B.A. and Festoff, B.W.: Insulin-like growth factor (IGF) binding proteins (IGFBPs) in mouse spinal cord during development. Biochem. Biophys. Res. Comm. 264:652-656, 1999. Abstract
Arnold PM, Ma JY, Citron BA, Zoubine MN, Festoff BW. Selective developmental regulation of gene expression for insulin-like growth factor-binding proteins in mouse spinal cord.
Spine. 2000 Jul 15;25(14):1765-70. Abstract
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