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Nathan Goodyear

Testosterone and glucose metabolism in men: current concepts and controversies - 0 views

joe.endocrinology-journals.org/...R37.full

Low T Testosterone metabolic syndrome MetS Diabetes men male glucose hormone hormones g

shared by Nathan Goodyear on 04 Feb 14 - No Cached
  • Around 50% of ageing, obese men presenting to the diabetes clinic have lowered testosterone levels relative to reference ranges based on healthy young men
  • The absence of high-level evidence in this area is illustrated by the Endocrine Society testosterone therapy in men with androgen deficiency clinical practice guidelines (Bhasin et al. 2010), which are appropriate for, but not specific to men with metabolic disorders. All 32 recommendations made in these guidelines are based on either very low or low quality evidence.
  • A key concept relates to making a distinction between replacement and pharmacological testosterone therapy
  • ...59 more annotations...
  • The presence of symptoms was more closely linked to increasing age than to testosterone levels
  • Findings similar to type 2 diabetes were reported for men with the metabolic syndrome, which were associated with reductions in total testosterone of −2.2 nmol/l (95% CI −2.41 to 1.94) and in free testosterone
  • low testosterone is more predictive of the metabolic syndrome in lean men
  • Cross-sectional studies uniformly show that 30–50% of men with type 2 diabetes have lowered circulating testosterone levels, relative to references based on healthy young men
  • In a recent cross-sectional study of 240 middle-aged men (mean age 54 years) with either type 2 diabetes, type 1 diabetes or without diabetes (Ng Tang Fui et al. 2013b), increasing BMI and age were dominant drivers of low total and free testosterone respectively.
  • both diabetes and the metabolic syndrome are associated with a modest reduction in testosterone, in magnitude comparable with the effect of 10 years of ageing
  • In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone with anaemia
  • In men, low testosterone is a marker of poor health, and may improve our ability to predict risk
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      probably the most important point made in this article
  • low testosterone identifies men with an adverse metabolic phenotype
  • Diabetic men with low testosterone are significantly more likely to be obese or insulin resistant
  • increased inflammation, evidenced by higher CRP levels
  • Bioavailable but not free testosterone was independently predictive of mortality
  • It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker, co-existing because of in-common risk factors.
  • In prospective studies, reviewed in detail elsewhere (Grossmann et al. 2010) the inverse association of low testosterone with metabolic syndrome or diabetes is less consistent for free testosterone compared with total testosterone
  • In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident metabolic syndrome
  • low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes
  • In cross-sectional studies of men with (Grossmann et al. 2008) and without (Bonnet et al. 2013) diabetes, SHBG but not testosterone was inversely associated with worse glycaemic control
  • SHBG may have biological actions beyond serving as a carrier protein for and regulator of circulating sex steroids
  • In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      expensive, laborious process filled with variables
  • Low free testosterone remains inversely associated with insulin resistance, independent of SHBG (Grossmann et al. 2008). This suggests that the low testosterone–dysglycaemia association is not solely a consequence of low SHBG.
  • Experimental evidence reviewed below suggests that visceral adipose tissue is an important intermediate (rather than a confounder) in the inverse association of testosterone with insulin resistance and metabolic disorders.
  • testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes
  • testosterone regulates the metabolic functions of mature adipocytes (Xu et al. 1991, Marin et al. 1995) and myocytes (Pitteloud et al. 2005) in ways that reduce insulin resistance.
  • Pre-clinical evidence (reviewed in Rao et al. (2013)) suggests that at the cellular level, testosterone may improve glucose metabolism by modulating the expression of the glucose-transported Glut4 and the insulin receptor, as well as by regulating key enzymes involved in glycolysis.
  • More recently testosterone has been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis
  • Interestingly, a reciprocal feedback also appears to exist, given that not only chronic (Cameron et al. 1990, Allan 2013) but also, as shown more recently (Iranmanesh et al. 2012, Caronia et al. 2013), acute hyperglycaemia can lower testosterone levels.
  • There is also evidence that testosterone regulates insulin sensitivity directly and acutely
  • In men with prostate cancer commencing androgen deprivation therapy, both total as well as, although not in all studies (Smith 2004), visceral fat mass increases (Hamilton et al. 2011) within 3 months
  • More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several large observational registry studies
  • Testosterone has also been shown to reduce the concentration of pro-inflammatory cytokines in some, but not all studies, reviewed recently in Kelly & Jones (2013). It is not know whether this effect is independent of testosterone-induced changes in body composition.
  • the observations discussed in this section suggest that it is the decrease in testosterone that causes insulin resistance and diabetes. One important caveat remains: the strongest evidence that low testosterone is the cause rather than consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor.
  • Several large prospective studies have shown that weight gain or development of type 2 diabetes is major drivers of the age-related decline in testosterone levels
  • there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in testosterone
  • Circulating testosterone, on an average 30%, is lower in obese compared with lean men
  • increased visceral fat is an important component in the association of low testosterone and insulin resistance
  • The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone levels
  • obesity is a dominant risk factor
  • men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat mass is already present before puberty
  • Only 5% of men with type 2 diabetes have elevated LH levels
  • inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity
  • Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH) secretion from GNRH neurons situated in the preoptic area
  • kisspeptin has emerged as one of the most potent secretagogues of GNRH release
  • hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
  • A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects
  • suppression of the diabesity-associated HPT axis is functional, and may hence be reversible
  • Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
  • weight gain and development of diabetes accelerate the age-related decline in testosterone
  • Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone levels than age alone
  • 55% of symptomatic androgen deficiency reverted to a normal testosterone or an asymptomatic state after 8-year follow-up, suggesting that androgen deficiency is not a stable state
  • Weight loss can reactivate the hypothalamic–pituitary–testicular axis
  • Leptin treatment resolves hypogonadism in leptin-deficient men
  • The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men
  • Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes
  • change in BMI was associated with the change in testosterone (Corona et al. 2013a,b).
  • weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression
  • There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
  • in men who improved their glycaemic control over time, testosterone levels increased. By contrast, in those men in whom glycaemic control worsened, testosterone decreased
  • testosterone levels should be measured after successful weight loss to identify men with an insufficient rise in their testosterone levels. Such men may have HPT axis pathology unrelated to their obesity, which will require appropriate evaluation and management.
  • Nathan Goodyear on 04 Feb 14
     
