humanin and Diabetes-Mellitus--Type-2

The prevalence of Alzheimer's disease (AD) is higher among type 2 diabetes mellitus (T2DM) patients. In T2DM patients, the progression of AD is more rapid. Furthermore, several pathophysiological pathways are common to AD and T2DM. Humanin is a recently introduced, mitochondrial-derived peptide with neuroprotective effects. Humanin can alter the mechanisms involved in AD and T2DM pathogenesis. Insulin resistance as well as oxidative stress has been shown to be associated with increased amyloid deposition in brain neurons and islet beta cells. Moreover, advanced glycation end products and lipid metabolism disorders are common pathways of oxidative stress and low-grade systemic inflammation in AD and T2DM. These common pathways may explain AD and T2DM pathogenesis and suggest common treatments for both diseases. Treatments for T2DM and AD attempt to slow cognitive decline, and recent investigations have focused on agents that may alter pathways common to AD and T2DM pathogenesis. Non-steroidal antiinflammatory drugs, such as interleukin-1 antagonists and statins, are possible drug candidates for both AD and T2DM.

Topics: Alzheimer Disease; Apolipoproteins E; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Oxidative Stress

Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.

Topics: Aged, 80 and over; Alzheimer Disease; Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Growth Differentiation Factor 15; Healthy Aging; Humans; Intracellular Signaling Peptides and Proteins

Mitochondrially derived peptides (MDPs) such as humanin (HN) have shown a remarkable ability to modulate neurological amyloids and apoptosis-associated proteins in cells and animal models. Recently, we found that humanin-like peptides also inhibit amyloid formation outside of neural environments in islet amyloid polypeptide (IAPP) fibrils and plaques, which are hallmarks of Type II diabetes. However, the biochemical basis for regulating amyloids through endogenous MDPs remains elusive. One hypothesis is that MDPs stabilize intermediate amyloid oligomers and discourage the formation of insoluble fibrils. To test this hypothesis, we carried out simulations and experiments to extract the dominant interactions between the S14G-HN mutant (HNG) and a diverse set of IAPP structures. Replica-exchange molecular dynamics suggests that MDPs cap the growth of amyloid oligomers. Simulations also indicate that HNG-IAPP heterodimers are 10 times more stable than IAPP homodimers, which explains the substoichiometric ability of HNG to inhibit amyloid growth. Despite this strong attraction, HNG does not denature IAPP. Instead, HNG binds IAPP near the disordered NFGAIL motif, wedging itself between amyloidogenic fragments. Shielding of NFGAIL-flanking fragments reduces the formation of parallel IAPP β-sheets and subsequent nucleation of mature amyloid fibrils. From ThT spectroscopy and electron microscopy, we found that HNG does not deconstruct mature IAPP fibrils and oligomers, consistent with the simulations and our proposed hypothesis. Taken together, this work provides new mechanistic insight into how endogenous MDPs regulate pathological amyloid growth at the molecular level and in highly substoichiometric quantities, which can be exploited through peptidomimetics in diabetes or Alzheimer's disease.

Topics: Diabetes Mellitus, Type 2; Humans; Intracellular Signaling Peptides and Proteins; Islet Amyloid Polypeptide; Mitochondria; Molecular Dynamics Simulation

Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of humanin that is important for humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.

Topics: Age Factors; Alzheimer Disease; Animals; Cell Line, Tumor; Cytokine Receptor gp130; Diabetes Mellitus, Type 2; HEK293 Cells; Hippocampus; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinases; Male; MAP Kinase Kinase Kinases; Memory; Mice; Mice, Inbred C57BL; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neurons; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor

Humanin (HN) is a 24-aa polypeptide that offers protection from Alzheimer's disease and myocardial infarction, increases insulin sensitivity, improves survival of β cells, and delays onset of diabetes. Here we examined the acute effects of HN on insulin secretion and potential mechanisms through which they are mediated. Effects of a potent HN analog, HNGF6A, on glucose-stimulated insulin secretion (GSIS) were assessed in vivo and in isolated pancreatic islets and cultured murine β cell line (βTC3) in vitro. Sprague-Dawley rats (3 mo old) that received HNGF6A required a significantly higher glucose infusion rate and demonstrated higher insulin levels during hyperglycemic clamps compared to saline controls. In vitro, compared to scrambled peptide controls, HNGF6A increased GSIS in isolated islets from both normal and diabetic mice as well as in βTC3 cells. Effects of HNGF6A on GSIS were dose dependent, K-ATP channel independent, and associated with enhanced glucose metabolism. These findings demonstrate that HNGF6A increases GSIS in whole animals, from isolated islets and from cells in culture, which suggests a direct effect on the β cell. The glucose-dependent effects on insulin secretion along with the established effects on insulin action suggest potential for HN and its analogs in the treatment of diabetes.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Glucose; Insulin; Insulin Secretion; Insulin-Secreting Cells; Intracellular Signaling Peptides and Proteins; KATP Channels; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptors, Leptin

Humanin is a small endogenous antiapoptotic peptide, originally identified as protective against Alzheimer's disease, but subsequently also found on human endothelium as well as carotid artery plaques. Endothelial dysfunction is a precursor to the development of atherosclerotic plaques, which are characterized by a highly proinflammatory, reactive oxygen species, and apoptotic milieu. Previous animal studies demonstrated that humanin administration may improve endothelial function. Thus the aim of this study was to test the hypothesis that patients with coronary endothelial dysfunction have reduced systemic levels of humanin. Forty patients undergoing coronary angiography and endothelial function testing were included and subsequently divided into two groups based on coronary blood flow (CBF) response to intracoronary acetylcholine (normal ≥ 50% increase from baseline, n = 20 each). Aortic plasma samples were obtained at the time of catheterization for the analysis of humanin levels and traditional biomarkers of atherosclerosis including C-reactive protein, Lp-Pla(2), and homocysteine. Baseline characteristics were similar in both groups. Patients with coronary endothelial dysfunction (change in CBF = -33 ± 25%) had significantly lower humanin levels (1.3 ± 1.1 vs. 2.2 ± 1.5 ng/ml, P = 0.03) compared with those with normal coronary endothelial function (change in CBF = 194 ± 157%). There was a significant and positive correlation between improved CBF and humanin levels (P = 0.0091) not seen with changes in coronary flow reserve (P = 0.76). C-reactive protein, Lp-Pla(2), and homocysteine were not associated with humanin levels. Thus we observed that preserved human coronary endothelial function is uniquely associated with higher systemic humanin levels, introducing a potential diagnostic and/or therapeutic target for patients with coronary endothelial function.

Topics: Acetylcholine; Adult; Atherosclerosis; Biomarkers; Blood Chemical Analysis; Coronary Angiography; Coronary Circulation; Coronary Disease; Coronary Vessels; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Heart Failure; Hemodynamics; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Lipids; Male; Microcirculation; Middle Aged; Vasodilator Agents

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.. 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.. 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.

Topics: Alzheimer Disease; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Liver; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Rats, Zucker