acute GC secretion during stress mobilizes peripheral amino acids from muscle as well as fatty acids and glycerol
from peripheral fat stores to provide substrates for glucose synthesis by the liver
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Leucine Regulates Translation Initiation of Protein Synthesis in Skeletal Muscle after ... - 0 views
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shared by Nathan Goodyear on 28 May 13
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Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to... - 0 views
joe.endocrinology-journals.org/...45.full
vitamin vitamin d muscle fat adipogenesis adipose cells overweight obesity
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shared by Nathan Goodyear on 13 Jan 13
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A practical model of low-volume high-intensity interval training induces mitochondrial ... - 0 views
jp.physoc.org/...1011.long
HIT high-intensity interval training exercise muscle mitochondria training
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Improving the Vitamin D Status of Vitamin D Deficient Adults Is Associated With Improve... - 0 views
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shared by Nathan Goodyear on 29 Nov 16
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Plasticity in mitochondrial cristae density allows metabolic capacity modulation in hum... - 0 views
onlinelibrary.wiley.com/...763493D2C50D44B6157B92C.f03t04
mitochondria exercise endurance exercise muscle
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shared by Nathan Goodyear on 14 Mar 12
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Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity - 0 views
ajpendo.physiology.org/...E1465.long
cortisol insulin resistance metabolic syndrome obesity overweight
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chronically elevated GC levels alter body fat distribution and increase visceral adiposity as well as metabolic abnormalities in a fashion reminiscent of metabolic syndrome
- ...9 more annotations...
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In adipocytes, cortisol inhibits lipid mobilization in the presence of insulin, thus leading to triglyceride accumulation and retention.
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Since the density of GC receptors is higher in intra-abdominal (visceral) fat than in other fat depots, the activity of cortisol leading to accumulation of fat is accentuated in visceral adipose tissue (24, 158), providing a mechanism by which excessive endogenous or exogenous GC lead to abdominal obesity and IR
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This may be explained by an increased intratissular/cellular concentration of cortisol in adipose tissues
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Intracellular GC may be produced from recycling of GC metabolites such as cortisone in adipose tissues
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Local GC recycling metabolism is mediated by 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2
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even if obese patients generally have normal or subnormal plasma cortisol concentrations (131, 158), triglyceride accumulation in visceral adipose tissue may be due, at least in part, to the local production of GC in insulin- and GC-responsive organs such as adipose tissue, liver, and skeletal muscle
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Changes in Ubiquitin Proteasome Pathway Gene Expression in Skeletal Muscle With Exercis... - 0 views
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shared by Nathan Goodyear on 28 Sep 16
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Chemistry and Structural Biology of Androgen Receptor - 0 views
www.ncbi.nlm.nih.gov/...PMC2096617
androgens Testosterone DHT dihydrotestosterone AR androgen receptors male hormones hormones
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- ...15 more annotations...
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5α-DHT is only about 5% as abundant in the blood as testosterone and is largely derived from peripheral metabolism of testosterone
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Approximately 90% of an oral dose of testosterone is metabolized before it reaches the systemic circulation
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there are three modes of action of testosterone. It may directly act through AR in target tissues where 5α-reductase is not expressed, be converted to 5α-DHT (5–10%) by 5α-reductase before binding to AR, or be aromatized to estrogen (0.2%) and act through the estrogen receptor
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estrogen plays a major role in regulating metabolic process,74,75 mood and cognition,76 cardiovascular disease,77,78 sexual function including libido,79 and bone turnover in men
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testosterone is the major androgen that acts in the “DHT-independent” tissues, such as skeletal muscle, where 5α-reductase is not expressed or is expressed at a very low level
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shared by Nathan Goodyear on 27 Jan 14
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Cordyceps sinensis promotes exercise endurance capacity of rats by activating skeletal ... - 0 views
www.sciencedirect.com/...S0378874111002923
Cordyceps Cordyceps sinensis exercise performance endurance
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Therapy in the Early Stage: Incretins - 0 views
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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
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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)
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β-cell failure
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Incretins are gut-derived hormones, members of the glucagon superfamily, released in response to nutrient ingestion (mainly glucose and fat)
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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
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Coenzyme Q10 and statins: biochemical and clinical... [Mitochondrion. 2007] - PubMed re... - 0 views
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physicians should be aware of this drug-nutrient interaction and be vigilant to the possibility that statin drugs may, in some cases, impair skeletal muscle and myocardial bioenergetics.
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shared by Nathan Goodyear on 30 Mar 15
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Testosterone level in men with type 2 diabetes mellitus and related metabolic... - 0 views
www.ncbi.nlm.nih.gov/...PMC4364844
low T low Testosterone Diabetes Testosterone men male hormones metabolic syndrome
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defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
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the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
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most population-based studies use the serum testosterone level corresponding to the lower limit, quoted from 8.7 to 12.7 nmol/L, of the normal range for young Caucasian men as the threshold
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Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.
