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Nathan Goodyear

Effects of Cortisol on Carbohydrate, Lipid, and Protein Metabolism: Studies of Acute Co... - 0 views

jcem.endojournals.org/...3553.full

cortisol glucose glucose homeostasis insulin resistance T3

shared by Nathan Goodyear on 01 Apr 13 - No Cached
  • Nathan Goodyear on 01 Apr 13
     
    This study they looked at the withdrawal of cortisol on glucose homeostasis.  The point is that cortisol has profound effects on glucose homeostasis.  Elevated cortisol or exogenous intake reduces T3 and increases insulin resistance.
Nathan Goodyear

Therapy in the Early Stage: Incretins - 0 views

care.diabetesjournals.org/...S264.full

incretins glucose diabetes

shared by Nathan Goodyear on 11 Dec 13 - No Cached
  • Increased resistance to insulin action in the skeletal muscle and liver associated with enhanced hepatic glucose output and impaired insulin secretion due to a progressive decline of β-cell function are long-recognized core defects
  • in addition, other mechanisms/organs are involved, augmenting the pathological pathways: adipocytes (altered fat metabolism due to insulin resistance), gastrointestinal tract (incretin deficiency and/or resistance), pancreatic α-cells (hyperglucagonemia and increased hepatic sensitivity to glucagon), kidneys (enhanced glucose reabsorption), and central nervous system (insulin resistance)
  • β-cell failure
    • Nathan Goodyear
      Nathan Goodyear on 11 Dec 13
       
      and studies have shown that a reduction in insulin function will decrease LH production and thus lead to a decrease in Testosterone production in men.
  • ...2 more annotations...
  • Incretins are gut-derived hormones, members of the glucagon superfamily, released in response to nutrient ingestion (mainly glucose and fat)
  • They exert a wide range of effects, including stimulation of pancreatic insulin secretion in a glucose-dependent manner and play an important role in the local gastrointestinal and whole-body physiology
  • Nathan Goodyear on 11 Dec 13
     
    good discussion on incretins and their role in glucose homeostasis. 
Nathan Goodyear

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 d... - 0 views

www.ncbi.nlm.nih.gov/...PMC3018764

glucose diabetes genes genetics

shared by Nathan Goodyear on 24 Jan 13 - No Cached
  • Nathan Goodyear on 24 Jan 13
     
    genetics play role in glucose homeostasis.
Nathan Goodyear

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment - 0 views

pharmrev.aspetjournals.org/...470.full

incretins hormone hormones glucose diabetes

shared by Nathan Goodyear on 11 Dec 13 - No Cached
  • Nathan Goodyear on 11 Dec 13
     
    incretins and glucose homeostasis
Nathan Goodyear

The role of testosterone in the m... [J Steroid Biochem Mol Biol. 2009] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...19444934

low T Testosterone low T low Testosterone lipids glucose diabetes metabolic syndrome SHBG metabolic syndrome IR insulin resistance

shared by Nathan Goodyear on 14 Aug 14 - No Cached
  • Nathan Goodyear on 14 Aug 14
     
    Testosterone plays an important role in glucose and lipid metabolism.  Thus, low Testosterone, will result in increased disruption in the homeostasis of glucose and lipids resulting in increased weight, insulin resistance, diabetes, metabolic syndrome... Low SHBG was also shown to be associated with MetS
Nathan Goodyear

ScienceDirect.com - Cell Metabolism - Estrogen Receptors and the Metabolic Network - 0 views

www.sciencedirect.com/...S1550413111003123

ER-alpha ER-beta estrogen receptor receptors metabolic syndrome MetS hormone hormones

shared by Nathan Goodyear on 11 Oct 12 - No Cached
  • The pro-opiomelanocortin (POMC) neurons have an anorexigenic action and, when activated, reduce food intake through the release of two peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine-and-amphetamine-regulated transcripts (CART). The neuropeptide Y (NPY) neurons, on the other hand, release NPY hormone and agouti gene-related protein (AgRP), which prevent the binding of α-MSH to MC3R and MC4R, increasing food intake
  • This suggests that the central anorexic effects of E2 may occur via ERβ
  • The main hypothalamic areas involved in food intake and satiety are the arcuate nucleus (ARC), the lateral hypothalamus (LH), the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), and the dorsomedial hypothalamus (DMH)
  • ...22 more annotations...
  • Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure
  • E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution
  • ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake
  • It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.
  • Both ERs have been identified in the ARC
  • Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.
  • Both ERs have been identified in the LH
  • both ERs have been identified in this nucleus
  • The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive
  • The VMH is ERα regulated
  • Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body
  • GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake
  • data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance
  • In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane
  • It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.
  • E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue
  • In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue
  • decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin
  • Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance
  • Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs
  • Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue
  • suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue
  • Nathan Goodyear on 11 Oct 12
     
    very nice article that looks at the balance of ER-alpha/ER-beta and their role in metabolic syndrome.  This article discusses the balance of  these receptors are tissue dependent in their effect.  I like their conclusion: "...but these mechanisms will never be completely understood if they are not considered in the context of a whole system.
Nathan Goodyear

Inflammatory cause of metabolic syndrome via brain stress and NF-κB - 0 views

www.ncbi.nlm.nih.gov/...PMC3314172

metabolic syndrome TLR cytokines hypothalamus brain neurology metabolic syndrome NF-kappaB DIO diet induced obesity over nutrition nutrition inflammation

shared by Nathan Goodyear on 09 Jul 13 - No Cached
  • Mechanistic studies further showed that such metabolic inflammation is related to the induction of various intracellular stresses such as mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and autophagy defect under prolonged nutritional excess
  • intracellular stress-inflammation process for metabolic syndrome has been established in the central nervous system (CNS) and particularly in the hypothalamus
  • the CNS and the comprised hypothalamus are known to govern various metabolic activities of the body including appetite control, energy expenditure, carbohydrate and lipid metabolism, and blood pressure homeostasis
  • ...56 more annotations...
  • Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids
  • a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)
  • Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
  • there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes
  • To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases
  • intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers
  • intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging
  • dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain
  • mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment
  • Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways
  • unfolded protein response (UPR) machinery
  • ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases
  • brain ER stress underlies neurodegenerative diseases
  • under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival
  • intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance
  • prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging
  • TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense
  • Most hypothalamic cell types including neurons and glia cells express TLRs
  • overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs
  • Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition
  • hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding
  • overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain
  • these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.
  • circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors
  • significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components
  • entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension
  • Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions
  • both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.
  • In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein
  • IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity
  • Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition
  • it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic
  • this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension
  • evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition
  • In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging
  • intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation
  • overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved
  • excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC
  • oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging
  • central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations
  • overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders
  • chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases
  • recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations
  • when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect
  • autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)
  • The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases
  • Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome
  • Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway
  • TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase
  • these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response
  • TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus
  • central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.
  • cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation
  • central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain
  • the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance
  • the hypothalamus, is the central regulator of energy and body weight balance [
  • Nathan Goodyear on 09 Jul 13
     
    Great article chronicles the biochemistry of "over nutrition" and inflammation through NF-kappaB activation and its impact on the brain.
Nathan Goodyear

Obesity in men: the hypogonadal-estrogen rece... [Med Hypotheses. 2008] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...17825496

obesity overweight insulin resistance ER-beta low T testosterone GLUT4 men hormone hormones

shared by Nathan Goodyear on 16 Oct 12 - No Cached
  • Nathan Goodyear on 16 Oct 12
     
    This article discusses there relationship of ER-beta and glucose homeostasis.  In this study, low testosterone was associated with increased ER-beta expression.  This resulted in down regulation of GLUT4 and the result is insulin resistance.
Nathan Goodyear