    Article discusses the expanding evidence of low T and Metabolic syndrome.
Nathan Goodyear

JCI - Inflammatory links between obesity and metabolic disease - 0 views

www.jci.org/57132

obesity overweight weight-loss inflammation metabolic disease

shared by Nathan Goodyear on 04 Jan 12 - No Cached
  • metainflammation
  • The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time
  • It is clear that inflammation participates in the link between obesity and disease
  • ...25 more annotations...
  • Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells
  • adipose tissue macrophage (ATM)
  • Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).
  • increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).
  • The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ
  • well-known regulators of lipid metabolism and mitochondrial activity
  • Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).
  • inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)
  • Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass
  • JNK, TLR4, ER stress)
  • NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells
  • Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity
  • DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)
  • saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)
  • Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)
  • Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)
  • Placental inflammation is a characteristic of maternal obesity
  • a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74
  • Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB
  • Nod-like receptor (NLR) family of PRRs
  • ceramides and sphingolipids
  • The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.
  • adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate
  • Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)
  • NF-κB, obesity also activates JNK in insulin-responsive tissues
  • Nathan Goodyear on 04 Jan 12
     
    must read to see our current knowledge on the link between inflammation and obesity.
Nathan Goodyear

Hypoadiponectinemia in Obesity and Type 2 Diabetes: Close Association with Insulin Resi... - 0 views

jcem.endojournals.org/...1930.short

obesity diabetes type II 2 insulin resistance IR adiponectin

shared by Nathan Goodyear on 17 Mar 12 - No Cached
  • Nathan Goodyear on 17 Mar 12
     
    obesity and type II diabetes found to be associated with low adiponectin and elevated insulin as found in insulin resistance.  This study revealed the inverse relationship of adiponectin and insulin resistance.  The interesting thing is that inflammation causes insulin resistance.  Here you can see the inflammation-insulin resistance-low adiponectin-obesity-diabetes link.
Nathan Goodyear

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

shared by Nathan Goodyear on 30 Mar 15 - No Cached
  • defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
  • the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
  • 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
    • Nathan Goodyear
      Nathan Goodyear on 31 Mar 15
       
      this equals 251 to 366 in serum Total Testosterone
  • ...57 more annotations...
  • 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.
  • −0.124 nmol/L/year in serum total testosterone
    • Nathan Goodyear
      Nathan Goodyear on 31 Mar 15
       
      this equates to a 4 ng/dl decline annually in total Testosterone.
  • In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
  • In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
  • 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
  • by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance
  • testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
  • In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
  • independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
  • In short, androgen improves insulin resistance by changing body composition and reducing body fat.
  • 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
  • In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
  • leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
  • 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
    • Nathan Goodyear
      Nathan Goodyear on 31 Mar 15
       
      So what is "unequivocal"?
  • 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
  • 30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone
  • 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
  • Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins
  • alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
  • listed in Table​T
  • 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
  • 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
  • subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
  • 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
  • Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan
  • 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
  • The reduction of total testosterone was 0.4% per year in both groups
  • 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
  • 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
  • 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.
  • Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
  • Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
  • The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
  • In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
  • a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
  • In India, men with CAG ≤19 had increased risk of prostate cancer
  • 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
  • assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
  • In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
  • a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
  • A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
  • Low testosterone is commonly associated with a high prevalence of MES
  • 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
  • MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
  • Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
  • In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
  • 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
  • To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
  • 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
  • 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
  • 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
  • low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38
  • 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
  • European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
  • 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
  • serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
  • Nathan Goodyear on 30 Mar 15
     
