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Nathan Goodyear

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views

  • More than half of cancer patients are treated with IR at some point during their treatment
  • fractionation schedule is the delivery of 1.8–2.0 Gy per day, five days per week
  • Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
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  • IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
  • IR is known to induce EMT in vitro
  • p53 is activated in response to IR-induced DNA damage
  • IR paradoxically also promotes tumour recurrence and metastasis
  • DNA double-strand breaks (DSBs)
  • cancer cells undergoing EMT acquire invasive and metastatic properties
  • changes in the tumour microenvironment (TME)
  • IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
  • EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
  • Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
  • EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
  • IR is known to induce stemness and metabolic alterations in cancer cells
  • transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
  • activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
  • Loss of E-cadherin is considered a hallmark of EMT
  • IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
  • IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
  • sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
  • ROS are known to play an important role in IR-induced EMT
  • High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
  • hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
  • Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
    • Nathan Goodyear
       
      NAC for all patients receiving radiation therapy
  • Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
  • IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
  • NF-κB signalling that promotes cell migration
  • ROS promote EMT to allow cancer cells to avoid hostile environments
  • HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
  • Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
  • levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
  • IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
  • IR induces vascular damage that causes hypoxia
  • ROS is implicated in IR-induced HIF-1 activation
  • IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
  • IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
  • The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
  • TGF-β signalling has been shown to play a crucial role in IR-induced EMT
  • AP-1 transcription factor is involved in IR-induced TGF-β1 expression
  • Wnt/β-catenin signalling is also implicated in IR-induced EMT
  • Notch signalling is known to be involved in IR-induced EMT
  • IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
  • PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
  • EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
  • ROS and RNS are also implicated in IR-induced EGFR activation
  • IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
  • IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
  • CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
  • Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
  • identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
  • CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
  • Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
  • signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
  • microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
  • Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
  • EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
  • Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
  • TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
  • some CSC subpopulations arise independently of EMT
  • IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
  • Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
  • IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
  • In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
  • IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
  • EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
  • STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
  • Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
  • metabolic reprogramming
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • metabolic reprogramming
  • tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
  • occurring within the same tumour
  • CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
  • mitochondrial function is crucial for maintaining CSC functionality
  • cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
  • HIF-1 then enhances glycolysis
  • CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
  • lactate transporter, monocarboxylate transporter (MCT)
  • nutrient microenvironment
  • Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
  • MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
  • metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
  • bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
  • the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
  • HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
  • regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
  • HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
  • HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
  • STAT3 has been implicated in EMT-induced metabolic changes as well
  • TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
  • Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
  • EMT, invasion, metastasis, and stemness
  • pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
  • decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
  • LDH catalyses the bidirectional conversion of lactate to pyruvate
  • High levels of LDHA are positively correlated with the expression of EMT and CSC markers
  • IR has been shown to induce metabolic changes in cancer cells
  • IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
  • IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
  • IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
  • IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
  • Lactate can activate latent TGF-
  • lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
  • promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
  • tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
  • immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
  • immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
  • intrinsic immunogenicity or induce tolerance
  • cancer immunoediting’
  • three phases: 1) elimination, 2) equilibrium, and 3) escape.
  • The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
  • IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
  • IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
  • TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
    • Nathan Goodyear
       
      And now the receipts
  • MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
    • Nathan Goodyear
       
      Receipts and mechanisms
  • IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
  • IR-induced Snail increases MMP-2 expression to promote EMT
  • Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
  • IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
  • Metabolic alterations
  • oncogenic metabolism
  • elicit various changes in the TME
  • Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
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    Important review article.
Nathan Goodyear

Hypoxia Regulates Insulin Receptor Substrate-2 Expression to Promote Breast Carcinoma C... - 0 views

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    IRS-2 expression, but not IRS-1 expression, is increased by hypoxia (HIF-1alpha), which selects for tumor cells with increased metastatic potential. IRS-2 is active to mediate insulin-like growth factor I-dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. It is Akt that increases insulin receptor expression. This ties hypoxia to increase in insulin signaling and insulin receptor expression. Boom!
Nathan Goodyear