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease - 0 views

hyper.ahajournals.org/...1218.long

renal kidney disease kidney disease renal disease low t low testosterone testosterone estrogen estradiol diabetes DM hormone hormones

shared by Nathan Goodyear on 05 Mar 13 - No Cached
  • Nathan Goodyear on 05 Mar 13
     
    Diabetes associated with low serum testosterone.  This study points to a 4.7 fold decrease.  This is accompanied by a 2.9 fold increase in estradiol.  Castration worsened this imbalance by decreasing the testosterone level further.  Likely the low T and increased aromatase activity aid in the development of diabetic renal disease. Numerous studies have shown that testosterone therapy improves glucose homeostasis.
Nathan Goodyear

Diet-induced obesity and low testosterone increase neuroinflammation and impair neural ... - 0 views

www.ncbi.nlm.nih.gov/...PMC4190446

Testosterone neuroinflammation glia insulin resistance obesity diabetes brain CNS PNS inflammation low T low Testosterone TNF-alpha IL-1beta

shared by Nathan Goodyear on 28 Apr 15 - No Cached
  • both obesity and low testosterone are also risk factors for neural dysfunction, including cognitive impairment [58–61] and development of AD
  • Levels of obesity and testosterone are often inversely correlated
  • diet-induced obesity causes significant metabolic disturbances and impairs central and peripheral nervous systems.
  • ...23 more annotations...
  • both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems
  • In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation
  • fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet
  • testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation
  • fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.
  • testosterone status did not significantly affect body weight
  • testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis
  • Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone
  • it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth
  • Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β
  • Testosterone status also affected metabolic and neural measures
  • many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression
  • neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation
  • testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions
  • glia are the primary sources of proinflammatory molecules in the CNS
  • poorer survival of neurons grown on glia from mice maintained on high-fat diet
  • Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group
  • significantly increased expression of TNFα and IL-1β in glia cultures derived from obese mice
  • testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions
  • IL-1β treatment has been shown to induce synapse loss and inhibit differentiation of neurons
  • Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration
  • testosterone prevented and/or restored thermal nociception in both diet groups
  • a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS
  • Nathan Goodyear on 28 Apr 15
     
    Study points to obesity and low Testosterone contribution of neuroinflammation.  No effect of body weight was seen with TRT.  This animal model found similar positive effects of TRT in insulin sensitivity.  Obesity and low T increase inflammatory cytokine production: this study found an increase in TNF-alpha and IL-1beta and TRT reduced TNF-alpha and IL-1beta to near base-line.  Testosterone is neuroprotective and this study reviewed the small volume of evaded that pointed to benefit from estradiol.  Testosterone's effect on glial survival was positive but not significant.  Obesity and low T were found to be associated with increased macrophage infiltration in the PNS with increased TNF-alpha and IL-1beta.   Testosterone therapy improved peripheral neuropathy via its positive effects on nocicieption.
Nathan Goodyear

Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Dis... - 0 views

www.ncbi.nlm.nih.gov/...PMC3448089

dysbiosis diet nutrition metabolic endotoxemia disease inflammation gut

shared by Nathan Goodyear on 27 Jul 14 - No Cached
  • The gut microbiota participates in the body’s metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders
  • Firmicutes and Bacteroidetes represent the two largest phyla in the human and mouse microbiota and a shift in the ratio of these phyla has been associated with many disease conditions, including obesity
  • In obese humans, there is decreased abundance of Bacteroidetes compared to lean individuals
  • ...21 more annotations...
  • weight loss in obese individuals results in an increase in the abundance of Bacteroidetes
  • there is conflicting evidence on the composition of the obese microbiota phenotype with regards to Bacteroidetes and Firmicutes ratios
  • Bifidobacteria spp. from the phyla Actinobacteria, has been shown to be depleted in both obese mice and human subjects
  • While it is not yet clear which specific microbes are inducing or preventing obesity, evidence suggests that the microbiota is a factor.
  • targeted manipulation of the microbiota results in divergent metabolic outcomes depending on the composition of the diet
  • The microbiota has been linked to insulin resistance or type 2 diabetes (T2D) via metabolic syndrome and indeed the microbiota of individuals with T2D is also characterized by an increased Bacteroidetes/Firmicutes ratio, as well as an increase in Bacillus and Lactobacillus spp
  • It was also observed that the ratio of Bacteriodes-Prevotella to C. coccoides-E. rectale positively correlated with glucose levels but did not correlate with body mass index [80]. This suggests that the microbiota may influence T2D in conjunction with or independently of obesity
  • In humans, high-fat Western-style diets fed to individuals over one month can induce a 71% increase in plasma levels of endotoxins, suggesting that endotoxemia may develop in individuals with GI barrier dyfunction connected to dysbiosis
  • LPS increases macrophage infiltration essential for systemic inflammation preceding insulin resistance, LPS alone does not impair glucose metabolism
  • early treatment of dysbiosis may slow down or prevent the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences
  • increased Firmicutes and decreased Bacteroidetes, which is the microbial profile found in lean phenotypes, along with an increase in Bifidobacteria spp. and Lactobacillus spp
  • mouse and rat models of T1D have been shown to have microbiota marked by decreased diversity and decreased Lactobacillus spp., as well as a decrease in the Firmicutes/Bacteroidetes ratio
  • microbial antigens through the innate immune system are involved in T1D progression
  • The microbiota appears to be essential in maintaining the Th17/Treg cell balance in intestinal tissues, mesenteric and pancreatic lymph nodes, and in developing insulitis, although progression to overt diabetes has not been shown to be controlled by the microbiota
  • There is evidence that dietary and microbial antigens independently influence T1D
  • Lactobacillus johnsonii N6.2 protects BB-rats from T1D by mediating intestinal barrier function and inflammation [101,102] and a combination probiotic VSL#3 has been shown to attenuate insulitis and diabetes in NOD mice
  • breast fed infants have higher levels of Bifidobacteria spp. while formula fed infants have higher levels of Bacteroides spp., as well as increased Clostridium coccoides and Lactobacillus spp
  • the composition of the gut microbiota strongly correlates with diet
  • In mice fed a diet high in fat, there are many key gut population changes, such as the absence of gut barrier-protecting Bifidobacteria spp
  • diet has a dominating role in shaping gut microbiota and changing key populations may transform healthy gut microbiota into a disease-inducing entity
  • “Western” diet, which is high in sugar and fat, causes dysbiosis which affects both host GI tract metabolism and immune homeostasis
  • Nathan Goodyear on 27 Jul 14
     
    Nice discussion of how diet, induces gut bacterial change, that leads to metabolic endotoxemia and disease.
Nathan Goodyear

Metabolic Effects of Dietary Fiber Consumption and Prevention of Diabetes - 0 views

jn.nutrition.org/...439.long

soluble insoluble fiber dietary diet nutrition diabetes

shared by Nathan Goodyear on 22 Oct 13 - No Cached
  • DF are highly complex substances that can be described as any nondigestible carbohydrates and lignins not degraded in the upper gut
  • Commonly, DF are classified according to their solubility in water, even though grading according to viscosity, gel-forming capabilities, or fermentation rate by the gut microbiota might be physiologically more relevant
  • Main sources of soluble DF are fruits and vegetables
  • ...8 more annotations...
  • n increased intake of total DF was inversely associated with markers of insulin resistance in several studies
  • consumption of insoluble DF increased whole body glucose disposal independent of changes in body weight in both short-term and more prolonged studies
  • Short-chain fatty acids (SCFA) such as acetate, propionate, and butyrate are produced by bacterial fermentation of indigestible DF polysaccharides in the colon
  • increased production of SCFA is assumed to be beneficial by reducing hepatic glucose output and improving lipid homeostasis
  • a high DF diet (oligofructose) reduced gram-negative bacterial content and body weight, whereas a high fat diet increased the proportion of a gram-negative bacterial lipopolysaccharides (LPS) containing microbiota in humans
  • Prospective cohort studies indicate that diets high in insoluble cereal DF and whole grains might reduce diabetes risk
  • soluble DF (i.e., pectin, inulin, and β-glucans)
  • cereal DF (i.e., cellulose and hemicelluloses)
  • Nathan Goodyear on 22 Oct 13
     