    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.
Nathan Goodyear

Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Lite... - 0 views

jaha.ahajournals.org/...e000272.full

Testosterone men male cardiovascular disease low T

shared by Nathan Goodyear on 20 Nov 13 - No Cached
  • Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates of all‐cause and cardiovascular‐related mortality.39,41,46–47 Patients suffering from CAD,13–18 CHF,137 T2DM,25–26 and obesity27–28
  • have all been shown to have lower levels of endogenous testosterone compared with those in healthy controls. In addition, the severity of CAD15,17,29–30 and CHF137 correlates with the degree of testosterone deficiency
  • In patients with CHF, testosterone replacement therapy has been shown to significantly improve exercise tolerance while having no effect on LVEF
  • ...66 more annotations...
  • testosterone therapy causes a shift in the skeletal muscle of CHF patients toward a higher concentration of type I muscle fibers
  • Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics26,68–69 and to lower the BMI in obese patients.
  • Lower levels of endogenous testosterone have been associated with longer duration of the QTc interval
  • testosterone replacement has been shown to shorten the QTc interval
  • negative correlation has been demonstrated between endogenous testosterone levels and IMT of the carotid arteries, abdominal aorta, and thoracic aorta
  • These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.
  • Current guidelines from the Endocrine Society make no recommendations on whether patients with heart disease should be screened for hypogonadism and do not recommend supplementing patients with heart disease to improve survival.
  • The Massachusetts Male Aging Study also projects ≈481 000 new cases of hypogonadism annually in US men within the same age group
  • since 1993 prescriptions for testosterone, regardless of the formulation, have increased nearly 500%
  • Testosterone levels are lower in patients with chronic illnesses such as end‐stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus (T2DM), obesity, and several genetic conditions such as Klinefelter syndrome
  • A growing body of evidence suggests that men with lower levels of endogenous testosterone are more prone to develop CAD during their lifetimes
  • There are 2 major potential confounding factors that the older studies generally failed to account for. These factors are the subfraction of testosterone used to perform the analysis and the method used to account for subclinical CAD.
  • The biologically inactive form of testosterone is tightly bound to SHBG and is therefore unable to bind to androgen receptors
  • The biologically inactive fraction of testosterone comprises nearly 68% of the total testosterone in human serum
  • The biologically active subfraction of testosterone, also referred to as bioavailable testosterone, is either loosely bound to albumin or circulates freely in the blood, the latter referred to as free testosterone
  • It is estimated that ≈30% of total serum testosterone is bound to albumin, whereas the remaining 1% to 3% circulates as free testosterone
  • it can be argued that using the biologically active form of testosterone to evaluate the association with CAD will produce the most reliable results
  • English et al14 found statistically significant lower levels of bioavailable testosterone, free testosterone, and free androgen index in patients with catheterization‐proven CAD compared with controls with normal coronary arteries
  • patients with catheterization‐proven CAD had statistically significant lower levels of bioavailable testosterone
  • In conclusion, existing evidence suggests that men with CAD have lower levels of endogenous testosterone,13–18 and more specifically lower levels of bioavailable testosterone
  • low testosterone levels are associated with risk factors for CAD such as T2DM25–26 and obesity
  • In a meta‐analysis of these 7 population‐based studies, Araujo et al41 showed a trend toward increased cardiovascular mortality associated with lower levels of total testosterone, but statistical significance was not achieved (RR, 1.25
  • the authors showed that a decrease of 2.1 standard deviations in levels of total testosterone was associated with a 25% increase in the risk of cardiovascular mortality
  • the relative risk of all‐cause mortality in men with lower levels of total testosterone was calculated to be 1.35
  • higher risk of cardiovascular mortality is associated with lower levels of bioavailable testosterone
  • Existing evidence seems to suggest that lower levels of endogenous testosterone are associated with higher rates of all‐cause mortality and cardiovascular mortality
  • studies have shown that lower levels of endogenous bioavailable testosterone are associated with higher rates of all‐cause and cardiovascular mortality
  • It may be possible that using bioavailable testosterone to perform mortality analysis will yield more accurate results because it prevents the biologically inactive subfraction of testosterone from playing a potential confounding role in the analysis
  • The earliest published material on this matter dates to the late 1930s
  • the concept that testosterone replacement therapy improves angina has yet to be proven wrong
  • In more recent studies, 3 randomized, placebo‐controlled trials demonstrated that administration of testosterone improves myocardial ischemia in men with CAD
  • The improvement in myocardial ischemia was shown to occur in response to both acute and chronic testosterone therapy and seemed to be independent of whether an intravenous or transdermal formulation of testosterone was used.
  • testosterone had no effect on endothelial nitric oxide activity
  • There is growing evidence from in vivo animal models and in vitro models that testosterone induces coronary vasodilation by modulating the activity of ion channels, such as potassium and calcium channels, on the surface of vascular smooth muscle cells