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−0.124 nmol/L/year in serum total testosterone
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In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
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In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
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testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo
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testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
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In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
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independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
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Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone
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In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
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leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
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Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone
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Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age
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As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level
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alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
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A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia
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Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study
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subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
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In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L
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Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes
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HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported
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pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α
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In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.
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Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
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Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
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The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
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In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
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a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
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the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population
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assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
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In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
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a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
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A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
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most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible
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MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
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Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
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In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
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weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost
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To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
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In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70
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low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile
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Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality
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low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25
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European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
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Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles
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serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
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Nice review of Testosterone levels and some of the evidence linking Diabetes with low T. However, the conclusion by the authors regarding what is causing the low T in men with Diabetes is baffling. The literature does not point to one cause, it is clearly multifactorial--obesity, inflammation, high aromatase activity...I would suggest the authors continue their readings in the manner.
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shared by Nathan Goodyear on 31 Oct 17
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Original Articles: Comparison of Insulin Action on Glucose versus Potassium Uptake in H... - 0 views
www.ncbi.nlm.nih.gov/...PMC3133473
diabetes insulin resistance potassium hyperkalemia glucose insulin
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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
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the commonly encountered “insulin-resistant” patients actually have preserved insulin-induced potassium disposal, one wonders why their high insulin levels are not causing hypokalemia
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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
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Hyperkalemia and hypokalemia are silent yet fatal disturbances because of their arrhythmogenic potentials
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When insulin levels are suppressed, plasma [K+] rises and pronounced hyperkalemia develops after a potassium load
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Insulin is a key defender against exogenous potassium load by using intracellular buffering to minimize hyperkalemia before renal excretion
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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.
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Searching For an Old New Cure: Ivermectin Deficiency Syndrome? « The Healthy ... - 0 views
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Ivermectin can inactivate the protein kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines
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PAK proteins encoded by the PAK1 gene are critical for cytoskeleton reorganization and nuclear signaling.
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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
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PAK1 has also been implicated for maintenance of glucose homeostasis in pancreatic beta cells and skeletal muscle
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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.
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Praziquantel , my other favorite parasite medication for liver flukes, synergistically enhances Paclitaxel (Taxol) efficacy to inhibit cancer cell growth
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shared by Nathan Goodyear on 03 Oct 17
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A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern i... - 0 views
journals.plos.org/...article
exercise epigenetics methylation obesity diabetes type 2 diabetes type II diabetes
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In skeletal muscle, HDAC4 has been found to be exported from the nucleus during exercise, suggesting that removal of the transcriptional repressive function could be a mechanism for exercise adaptation [50]. For HDAC4, we observed increased levels of DNA methylation and a simultaneous decrease in mRNA expression in adipose tissue in response to the exercise intervention. Additionally, the functional experiments in cultured adipocytes suggested increased lipogenesis when Hdac4 expression was reduced
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NCOR2 also exhibited increased levels of DNA methylation and a simultaneous decrease in mRNA expression in adipose tissue in response to the exercise intervention, and furthermore we observed increased lipogenesis when Ncor2 expression was down regulated in the 3T3-L1 cell line. NCOR2 is a nuclear co-repressor, involved in the regulation of genes important for adipogenesis and lipid metabolism, and with the ability to recruit different histone deacetylase enzymes, including HDAC4
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Study finds 6 month exercise program in men induced epigenetic change via DNA methylation of CPG islands in adipose cells effecting metabolism and altering obesity and type II diabetes risk. The study looked at 2 genes: HDAC4 and NCOR2 and found that exercise decreased expression via methylation altering adipogenesis and lipid metabolism.
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Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Tr... - 0 views
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In this study, we have demonstrated microscopic pathology ranging from minimal to moderate in multiple different tissues previously reported to be involved with LD, including the nervous system (central and peripheral), heart, skeletal muscle, joint-associated tissues, and urinary bladder 12 to 13 months following tick-inoculation of rhesus macaques by Bb strain B31
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Based on histomorphology, inflammation consisted predominantly of lymphocytes and plasma cells, with rare scattered histiocytes
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in rare instances, morphologically intact spirochetes were observed in inflamed brain and heart tissue sections from doxycycline-treated animals
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colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable
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The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment
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The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD
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In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal
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Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum
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We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro
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The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic
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The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well
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Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).
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we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.
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Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.
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In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment
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This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.
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The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s
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Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere
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approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6
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Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)
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host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic
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Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses
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half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.
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Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces
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Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs
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A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal
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three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures
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Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)
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Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer ... - 0 views
- ...24 more annotations...
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daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature
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chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks
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long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness
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both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds
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CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces
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the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis
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TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA
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HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells
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In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks
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Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy
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Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.
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daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD