Humanin: A Novel Central Regulator of Peripheral Insulin Action

Abstract

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.

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

“…Approximately 14 days later, rats were sedated for surgical placement of indwelling catheters into the right internal jugular vein and the left carotid artery as described (Muzumdar et al ., 2006a,b; Einstein et al ., 2008; Muzumdar et al ., 2009; Einstein et al ., 2010). Animals were treated with analgesic as needed postoperatively and recovery was monitored until animals were within 3–5% of their preoperative weight (~ 7 days) before conducting clamp studies.…”

“…In preparation for clamp studies, rats were sedated with 2% isoflurane for stereotactic placement of a steel‐guide cannula (Plastics One, Roanoke, VA, USA) reaching the 3rd ventricle (coordinates from bregma: +0.2 mm A/P, −9.0 mm D/V, 0.0 directly on the midsagittal suture) and the implant was secured in place with dental cement as described (Muzumdar et al ., 2006a,b, 2009). Approximately 14 days later, rats were sedated for surgical placement of indwelling catheters into the right internal jugular vein and the left carotid artery as described (Muzumdar et al ., 2006a,b; Einstein et al ., 2008; Muzumdar et al ., 2009; Einstein et al ., 2010).…”

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

“…Humanin has also been shown to increase insulin sensitivity in the peripheral tissues via STAT3-mediated activation of the central nervous system (26) and preserve endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic apolipoprotein E-deficient mice (27).…”

From evolutionary bystander to master manipulator: the emerging roles for the mitochondrial genome as a modulator of nuclear gene expression

“…Seemingly acting as an antiapoptotic agent, humanin is hypothesized to be of fundamental importance for cell function and has been identified as a pivotal element in several agerelated disease phenotypes, including Alzheimer's disease 26 and T2DM. 27 Interestingly, humanin levels are reduced in aged individuals and it is, therefore, tempting to speculate that such reduced levels may be indicative of age-related disease onset. 27,28 The humanin mtDNA sequence also maps to 13 nuclear-located regions with 10 of these being functionally relevant, indicating the existence of putative tissue-specific isoforms.…”

“…27 Interestingly, humanin levels are reduced in aged individuals and it is, therefore, tempting to speculate that such reduced levels may be indicative of age-related disease onset. 27,28 The humanin mtDNA sequence also maps to 13 nuclear-located regions with 10 of these being functionally relevant, indicating the existence of putative tissue-specific isoforms. These regions show high conservation with chimpanzee and establish a direct link between the mtDNA and nuclear function.…”