  • Experimental studies suggest that the most likely mechanism of action for testosterone on vascular smooth muscle cells is via modulation of action of non‐ATP‐sensitive potassium ion channels, calcium‐activated potassium ion channels, voltage‐sensitive potassium ion channels, and finally L‐type calcium ion channels
  • Corona et al confirmed those results by demonstrating that not only total testosterone levels are lower among diabetics, but also the levels of free testosterone and SHBG are lower in diabetic patients
  • Laaksonen et al65 followed 702 Finnish men for 11 years and demonstrated that men in the lowest quartile of total testosterone, free testosterone, and SHBG were more likely to develop T2DM and metabolic syndrome.
  • Vikan et al followed 1454 Swedish men for 11 years and discovered that men in the highest quartile of total testosterone were significantly less likely to develop T2DM
  • authors demonstrated a statistically significant increase in the incidence of T2DM in subjects receiving gonadotropin‐releasing hormone antagonist therapy. In addition, a significant increase in the rate of myocardial infarction, stroke, sudden cardiac death, and development of cardiovascular disease was noted in patients receiving antiandrogen therapy.67
  • Several authors have demonstrated that the administration of testosterone in diabetic men improves the homeostatic model of insulin resistance, hemoglobin A1c, and fasting plasma glucose
  • Existing evidence strongly suggests that the levels of total and free testosterone are lower among diabetic patients compared with those in nondiabetics
  • insulin seems to be acting as a stimulant for the hypothalamus to secret gonadotropin‐releasing hormone, which consequently results in increased testosterone production. It can be argued that decreased stimulation of the hypothalamus in diabetics secondary to insulin deficiency could result in hypogonadotropic hypogonadism
  • BMI has been shown to be inversely associated with testosterone levels
  • This interaction may be a result of the promotion of lipolysis in abdominal adipose tissue by testosterone, which may in turn cause reduced abdominal adiposity. On the other hand, given that adipose tissue has a higher concentration of the enzyme aromatase, it could be that increased adipose tissue results in more testosterone being converted to estrogen, thereby causing hypogonadism. Third, increased abdominal obesity may cause reduced testosterone secretion by negatively affecting the hypothalamus‐pituitary‐testicular axis. Finally, testosterone may be the key factor in activating the enzyme 11‐hydroxysteroid dehydrogenase in adipose tissue, which transforms glucocorticoids into their inactive form.
  • increasing age may alter the association between testosterone and CRP. Another possible explanation for the association between testosterone level and CRP is central obesity and waist circumference
  • Bai et al have provided convincing evidence that testosterone might be able to shorten the QTc interval by augmenting the activity of slowly activating delayed rectifier potassium channels while simultaneously slowing the activity of L‐type calcium channels
  • consistent evidence that supplemental testosterone shortens the QTc interval.
  • Intima‐media thickness (IMT) of the carotid artery is considered a marker for preclinical atherosclerosis
  • Studies have shown that levels of endogenous testosterone are inversely associated with IMT of the carotid artery,126–128,32,129–130 as well as both the thoracic134 and the abdominal aorta
  • 1 study has demonstrated that lower levels of free testosterone are associated with accelerated progression of carotid artery IMT
  • another study has reported that decreased levels of total and bioavailable testosterone are associated with progression of atherosclerosis in the abdominal aorta
  • These findings suggest that normal physiologic testosterone levels may help to protect men from the development of atherosclerosis
  • Czesla et al successfully demonstrated that the muscle specimens that were exposed to metenolone had a significant shift in their composition toward type I muscle fibers
  • Type I muscle fibers, also known as slow‐twitch or oxidative fibers, are associated with enhanced strength and physical capability
  • It has been shown that those with advanced CHF have a higher percentage of type II muscle fibers, based on muscle biopsy
  • Studies have shown that men with CHF suffer from reduced levels of total and free testosterone.137 It has also been shown that reduced testosterone levels in men with CHF portends a poor prognosis and is associated with increased CHF mortality.138 Reduced testosterone has also been shown to correlate negatively with exercise capacity in CHF patients.
  • Testosterone replacement therapy has been shown to significantly improve exercise capacity, without affecting LVEF
  • the results of the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not cause an increase in the rate of adverse cardiovascular events
  • Data from 3 meta‐analyses seem to contradict the commonly held belief that testosterone administration may increase the risk of developing prostate cancer
  • One meta‐analysis reported an increase in all prostate‐related adverse events with testosterone administration.146 However, when each prostate‐related event, including prostate cancer and a rise in PSA, was analyzed separately, no differences were observed between the testosterone group and the placebo group
  • the existing data from the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not increase the risk of adverse cardiovascular events
  • the authors correctly point out the weaknesses of their study which include retrospective study design and lack of randomization, small sample size at extremes of follow‐up, lack of outcome validation by chart review and poor generalizability of the results given that only male veterans with CAD were included in this study
    • Nathan Goodyear
      Nathan Goodyear on 04 Dec 13
       
