Humanin: A novel central regulator of peripheral insulin action

Radhika H. Muzumdar, Derek M. Huffman, Gil Atzmon, Cristoph Buettner, Laura J. Cobb, Sigal Fishman, Temuri Budagov, Lingguang Cui, Francine H. Einstein, Aruna Poduval, David Hwang, Nir Barzilai, Pinchas Cohen

Research output: Contribution to journalArticle

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Abstract

Background: Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). A novel mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity. Methods and Findings: Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice. Conclusions: We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.

Original languageEnglish (US)
Article numbere6334
JournalPLoS One
Volume4
Issue number7
DOIs
StatePublished - Jul 22 2009

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insulin
Insulin
Alzheimer disease
noninsulin-dependent diabetes mellitus
insulin resistance
Medical problems
Type 2 Diabetes Mellitus
liver
neurotoxicity
Insulin Resistance
hypothalamus
Alzheimer Disease
humanin
blood glucose
hepatocytes
skeletal muscle
cortex
mitochondria
rodents
pathogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Muzumdar, R. H., Huffman, D. M., Atzmon, G., Buettner, C., Cobb, L. J., Fishman, S., ... Cohen, P. (2009). Humanin: A novel central regulator of peripheral insulin action. PLoS One, 4(7), [e6334]. https://doi.org/10.1371/journal.pone.0006334

Humanin : A novel central regulator of peripheral insulin action. / Muzumdar, Radhika H.; Huffman, Derek M.; Atzmon, Gil; Buettner, Cristoph; Cobb, Laura J.; Fishman, Sigal; Budagov, Temuri; Cui, Lingguang; Einstein, Francine H.; Poduval, Aruna; Hwang, David; Barzilai, Nir; Cohen, Pinchas.

In: PLoS One, Vol. 4, No. 7, e6334, 22.07.2009.

Research output: Contribution to journalArticle

Muzumdar, RH, Huffman, DM, Atzmon, G, Buettner, C, Cobb, LJ, Fishman, S, Budagov, T, Cui, L, Einstein, FH, Poduval, A, Hwang, D, Barzilai, N & Cohen, P 2009, 'Humanin: A novel central regulator of peripheral insulin action', PLoS One, vol. 4, no. 7, e6334. https://doi.org/10.1371/journal.pone.0006334
Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S et al. Humanin: A novel central regulator of peripheral insulin action. PLoS One. 2009 Jul 22;4(7). e6334. https://doi.org/10.1371/journal.pone.0006334
Muzumdar, Radhika H. ; Huffman, Derek M. ; Atzmon, Gil ; Buettner, Cristoph ; Cobb, Laura J. ; Fishman, Sigal ; Budagov, Temuri ; Cui, Lingguang ; Einstein, Francine H. ; Poduval, Aruna ; Hwang, David ; Barzilai, Nir ; Cohen, Pinchas. / Humanin : A novel central regulator of peripheral insulin action. In: PLoS One. 2009 ; Vol. 4, No. 7.
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