[Effects of testosterone on insulin r... [Zhonghua Yi Xue Za Zhi. 2006] - PubMed - NCBI - 0 views

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    Testosterone shown to improve GLUT 4 and IRS-1 expression with low dose short term therapy; in contrast, high dose, prolonged therapy shown to down regulate IRS-1 and GLUT 4 expression.  This shows the importance of using saliva for evaluation versus serum.  Serum testing routinely leads to over treatment with high dosages of testosterone.
Nathan Goodyear

Communication between genomic and non-genomic signaling events coordinate steroid hormo... - 0 views

  • steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
  • This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
  • In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
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  • some steroid hormone-induced nuclear events can occur in minutes
  • the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
  • Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
  • NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
  • Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
  • ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
  • G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
  • hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
  • GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
  • androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
  • non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
  • Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
  • ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
  • 17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
  • Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
  • A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
    • Nathan Goodyear
       
      This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
  • Further, ER activates IGF-IR pathways including MAPK
  • GPER is involved in the transactivation of the EGFR independent of classical ER
  • tight interconnection between genomic and non-genomic effects of NRs.
  • non-genomic pathways can also lead to genomic effects
  • androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
  • However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
  • extranuclear steroid hormone actions can potentially reprogram nuclear NR events
  • estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
  • epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells
Nathan Goodyear

http://onlinelibrary.wiley.com/store/10.2164/jandrol.108.005751/asset/jandrol.108.00575... - 0 views

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    Pubmed search finds low T associated IR, type II diabetes, Metabolic syndrome, and increased visceral fat in men.
Nathan Goodyear

Original Articles: Comparison of Insulin Action on Glucose versus Potassium Uptake in H... - 0 views

  • When treating hyperkalemia, insulin remains efficacious in diabetics and nondiabetics and one does not need to resort to b-agonists, and diabetics do not require different doses of insulin to shift potassium
  • the commonly encountered “insulin-resistant” patients actually have preserved insulin-induced potassium disposal, one wonders why their high insulin levels are not causing hypokalemia
  • insulin independently regulates glucose and potassium uptake into cells and this independence explains why in noninsulin-dependent diabetic insulin resistance leads to impaired insulin uptake into cells but has no effect on the cell's potassium disposal
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  • insulin suppresses glycogenolysis, gluconeogenesis, lipolysis and fatty acid release, and protein catabolism and is the principal hormone that stimulates glucose uptake into mainly skeletal muscle and to a certain extent adipocytes
  • Plasma [K+] is a major determinant of the resting potential of all cells
  • Hyperkalemia and hypokalemia are silent yet fatal disturbances because of their arrhythmogenic potentials
  • Basal insulin maintains fasting plasma [K+] within the normal range
  • When insulin levels are suppressed, plasma [K+] rises and pronounced hyperkalemia develops after a potassium load
  • Potassium is a well proven insulin secretagogue
  • Insulin is a key defender against exogenous potassium load by using intracellular buffering to minimize hyperkalemia before renal excretion
  • Hyperkalemia is often encountered in patients with diabetes
  • The insulin-deficient state in type 1 diabetes predisposes to hyperkalemia because of an impaired ability of potassium to enter cells. During hyperglycemic hypertonic states in type 1 and type 2 diabetics, potassium is carried out of cells by convective flux as the most abundant intracellular cation
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    good review of the potassium, glucose, insulin relationship mostly in diabetes.  In diabetes, hyperkalemia is present due to the hyperglycemia and the associated exchange.  Inuslin independantly regulates potassium and glucose intake into the cell.  INterestingly, in IR found in diabetes, the hyperkalemia is the norm, which should cause hypokalemia--the authors were perplexed by this finding.
Nathan Goodyear

http://onlinelibrary.wiley.com/store/10.1113/jphysiol.2012.240952/asset/tjp5465.pdf;jse... - 0 views

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    Study finds sprint interval training increases PLIN 2 and PLIN 5 as in endurance training.  PLIN2/5 are increased and play role in intramuscluar triglyceride breakdown.  Increased IMTG is found in IR.  This aids insulin resistance.  Other studies have found that SIT increased PLIN5 > ET.  Exercise impacts muscle and fat through epigenetics.
Nathan Goodyear