      The authors here present Total Testosterone as a "confounding" value
    • Nathan Goodyear
      Nathan Goodyear on 09 Dec 13
       
      This would be HSD-II
  • the studies that failed to find an association between testosterone and CRP used an older population group
  • low testosterone may influence the severity of CAD by adversely affecting the mediators of the inflammatory response such as high‐sensitivity C‐reactive protein, interleukin‐6, and tumor necrosis factor–α
  • Nathan Goodyear on 20 Nov 13
     
    Good review of Testosterone and CHD.  Low T is associated with increased all cause mortality and cardiovascular mortality, CAD, CHF, type II diabetes, obesity, increased IMT,  increased severity of CAD and CHF.  Testosterone replacement in men with low T has been shown to improve exercise tolerance in CHF, improve insulin resistance, improve HgbA1c and lower BMI in the obese.
Nathan Goodyear

Nutrition & Metabolism | Full text | Fructose, insulin resistance, and metabolic dyslip... - 0 views

www.nutritionandmetabolism.com/...5

fructose metabolic syndrome metabolic syndrome insulin resistance obesity nutrition metabolism

shared by Nathan Goodyear on 16 Sep 13 - Cached
  • For thousands of years humans consumed fructose amounting to 16–20 grams per day
  • daily consumptions amounting to 85–100 grams of fructose per day
  • Of key importance is the ability of fructose to by-pass the main regulatory step of glycolysis, the conversion of glucose-6-phosphate to fructose 1,6-bisphosphate, controlled by phosphofructokinase
  • ...29 more annotations...
  • Thus, while glucose metabolism is negatively regulated by phosphofructokinase, fructose can continuously enter the glycolytic pathway. Therefore, fructose can uncontrollably produce glucose, glycogen, lactate, and pyruvate, providing both the glycerol and acyl portions of acyl-glycerol molecules. These particular substrates, and the resultant excess energy flux due to unregulated fructose metabolism, will promote the over-production of TG (reviewed in [53]).
  • Glycemic excursions and insulin responses were reduced by 66% and 65%, respectively, in the fructose-consuming subjects
  • reduction in circulating leptin both in the short and long-term as well as a 30% reduction in ghrelin (an orexigenic gastroenteric hormone) in the fructose group compared to the glucose group.
  • A prolonged elevation of TG was also seen in the high fructose subjects
  • Both fat and fructose consumption usually results in low leptin concentrations which, in turn, leads to overeating in populations consuming energy from these particular macronutrients
  • Chronic fructose consumption reduces adiponectin responses, contributing to insulin resistance
  • A definite relationship has also been found between metabolic syndrome and hyperhomocysteinemia
  • the liver takes up dietary fructose rapidly where it can be converted to glycerol-3-phosphate. This substrate favours esterification of unbound FFA to form the TG
  • Fructose stimulates TG production, but impairs removal, creating the known dyslipidemic profile
  • the effects of fructose in promoting TG synthesis are independent of insulinemia
  • Although fructose does not appear to acutely increase insulin levels, chronic exposure seems to indirectly cause hyperinsulinemia and obesity through other mechanisms. One proposed mechanism involves GLUT5
  • If FFA are not removed from tissues, as occurs in fructose fed insulin resistant models, there is an increased energy and FFA flux that leads to the increased secretion of TG
  • In these scenarios, where there is excess hepatic fatty acid uptake, synthesis and secretion, 'input' of fats in the liver exceed 'outputs', and hepatic steatosis occurs
  • Carbohydrate induced hypertriglycerolemia results from a combination of both TG overproduction, and inadequate TG clearance
  • fructose-induced metabolic dyslipidemia is usually accompanied by whole body insulin resistance [100] and reduced hepatic insulin sensitivity
  • Excess VLDL secretion has been shown to deliver increased fatty acids and TG to muscle and other tissues, further inducing insulin resistance
  • the metabolic effects of fructose occur through rapid utilization in the liver due to the bypassing of the regulatory phosphofructokinase step in glycolysis. This in turn causes activation of pyruvate dehydrogenase, and subsequent modifications favoring esterification of fatty acids, again leading to increased VLDL secretion
  • High fructose diets can have a hypertriglyceridemic and pro-oxidant effect
  • Oxidative stress has often been implicated in the pathology of insulin resistance induced by fructose feeding
  • Administration of alpha-lipoic acid (LA) has been shown to prevent these changes, and improve insulin sensitivity
  • LA treatment also prevents several deleterious effects of fructose feeding: the increases in cholesterol, TG, activity of lipogenic enzymes, and VLDL secretion
  • Fructose has also been implicated in reducing PPARα levels
  • PPARα is a ligand activated nuclear hormone receptor that is responsible for inducing mitochondrial and peroxisomal β-oxidation
  • decreased PPARα expression can result in reduced oxidation, leading to cellular lipid accumulation
  • fructose diets altered the structure and function of VLDL particles causing and increase in the TG: protein ratio
  • LDL particle size has been found to be inversely related to TG concentration
  • therefore the higher TG results in a smaller, denser, more atherogenic LDL particle, which contributes to the morbidity of the metabolic disorders associated with insulin resistance
  • High fructose, which stimulates VLDL secretion, may initiate the cycle that results in metabolic syndrome long before type 2 diabetes and obesity develop
  • A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, disturbs normal hepatic carbohydrate metabolism leading to two major consequences (Figure 2): perturbations in glucose metabolism and glucose uptake pathways, and a significantly enhanced rate of de novo lipogenesis and TG synthesis, driven by the high flux of glycerol and acyl portions of TG molecules coming from fructose catabolism
  • Nathan Goodyear on 16 Sep 13
     
    Fructose and metabolic syndrome.  Good discussion of the impact of high fructose intake and metabolic dysfunction.  This study also does a great job of highlighting the historical change of fructose intake.
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

ScienceDirect - Trends in Immunology : Inflammation: the link between insulin resistanc... - 0 views

www.sciencedirect.com/science

inflammation obesity insulin resistance diabetes

shared by Nathan Goodyear on 09 Mar 11 - No Cached
  • Inflammation: the link between insulin resistance, obesity and diabetes
  • Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-α and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
  • Nathan Goodyear on 09 Mar 11
     
    Inflammation: the link between insulin resistance, obesity and diabetes
Nathan Goodyear

Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 di... - 0 views

www.ajandrology.com/article.asp

Testosterone therapy diabetes lipids glucose triglycerides men male hormone hormones