    Good discussion of dietary fiber intake and Diabetes.  
Nathan Goodyear

Inborn-like errors of metabolism are determinants of breast cancer risk, clinical respo... - 0 views

www.ncbi.nlm.nih.gov/...PMC6114970

cancer metabolism breast cancer glutamine glutamate aspartate oncogenes

shared by Nathan Goodyear on 24 Sep 18 - No Cached
  • We now recognize that human cancers evolve in an environment of metabolic stress. Rapidly proliferating tumor cells deprived of adequate oxygen, nutrients, hormones and growth factors up-regulate pathways that address these deficiencies to overcome hypoxia (HIF), vascular insufficiency (VEGF), growth factor deprivation (EGFR, HER2) and the loss of hormonal support (ER, PR, AR) all to enhance survival and proliferation
  • RAS, PI3K, TP53 and MYC
  • The results suggest that breast cancer could be preceded by systemic subclinical disturbances in glucose-insulin homeostasis characterized by mild, likely asymptomatic, IEM-like biochemical changes
  • ...16 more annotations...
  • The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis
  • The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8
  • four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders
  • growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy
  • glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population
  • blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure ​(Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure ​(Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively
  • glutamine consumption associated with parallel increases in glutamate and aspartate (Figure ​(Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”
  • Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death
  • changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy
  • lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes
  • the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis
  • these metabolic disturbances would be expected to remain extant after therapeutic interventions
  • accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients
  • Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)
  • liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis
  • cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress
  • Nathan Goodyear on 24 Sep 18
     
    Breast cancer is a metabolic disease.  Now, where have I heard that cancer is a metabolic disease?
Nathan Goodyear

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment - 0 views

www.ncbi.nlm.nih.gov/...PMC2696340

incretins diabetes

shared by Nathan Goodyear on 09 Apr 13 - No Cached
  • Nathan Goodyear on 09 Apr 13
     
    good review of incretins
Nathan Goodyear

Testosterone supplementation in men with type 2 di... [Aging Male. 2003] - PubMed result - 0 views

www.ncbi.nlm.nih.gov/...12809074

testosterone supplementation diabetes obesity

shared by Nathan Goodyear on 02 Mar 11 - No Cached
  • the benefit of testosterone supplementation therapy exceeds the correction of symptoms of androgen deficiency and also includes glucose homeostasis and metabolic control.
  • Nathan Goodyear on 02 Mar 11
     
    Testosterone therapy in men with Diabetes
Nathan Goodyear

Incretin-based therapies: can we achieve glycemic control and cardioprotection? - 0 views

joe.endocrinology-journals.org/...T17.full

incretin incretins GLP-1 glucagon-like peptide 1) glucose homeostasis

shared by Nathan Goodyear on 24 Mar 14 - No Cached
  • Nathan Goodyear on 24 Mar 14
     
    Good discussion on the incretin: (Glucagon-like peptide 1 (GLP-1).
Nathan Goodyear

Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk - 0 views

jme.endocrinology-journals.org/...R51.full

metabolic endotoxemia obesity insulin resistance cardiovascular disease LPS inflammation

shared by Nathan Goodyear on 04 Aug 14 - No Cached
  • Weight gain has been associated with a higher gut permeability
  • a high-fat diet promotes LPS absorption
  • higher concentrations of fatty acids impair intestinal barrier integrity
  • ...37 more annotations...
  • The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors
  • TLRs are PRRs that recognize microbe-associated molecular patterns
  • TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain
  • The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients
  • Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.
  • Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption
  • LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.
  • In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.
  • In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.
  • the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels
  • dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.
  • This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.
  • n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations
  • it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).
  • this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A
  • these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.
  • This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.
  • endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis
  • in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.
  • T2DM patients have mean values of LPS that are 76% higher than healthy controls
  • LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic
  • LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells
  • Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease
  • The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile
  • All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features
  • LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism
  • When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome
  • It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis
  • On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα
  • high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs
  • prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls
  • Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers
  • This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation
  • high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk
  • LPS has been shown to promote atherosclerosis
  • markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk
  • As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.
  • Nathan Goodyear on 04 Aug 14
     