Nutrition & Metabolism | Full text | DHEA administration and exercise training improves... - 0 views

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    Obese rat model finds an improvement in IR with DHEA and exercise.
Nathan Goodyear

Hypoxia Decreases Insulin Signaling Pathways in Adipocytes | Diabetes - 0 views

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    Hypoxia, via HIF-1alpha, inhibits Insulin:insulin receptor signaling, and inhibits IRS signaling.
Nathan Goodyear

High Glucose-Induced Expression of Proinflammatory Cytokine and Chemokine Genes in Mono... - 0 views

  • HG significantly increased the expression of monocyte chemoattractant protein-1 (MCP-1), TNF-α, β2-integrin, interleukin-1β, and others. HG treatment increased transcription of the MCP-1 gene, MCP-1 protein levels, and adhesion of THP-1 cells to endothelial cells. HG-induced MCP-1 mRNA expression and monocyte adhesion were blocked by specific inhibitors of oxidant stress, protein kinase C, ERK1/2, and p38 mitogen-activated protein kinases
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    High glucose associated with significant increase in inflammatory signaling.
Nathan Goodyear

Testosterone: a metabolic hormone in health and disease - 0 views

  • E2 and the inflammatory adipocytokines tumour necrosis factor α (TNFα) and interleukin 6 (IL6) inhibit hypothalamic production of GNRH and subsequent release of LH and FSH from the pituitary
  • Leptin, an adipose-derived hormone with a well-known role in regulation of body weight and food intake, also induces LH release under normal conditions via stimulation of hypothalamic GNRH neurons
  • In human obesity, whereby adipocytes are producing elevated amounts of leptin, the hypothalamic–pituitary axis becomes leptin resistant
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  • there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin
  • Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen status
  • increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated with a decrease in Leydig cell testosterone secretion in men
  • ADT for the treatment of prostatic carcinoma in some large epidemiological studies has been shown to be associated with an increased risk of developing MetS and T2DM
  • Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated insulin levels and worsening glycaemic control
  • Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic control following ADT
  • The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor (AR)
  • Low levels of testosterone have been associated with an atherogenic lipoprotein profile, characterised by high LDL and triglyceride levels
  • a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic men
  • up to 70% of the body's insulin sensitivity is accounted for by muscle
  • Testosterone deficiency is associated with a decrease in lean body mass
  • relative muscle mass is inversely associated with insulin resistance and pre-diabetes
  • GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal muscle cells following testosterone treatment at low dose and short-time incubations
  • local conversion of testosterone to DHT and activation of AR may be important for glucose uptake
  • inverse correlation between testosterone levels and adverse mitochondrial function
  • orchidectomy of male Wistar rats and associated testosterone deficiency induced increased absorption of glucose from the intestine
  • (Kelley & Mandarino 2000). Frederiksen et al. (2012a) recently demonstrated that testosterone may influence components of metabolic flexibility as 6 months of transdermal testosterone treatment in aging men with low–normal bioavailable testosterone levels increased lipid oxidation and decreased glucose oxidation during the fasting state.
  • Decreased lipid oxidation coupled with diet-induced chronic FA elevation is linked to increased accumulation of myocellular lipid, in particular diacylglycerol and/or ceramide in myocytes
  • In the Chang human adult liver cell line, insulin receptor mRNA expression was significantly increased following exposure to testosterone
  • Testosterone deprivation via castration of male rats led to decreased expression of Glut4 in liver tissue, as well as adipose and muscle
  • oestrogen was found to increase the expression of insulin receptors in insulin-resistant HepG2 human liver cell line
  • FFA decrease hepatic insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance.
  • Only one, albeit large-scale, population-based cross-sectional study reports an association between low serum testosterone concentrations and hepatic steatosis in men (Völzke et al. 2010)
  • This suggests that testosterone may confer some of its beneficial effects on hepatic lipid metabolism via conversion to E2 and subsequent activation of ERα.
  • hypogonadal men exhibiting a reduced lean body mass and an increased fat mass, abdominal or central obesity
  • visceral adipose tissue was inversely correlated with bioavailable testosterone
  • there was no change in visceral fat mass in aged men with low testosterone levels following 6 months of transdermal TRT, yet subcutaneous fat mass was significantly reduced in both the thigh and the abdominal areas when analysed by MRI (Frederiksen et al. 2012b)
  • ADT of prostate cancer patients increased both visceral and subcutaneous abdominal fat in a 12-month prospective observational study (Hamilton et al. 2011)
  • Catecholamines are the major lipolysis regulating hormones in man and regulate adipocyte lipolysis through activation of adenylate cyclase to produce cAMP
  • deficiency of androgen action decreases lipolysis and is primarily responsible for the induction of obesity (Yanase et al. 2008)
  • may be some regional differences in the action of testosterone on subcutaneous and visceral adipose function
  • proinflammatory adipocytokines IL1, IL6 and TNFα are increased in obesity with a downstream effect that stimulates liver production of CRP
  • observational evidence suggests that IL1β, IL6, TNFα and CRP are inversely associated with serum testosterone levels in patients
  • TRT has been reported to significantly reduce these proinflammatory mediators
  • This suggests a role for AR in the metabolic actions of testosterone on fat accumulation and adipose tissue inflammatory response
  • testosterone treatment may have beneficial effects on preventing the pathogenesis of obesity by inhibiting adipogenesis, decreasing triglyceride uptake and storage, increasing lipolysis, influencing lipoprotein content and function and may directly reduce fat mass and increase muscle mass
  • Early interventional studies suggest that TRT in hypogonadal men with T2DM and/or MetS has beneficial effects on lipids, adiposity and parameters of insulin sensitivity and glucose control
  • Evidence that whole-body insulin sensitivity is reduced in testosterone deficiency and increases with testosterone replacement supports a key role of this hormone in glucose and lipid metabolism
  • Impaired insulin sensitivity in these three tissues is characterised by defects in insulin-stimulated glucose transport activity, in particular into skeletal muscle, impaired insulin-mediated inhibition of hepatic glucose production and stimulation of glycogen synthesis in liver, and a reduced ability of insulin to inhibit lipolysis in adipose tissue
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    Great review of the Hypogonadal-obesity-adipocytokine hypothesis.
Nathan Goodyear