shared by Nathan Goodyear on 17 Jan 14 - No Cached
  • up to 40% of men with T2DM have testosterone deficiency
  • Among diabetic patients, a reduction in sex hormone binding globulin levels induced by insulin resistance leads to a further decline of testosterone levels
  • low bioavailable testosterone concentration was related to decreased lean body mass and muscle strength
  • ...13 more annotations...
  • Testosterone deficiency has a high prevalence in men with T2DM, and it is also associated with impaired insulin sensitivity, increased percentage body fat, central obesity, dyslipidemia, hypertension and cardiovascular diseases (CVD)
  • A meta-analysis of four randomized controlled trials (RCTs) showed that TRT seemed to improve glycemic control as well as fat mass in T2DM subjects with low testosterone levels and sexual dysfunction.
  • testosterone administration could increase muscle mass and strength
  • Insulin stimulates glucose uptake into muscle and adipose tissue via the Glut4 glucose transporter isoform. When insulin activates signaling via the insulin receptor, Glut4 interacts with insulin receptor substrate 1 to initialize intracellular signaling and facilitate glucose transportation into the cell
  • The benefits of TRT on glucose metabolism can mainly be explained by its influence on the insulin signaling pathway
  • Insulin resistance as assessed by, which is calculated from the equation (If*Gf/22.5, where If is fasting insulin and Gf is fasting glucose), was definitely improved by TRT after testosterone administration in three studies
  • Testosterone was observed to elevate the expression levels and stimulate translocation of Glut4 in cultured skeletal muscle cells and to upregulate Glut4 by activating insulin receptor signaling pathways in neonatal rats
  • These effects were inhibited by a dihydrotestosterone (DHT) blocker, indicating that glucose uptake may correlate with conversion of testosterone to DHT and activation of the androgen receptor.
  • TRT reduced triglyceride levels
  • TRT has been reported to have a positive effect in the decrease of total and LDL cholesterol levels and triglycerides in hypogonadal men
  • a recent meta-analysis showed that statins could significantly lower testosterone concentrations.
  • Epidemiological studies have found a negative relationship between testosterone levels and typical cardiovascular risk markers, such as body mass index, waist circumference, visceral adiposity and carotid intima-media thickness.
  • Testosterone treatment was shown to raise hemoglobin, hematocrit and thromboxane, all of which might give rise to CVD
  • Nathan Goodyear on 17 Jan 14
     
    Low Testosterone is a very significant problem in men with type II Diabetes.  Estimated to reach 40%, likely much higher.  They based these estimates only on T levels and sexual symptoms. Testosterone improves glycemic control primarily through Increased transcription and transloction of GLUT4 insulin receptors to the cell surface.  Inflammation reduction is also a mechanism.  Testosteorne lowers Triglycerides in the traditional lipid profile.  Studies are mixed on the other aspects of  lipids.  
Nathan Goodyear

International Journal of Impotence Research - Obesity, low testosterone levels and erec... - 0 views

www.nature.com/...ijir200842a.html

low T low Testosterone men male hormone hormones ED erectile dysfunction Testosterone diabetes metabolic syndrome obesity

shared by Nathan Goodyear on 27 Jan 15 - No Cached
  • Studies have shown that ED may be an early biomarker of general endothelial dysfunction, atherosclerosis and CVD
  • testosterone treatment of hypogonadal young and older men improves sexual function, increases lean mass and decreases fat mass
  • In men with low serum testosterone (for example, <8 or 230 nmol l−1) with obesity, metabolic syndrome and diabetes mellitus, treatment with testosterone is warranted
  • ...12 more annotations...
  • In obese middle-aged men, testosterone treatment reduced visceral adipocity, insulin resistance, serum cholesterol and glucose levels
  • testosterone replacement has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure in hypogonadal men with the metabolic syndrome as well as type 2 diabetes mellitus
  • Testosterone significantly inhibits lipoprotein lipase activity, which reduces triglycerides uptake into adipocytes in the abdominal adipose tissue
  • testosterone treatment decreased endogenous inflammatory cytokines (tumor necrosis factor-α and IL-1β) and lipids (total cholesterol) and increased IL-10 in hypogonadal men
  • Testosterone treatment reduced leptin and adiponectin levels in hypogonadal type 2 diabetic men after 3 months of testosterone replacement
  • available data clearly show a relationship between obesity, low testosterone levels and ED
  • Obesity adversely affects endothelial function and lowers serum testosterone levels through the development of insulin resistance and metabolic syndrome
  • Metabolic disturbances as well as production of cytokines and adipokines by inflamed fat cells may be causal factors in the development of ED
  • The onset of ED and the associated risk of CVD may be delayed through lifestyle modifications that affect obesity, such as diet and exercise
  • Very low testosterone levels contribute to the development of ED in obesity, metabolic syndrome and type 2 diabetes mellitus
  • Obesity is associated with low total testosterone levels that can be explained at least partially by lower sex hormone-binding globulin (SHBG) in obese men
  • epidemiological studies have shown a negative correlation between BMI and total testosterone and to a lesser extent with free and bioavailable (biologically active) testosterone levels
  • Nathan Goodyear on 27 Jan 15
     
    Obesity is associated with low Testosterone and ED in men.
obat sehat

Diabetes - 0 views

sehatobat.blogspot.com/...es-alami-solusi-mengatasi.html

obesity hormones disease

shared by obat sehat on 04 Dec 12 - No Cached
  • obat sehat on 04 Dec 12
     
    Insulin is a hormone produced by the pancreas to control blood sugar. Diabetes can be caused by too little insulin, resistance to insulin, or both. To understand diabetes, it is important to first understand the normal process by which food is broken down and used by the body for energy. Several things happen when food is digested: A sugar called glucose enters the bloodstream. Glucose is a source of fuel for the body. An organ called the pancreas makes insulin. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel. People with diabetes have high blood sugar because their body cannot move sugar into fat, liver, and muscle cells to be stored for energy. This is because either: Their pancreas does not make enough insulin Their cells do not respond to insulin normally Both of the above There are two major types of diabetes. The causes and risk factors are different for each type: Type 1 diabetes can occur at any age, but it is most often diagnosed in children, teens, or young adults. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown. Type 2 diabetes makes up most diabetes cases. It most often occurs in adulthood. However, because of high obesity rates, teens and young adults are now being diagnosed with it. Many people with type 2 diabetes do not know they have it. Gestational diabetes is high blood sugar that develops at any time during pregnancy in a woman who does not have diabetes. Diabetes affects more than 20 million Americans. Over 40 million Americans have pre-diabetes (which often comes before type 2 diabetes).
Nathan Goodyear