    Very nice updated review on Metabolic endotoxemia
Nathan Goodyear

Searching For an Old New Cure: Ivermectin Deficiency Syndrome? « The Healthy ... - 0 views

thehealthyplanet.com/...ivermectin-deficiency-syndrome

Ivermectin cancer PAK1 oncogene oncogenes

shared by Nathan Goodyear on 21 Mar 18 - No Cached
  • Ivermectin can inactivate the protein kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines
  • PAK proteins encoded by the PAK1 gene are critical for cytoskeleton reorganization and nuclear signaling.
  • PAK-1 kinase is required for the growth of more than 70% of human cancers such as pancreatic, colon, breast and prostate cancers, and neurofibromatosis
  • ...5 more annotations...
  • The p21 activated Kinase PAK1 is implicated in tumor genesis.
  • Inhibiting PAK1 signals induce tumor cell apoptosis (cell death)
  • PAK1 has also been implicated for maintenance of glucose homeostasis in pancreatic beta cells and skeletal muscle
  • Ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells (Blood, November 4, 2010, vol.115). The paper states Ivermectin synergizes with chemo agents cytarabine and daunorubicin to induce cell death in leukemia cells.
  • Praziquantel , my other favorite parasite medication for liver flukes, synergistically enhances Paclitaxel (Taxol) efficacy to inhibit cancer cell growth
  • Nathan Goodyear on 21 Mar 18
     
    Just a commentary but with important information on ivermectin in its inhibitory activity against another oncogene PAK1.
Nathan Goodyear

Nutrients | Free Full-Text | Effect of Probiotics on Metabolic Outcomes in Pregnant Wom... - 0 views

www.mdpi.com/...htm

probiotics alternative medicine natural medicine natural therapies diabetes gestational diabetes

shared by Nathan Goodyear on 15 May 17 - No Cached
  • The gut microbial composition is altered during pregnancy
  • probiotic supplements may contribute to the maintenance of bacterial diversity and glucose homeostasis in individuals with metabolic disturbances
  • Assessment of four randomized controlled trials in this review involving 288 pregnant women with GDM found that a 6–8 week probiotic intervention did not improve FBG or LDL-cholesterol levels
  • ...5 more annotations...
  • probiotic supplementation in women with GDM was associated with significant reductions in insulin resistance
  • One proposed method is by the production of short chain fatty acids (SCFAs), generated as a by-product of bacterial fermentation of dietary fibers. SCFAs act as an energy source for intestinal cells and have been found to regulate the production of hormones effecting energy intake and expenditure such as leptin and grehlin
  • Another hypothesized mechanism of SCFA action includes reducing gastrointestinal permeability by upregulating transcription of tight junction proteins, enhancing production of Glucagon-like peptide-2 (GLP-2) which promotes crypt cell proliferation, and reducing inflammation in colonic epithelial cells by increasing PPAR-gamma activation
  • Maintenance of the integrity of the gut barrier minimizes the concentration of lipopolysaccharide (LPS) in circulation
  • LPS is a structural component of gram negative bacterial cell walls, which induces an immune-cell response upon absorption into the human bloodstream, stimulating proinflammatory cytokine production and the onset of insulin resistance and hyperglycemia
  • Nathan Goodyear on 15 May 17
     
    Review (4 studies) found that 6-8 weeks of probiotic therapy of pregnant women with gestational diabetes improved insulin resistance.
  • Open TeleShop on 17 May 17
     
    Hey Dear Check Out Our Online Shopping store in all Over Pakistan.As Seen as On Tv Products Like as Health Beauty,Fitness,Homeware,Kitchenware,And Other Electronic Products in Pakistan Check Out Now| www.openTeleshop.Com
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