Insulin-like growth factor receptor-1 (IGF-IR) as a target for prostate cancer therapy - 0 views

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    Insulin and IGF-1 receptors show 70% homology.
Nathan Goodyear

Obesity - Dietary Capsaicin Reduces Obesity-induced Insulin Resistance and Hepatic Stea... - 0 views

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    This study looks at the effects of capsaicin on inflammation and obesity.  Capsaicin decreases IL-1B, IL-6, TNF-alpha and MCP-1.  This reduces insulin and leptin levels, as well as increase adiponectin activity.  This article also briefly discusses curcumin, which has similar activity.
Nathan Goodyear

The Dark Side of Testosterone Deficiency: II. Type 2 Diabetes and Insulin Resistance --... - 1 views

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    low Testosterone associated with insulin resistance, type II diabetes, metabolic syndrome, and increased fat.  These will all translate to increased mortality.
Nathan Goodyear

Plant-Based Nutritional Supplementation Attenuates LPS-Induced Low-Grade Systemic Activ... - 0 views

  • consumption of this particular diet for at least a 2-month period helped to reduce the outcomes of both acute and chronic inflammation induced by LPS.
  • chronic inflammation compromised both glucose and insulin tolerance, which is normally seen in certain chronic metabolic diseases
  • LPS resulted in an increase in neopterin levels, which is a marker for immune system activation
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  • diet enriched in fruits and vegetables (and consequently phytochemicals) was able to reverse the process and maintain and even elevate insulin sensitivity and glucose tolerance
  • LPS-mediated effects are related to an increase in TLR4 levels that triggers the activation of nuclear factor-kB (NF-kB), a transcription factor that activates a cascade of inflammatory mediators [41]. These factors control the transcription of inflammatory mediators, such as IL-1β, IL-6, TNF-α, TNF-β, INF-α, INFβ, INF-γ
  • Inflammation can alter insulin action and give rise to diabetes and obesity by blocking insulin receptor downstream events, impairing insulin receptor substrate 1 (IRS-1) activation and phosphatidylinositol 3-kinase-dependent (PI3K) pathways, therefore compromising insulin signaling
  • systemic inflammation (generated by LPS) also increased neopterin levels in the urine and resulted in altered neuronal activity by decreasing dopamine (DA) metabolism
  • an increase in neopterin levels has been recognized a sensitive biomarker for immune system activation
  • Our experiments denoted that these diets were able to diminish inflammatory mediators and oxidative damage
Nathan Goodyear

Diabetology & Metabolic Syndrome | Full text | Visceral adiposity, insulin resistance a... - 0 views

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    adipose tissue and it's biological activity contribution to cancer risk.  Good review of our current understanding on how adipose tissue increases the favorably of cancer.
Nathan Goodyear

Inflammation and insulin resistance 10.1016/j.febslet.2007.11.057 : FEBS Letters | Scie... - 0 views

  • A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
  • Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
  • Insulin is a pleiotropic hormone
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  • the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
  • Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
  • Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
  • adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
  • One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
  • The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
  • elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
  • overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
  • Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
  • In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
  • macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
  • saturated fatty acids are the most potent inducers of this inflammatory response
  • Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
  • Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
  • In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
  • elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
  • Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
  • C-reactive protein (CRP)
  • these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
  • the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
  • It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
  • Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
  • Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
  • Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
  • Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
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    Great review of all the known components in the inflammation, insulin resistance link
Nathan Goodyear

What dietary modification best improves insulin sensitivity and why? - Weickert - 2012 ... - 0 views

  • cereal-fibre intake, under isoenergetic conditions, improves whole-body IR in both short-term and more prolonged studies
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    Great review of macronutrients and insulin resistance.  Caloric reduction plus exercise still the best method to reduce insulin resistance.   Long-term high protein intake increases insulin resistance.
Nathan Goodyear

Branched-chain amino acids in liver diseases - 0 views

  • Serum concentrations of BCAAs are decreased, while the concentrations of the aromatic amino acids (AAAs) phenylalanine and tyrosine are increased, in patients with advanced liver diseases, resulting in a low ratio of BCAAs to AAAs, a ratio called the Fischer ratio
  • BCAAs were reported to stimulate the production of hepatocyte growth factor
  • a simplified Fischer ratio, the BCAA to tyrosine ratio (BTR), has been reported useful for predicting serum albumin concentration one year later
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  • BCAA supplementation was shown to delay the progression of CCl4-induced chronic liver injury in a rat model by reducing hepatic apoptosis
  • BCAAs promoted hepatocyte regeneration in a rat model of hepatectomy
  • BCAA supplementation for advanced cirrhotic patients improves nutritional status and quality of life
  • BCAAs activate mTOR and subsequently increase the production of eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase, which upregulate the synthesis of albumin
  • BCAAs were shown to improve homeostasis model assessment scores for insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) in patients with chronic liver disease, indicating that BCAAs can ameliorate insulin resistance
  • Several clinical trials have suggested that BCAA supplementation improves the prognosis of cirrhotic patients
  • A low Fischer ratio has been associated with hepatic encephalopathy
  • Treatment with BCAAs may therefore have a beneficial effect on patients with hepatic encephalopathy mainly by compensating decreased ratio of BCAAs to AAAs, but not by reducing serum ammonia levels
  • Two randomized studies also showed that BCAAs did not clearly prevent HE in patients with advanced cirrhosis, although BCAAs prevented the progression of hepatic failure
  • a systematic review with meta-analyses on the effect of oral BCAAs for the treatment of HE was published[66]. The review has revealed that supplementation of oral BCAAs in cirrhotic patients inhibits the manifestation of HE, especially in patients with overt HE rather than those with minimal HE, but showed no effect on the survival of those patients[66]. Thus, oral administration of BCAAs is the treatment of choice in cirrhotic patients with HE
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    good review of BCAA and liver disease: both mechanisms and therapy.
Nathan Goodyear

Metabolic Effects of Fructose and the Worldwide Increase in Obesity - 0 views

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    high fructose intake results in insulin resistance, obesity, type II DM, and high blood pressure
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