Testosterone Deficiency, Cardiac Health, and Older Men - 0 views

www.hindawi.com/...143763

low T Testosterone obesity type II diabetes diabetes health wellness metabolic syndrome lipids cholesterol hypogonadism TDS testicular dysgenesis syndrome men male hormone hormones prostate cancer

shared by Nathan Goodyear on 12 May 14 - No Cached
  • Studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally [39] and to produce modest but consistent improvement in exercise-induced angina and reverse associated ECG changes [40]. The mechanism of action is via blockade of calcium channels with effect of similar magnitude to nifedipine
    • Nathan Goodyear
      Nathan Goodyear on 12 May 14
       
      This directly refutes the recent studies (3) that Testosterone therapy increases cardiovascular events.
    • Nathan Goodyear
      Nathan Goodyear on 13 May 14
       
      Testosterone acts as a calcium channel blocker inducing vasodilation.
  • men with chronic stable angina pectoris, the ischaemic threshold increased after 4 weeks of TRT and a recent study demonstrates improvement continuing beyond 12 months [
  • Exercise capacity in men with chronic heart failure increased after 12 weeks
  • ...36 more annotations...
  • Studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels
  • Medications such as chronic analgesics, anticonvulsants, 5ARIs, and androgen ablation therapy are associated with increased risk of testosterone deficiency and insulin resistance
  • Women with T2D or metabolic syndrome characteristically have low SHBG and high free testosterone
    • Nathan Goodyear
      Nathan Goodyear on 12 May 14
       
      This stands in polar opposite of that with men.
  • Hypogonadism is a common feature of the metabolic syndrome
  • The precise interaction between insulin resistance, visceral adiposity, and hypogonadism is, as yet, unclear but the important mechanisms are through increased aromatase production, raised leptin levels, and increase in inflammatory kinins
  • levels of testosterone are reduced in proportion to degree of obesity
  • Men should be encouraged to combine aerobic exercise with strength training. As muscle increases, glucose will be burned more efficiently and insulin levels will fall. A minimum of 30 minutes exercise three times weekly should be advised
  • Testosterone increases levels of fast-twitch muscle fibres
  • By increasing testosterone, levels of type 2 fibres increase and glucose burning improves
  • Weight loss will increase levels of testosterone
  • studies now clearly show that low testosterone leads to visceral obesity and metabolic syndrome and is also a consequence of obesity
  • In the case of MMAS [43], a baseline total testosterone of less than 10.4 nmol/L was associated with a greater than 4-fold incidence of type 2 diabetes over the next 9 years
  • There is high level evidence that TRT improves insulin resistance
  • Low testosterone predicts increased mortality and testosterone therapy improves survival in 587 men with type 2 diabetes
  • A similar retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% ( ) in the treated group with the greatest effect in younger men and those with type 2 diabetes
  • the presence of ED has been shown to be an independent risk factor, particularly in hypogonadal men, increasing the risk of cardiac events by over 50%
  • A recent online publication on ischaemic heart disease mortality in men concluded optimal androgen levels are a biomarker for survival
  • inverse associations between low TT or FT (Table 2) and the severity of CAD
  • A recent 10 year study from Western Australia involving 3690 men followed up from 2001–2010 concluded that TT and FT levels in the normal range were associated with decreased all-cause and cardiovascular mortality, for the first time suggesting that both low and DHT are associated with all-cause mortality and higher levels of DHT reduced cardiovascular risk
  • TDS is associated with increased cardiovascular and all-cause mortality
  • The effect of treatment with TRT reduced the mortality rate of treated cohort (8.4%) to that of the eugonadal group whereas the mortality for the untreated remained high at 19.2%
  • hypogonadal men had slightly increased triglycerides and HDL
  • Men with angiographically proven CAD (coronary artery disease) have significantly lower testosterone levels [29] compared to controls ( ) and there was a significant inverse relationship between the degree of CAD and TT (total testosterone) levels
  • TRT has also been shown to reduce fibrinogen to levels similar to fibrates
  • men treated with long acting testosterone showed highly significant reductions in TC, LDL, and triglycerides with increase in HDL, associated with significant reduction in weight, BMI, and visceral fat
  • Low androgen levels are associated with an increase in inflammatory markers
  • In the Moscow study, C-reactive protein was reduced by TRT at 30 weeks versus placebo
  • In some studies, a decline in diastolic blood pressure has been observed, after 3–9 months [24, 26] and in systolic blood pressure
  • A decline was noted in IL6 and TNF-alpha
  • No studies to date show an increase in LUTS/BPH symptoms with higher serum testosterone levels
  • TRT has been shown to upregulate PDE5 [65] and enhance the effect of PDE5Is (now an accepted therapy for both ED and LUTS), it no longer seems logical to advice avoidance of TRT in men with mild to moderate BPH.
    • Nathan Goodyear
      Nathan Goodyear on 12 May 14
       
      What about just starting with normalization of Testosterone levels first.
  • Several meta-analyses have failed to show a link between TRT and development of prostate cancer [66] but some studies have shown a tendency for more aggressive prostate cancer in men with low testosterone
    • Nathan Goodyear
      Nathan Goodyear on 12 May 14
       
