Humanin: a novel central regulator of peripheral insulin action.

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

PloS one22 Jul 2009Cited by 217 (Europe PMC)

PMID19623253PMCIDPMC2709436DOI10.1371/journal.pone.0006334PepBankPUB-19623253

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Summary

BackgroundDecline 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 findingsUsing 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.ConclusionsWe 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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study10

4 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In animals studied with clamp technology, continuous intracerebroventricular infusion of HN significantly improved overall insulin sensitivity.
In plain wordsIn animals, humanin infused into the brain improved how well the body responds to insulin.
Peptide
Humanin
Outcome
IncreaseOverall insulin sensitivity with central HN
Study
n: not reported in source
Insulin clamp
Outcome group
Glycemic control · Metabolic and weight
Studied dose
Dose not stated · intracerebroventricularAs given in this study.
Source sentences
Summary
Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity.
1 context sentence(design, population, supporting numbers)
Summary · context
Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action.
Show in the study text Report a problemFND-1962325301
02AnimalAnimal study (in vivo)Mechanism
In animals, the central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling.
In plain wordsIn animals, humanin's effect on insulin response in the brain went along with activation of STAT-3 signalling.
Peptide
Humanin
Outcome
IncreaseHypothalamic STAT-3 signaling with central HN
Study
n: not reported in source
Insulin clamp
Outcome group
Receptor activity and mechanism · Metabolic and weight
Studied dose
Dose not stated · intracerebroventricularAs given in this study.
Source sentences
Summary
The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling
1 context sentence(design, population, supporting numbers)
Summary · context
Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action.
Show in the study text Report a problemFND-1962325302
03AnimalAnimal study (in vivo)Mechanism
In animals, the central effects of HN on insulin action were negated by co-inhibition of hypothalamic STAT-3.
In plain wordsIn animals, blocking STAT-3 in the brain removed humanin's effect on insulin response.
Peptide
Humanin
Outcome
No significant changeCentral HN effect on insulin action with STAT-3 inhibition
Study
n: not reported in source
Insulin clamp with hypothalamic STAT-3 inhibition
Outcome group
Receptor activity and mechanism · Metabolic and weight
Studied dose
Dose not stated · intracerebroventricularAs given in this study.
Source sentences
Summary
effects that were negated by co-inhibition of hypothalamic STAT-3.
1 context sentence(design, population, supporting numbers)
Summary · context
Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action.
Show in the study text Report a problemFND-1962325303
04LabIn vitro (cells)Mechanism
HN had no direct effect on primary hepatocytes.
In plain wordsIn cells, humanin had no direct effect on liver cells.
Peptide
Humanin
Outcome
No significant changeDirect effect of HN on primary hepatocytes
Study
n: not reported in source
Primary hepatocytes
Outcome group
Receptor activity and mechanism · Liver
Studied dose
Dose not stated
Source sentences
Summary
This is consistent with the lack of a direct effect of HN on primary hepatocytes.
Show in the study text Report a problemFND-1962325306

Natural levels measured3

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

05HumanEndogenous levelObservational studyOther
In humans, circulating levels of HN were decreased with age.
In plain wordsIn people, the body's own humanin in the blood was lower with older age.
Peptide
Humanin
Outcome
DecreaseCirculating HN level with age in humans
Study
n: not reported in source
Circulating HN
Outcome group
Aging markers · Aging and longevity
Source sentences
Summary
and circulating levels of HN were decreased with age in humans and mice.
This result measures the body's own Humanin. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-1962325309
06AnimalEndogenous levelAnimal study (in vivo)Other
In rodents, the amount of detectable HN in hypothalamus, skeletal muscle and cortex decreased with age.
In plain wordsIn rodents, the body's own humanin in the brain and muscle fell with age.
Peptide
Humanin
Outcome
DecreaseHN level in tissues with age
Study
rodentn: not reported in source
Hypothalamus, skeletal muscle and cortex
Outcome group
Aging markers · Aging and longevity
Source sentences
Summary
Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents
This result measures the body's own Humanin. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-1962325308
07AnimalEndogenous levelAnimal study (in vivo)Other
In mice, circulating levels of HN were decreased with age.
In plain wordsIn mice, the body's own humanin in the blood was lower with older age.
Peptide
Humanin
Outcome
DecreaseCirculating HN level with age in mice
Study
mousen: not reported in source
Circulating HN
Outcome group
Aging markers · Aging and longevity
Source sentences
Summary
and circulating levels of HN were decreased with age in humans and mice.
This result measures the body's own Humanin. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-1962325310

Studies that did not test the peptide alone3

In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Humanin.

08AnimalNot a test of Humanin aloneAnimal study (in vivo)Efficacy outcome
In animals, peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN.
In plain wordsIn animals, intravenous humanin derivatives improved insulin response like humanin given into the brain.
Peptide
Humanin
Outcome
IncreaseInsulin sensitivity with peripheral IV HN derivatives
Study
n: not reported in source
Insulin clamp
Outcome group
Glycemic control · Metabolic and weight
Source sentences
Summary
Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN.
1 context sentence(design, population, supporting numbers)
Summary · context
Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-1962325304
09AnimalNot a test of Humanin aloneAnimal study (in vivo)Mechanism
In animals, inhibition of hypothalamic STAT-3 completely negated the effects of an intravenous HN analog on liver.
In plain wordsIn animals, blocking STAT-3 in the brain removed the liver effects of an intravenous humanin analog.
Peptide
Humanin
Outcome
No significant changeLiver effects of IV HN analog with STAT-3 inhibition
Study
n: not reported in source
Insulin clamp with hypothalamic STAT-3 inhibition
Outcome group
Receptor activity and mechanism · Liver
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-1962325305
10AnimalNot a test of Humanin aloneAnimal study (in vivo)Efficacy outcome
In Zucker diabetic fatty rats, a single treatment with a highly potent HN analog significantly lowered blood glucose.
In plain wordsIn diabetic rats, one dose of a strong humanin analog lowered blood glucose.
Peptide
Humanin
Outcome
DecreaseBlood glucose after a single dose of a highly potent HN analog
Study
ratn: not reported in source
Zucker diabetic fatty rats
Outcome group
Glycemic control · Metabolic and weight
Source sentences
Summary
Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-1962325307

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Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

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