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Genetic influences on glucose neurotoxicity, aging, and diabetes: a possible role for glucose hysteresis

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Genetics and Evolution of Aging

Part of the book series: Contemporary Issues in Genetics and Evolution ((CIGE,volume 3))

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Abstract

Glucose may drive some age-correlated impairments and may mediate some effects of dietary restriction on senescence. The hypothesis that cumulative deleterious effects of glucose may impair hypothalamic neurons during aging, leading to hyperinsulinemia and other age-correlated pathologies, is examined in the context of genetic influences. Susceptibility to toxic effects of gold-thio-glucose (GTG) is correlated with longevity across several mouse strains. GTG and chronic hyperglycemia induce specific impairments in the ventromedial hypothalamus similar to impairments which occur during aging. GTG and a high-calorie diet both induce chronic hyperinsulinemia, leading initially to hypoglycemia, followed by the development of insulin resistance and hyperglycemia. Aging in humans and rodents appears to entail a similar pattern of hyperinsulinemia followed by insulin resistance. In humans, genetic susceptibility to high-calorie diet-induced impairments in glucose metabolism is extremely common in many indigenous populations, possibly due to the selection of the ‘thrifty genotype’. It is suggested that the ‘thrifty genotype’ may entail enhanced sensitivity to the neurotoxic effects of glucose, and may represent an example of antagonistic pleiotropy in human evolution. These data are consistent with the hypothesis that genetic susceptibility of hypothalamic neurons to the cumulative toxic effects of glucose (glucose neurohumoral hysteresis) may correlate with genetic influences on longevity.

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  1. Mt. Sinai School of Medicine and Molecular Medicine and Diagnostic Laboratory, Fishberg Center for Neurobiology, Bronx VAMC, Gustave Levy Pl., Box 1065, New York, NY, 10129, USA

    Charles V. Mobbs

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  1. University of California, Irvine, USA

    Michael R. Rose

  2. University of Southern California, Los Angeles, USA

    Caleb E. Finch

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Mobbs, C.V. (1994). Genetic influences on glucose neurotoxicity, aging, and diabetes: a possible role for glucose hysteresis. In: Rose, M.R., Finch, C.E. (eds) Genetics and Evolution of Aging. Contemporary Issues in Genetics and Evolution, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-1671-0_23

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  • DOI: https://doi.org/10.1007/978-94-017-1671-0_23

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