Humanin: a novel central regulator of peripheral insulin action.
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.


RESULTS
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.
Muzumdar
Radhika H
RH
Department of Pediatrics, Children's Hospital at Montefiore, Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Huffman
Derek M
DM
Atzmon
Gil
G
Buettner
Christoph
C
Cobb
Laura J
LJ
Fishman
Sigal
S
Budagov
Temuri
T
Cui
Lingguang
L
Einstein
Francine H
FH
Poduval
Aruna
A
Hwang
David
D
Barzilai
Nir
N
Cohen
Pinchas
P
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
D001786:Blood Glucose; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C427211:humanin