      And if one would have looked at their estrogen levels, I guarantee they would have been found to be elevated.
  • low bioavailable testosterone and high SHBG were associated with a 4.9- and 3.2-fold risk of positive biopsy
  • Current EAU, ISSAM, and BSSM guidance [1, 2] is that there is “no evidence TRT is associated with increased risk of prostate cancer or activation of subclinical cancer.”
  • Men with prostate cancer, treated with androgen deprivation, develop an increase of fat mass with an altered lipid profile
  • Erectile dysfunction is an established marker for future cardiovascular risk and the major presenting symptom leading to a diagnosis of low testosterone
Nathan Goodyear

JCI - Chronic inflammation in fat plays a crucial role in the development of obesity-re... - 0 views

www.jci.org/19451

inflammation obesity overweight WAT adipose tissue fat insulin resistance type II diabetes DM

shared by Nathan Goodyear on 20 Mar 12 - No Cached
  • Nathan Goodyear on 20 Mar 12
     
    how inflammation contributes to obesity.  Nice discussion of the inflammatory signaling that leads to obesity.  This occurs predominately in white adipose tissue WAT.  This leads to insulin resistance and type II DM.
Nathan Goodyear

Testosterone and glucose metabolism in men: current concepts and controversies - 0 views

joe.endocrinology-journals.org/...R37.full

shared by Nathan Goodyear on 04 Feb 14 - No Cached
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      80% of E2 production in men, that will cause low T in men, comes from SQ adiposity.  This leads to increase in visceral adiposity.
  • Only 5% of men with type 2 diabetes have elevated LH levels (Dhindsa et al. 2004, 2011). This is consistent with recent findings that the inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity
  • Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH) secretion
  • ...32 more annotations...
  • kisspeptin has emerged as one of the most potent secretagogues of GNRH release
  • Consistent with the hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
  • Figure 4
  • Interestingly, a recent 16-week study of experimentally induced hypogonadism in healthy men with graded testosterone add-back either with or without concomitant aromatase inhibitor treatment has in fact suggested that low oestradiol (but not low testosterone) may be responsible for the hypogonadism-associated increase in total body and intra-abdominal fat mass
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      This does not fit with the research on receptors, specifically estrogen receptors.  These studies that the authors are referencing are looking at "circulating" levels, not tissue levels.
  • A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects
  • Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
  • This is supported by observational studies showing that weight gain and development of diabetes accelerate the age-related decline in testosterone
  • Weight loss can reactivate the hypothalamic–pituitary–testicular axis
  • The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men
  • Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes
  • Several observational and randomised studies reviewed in Grossmann (2011) have shown that weight loss, whether by diet or surgery, leads to substantial increases in testosterone, especially in morbidly obese men
  • This suggests that weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression
  • There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
  • in those men in whom glycaemic control worsened, testosterone decreased
  • successful weight loss combined with optimisation of glycaemic control may be sufficient to normalise circulating testosterone levels in the majority of such men
  • weight loss, optimisation of diabetic control and assiduous care of comorbidities should remain the first-line approach.
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      This obviously goes against marketing-based medicine
  • In part, the discrepant results may be due to the fact men in the Vigen cohort (Vigen et al. 2013) had a higher burden of comorbidities. Given that one (Basaria et al. 2010), but not all (Srinivas-Shankar et al. 2010), RCTs in men with a similarly high burden of comorbidities reported an increase in cardiovascular events in men randomised to testosterone treatment (see section on Testosterone therapy: potential risks below) (Basaria et al. 2010), testosterone should be used with caution in frail men with multiple comorbidities
  • The retrospective, non-randomised and non-blinded design of these studies (Shores et al. 2012, Muraleedharan et al. 2013, Vigen et al. 2013) leaves open the possibility for residual confounding and multiple other sources of bias. These have been elegantly summarised by Wu (2012).
  • Effects of testosterone therapy on body composition were metabolically favourable with modest decreases in fat mass and increases in lean body mass
  • This suggests that testosterone has limited effects on glucose metabolism in relatively healthy men with only mildly reduced testosterone.
  • it is conceivable that testosterone treatment may have more significant effects on glucose metabolism in uncontrolled diabetes, akin to what has generally been shown for conventional anti-diabetic medications.
  • the evidence from controlled studies show that testosterone therapy consistently reduces fat mass and increases lean body mass, but inconsistently decreases insulin resistance.
  • Interestingly, testosterone therapy does not consistently improve glucose metabolism despite a reduction in fat mass and an increase in lean mass
  • the majority of RCTs (recently reviewed in Ng Tang Fui et al. (2013a)) showed that testosterone therapy does not reduce visceral fat
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      visceral and abdominal adiposity are biologically different and thus the risks associated with the two are different.
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      yet low T is associated with an increase in visceral adiposity--confusing!
  • testosterone therapy decreases SHBG
  • testosterone is inversely associated with total cholesterol, LDL cholesterol and triglyceride (Tg) levels, but positively associated with HDL cholesterol levels, even if adjusted for confounders
  • Although observational studies show a consistent association of low testosterone with adverse lipid profiles, whether testosterone therapy exerts beneficial effects on lipid profiles is less clear
  • Whereas testosterone-induced decreases in total cholesterol, LDL cholesterol and Lpa are expected to reduce cardiovascular risk, testosterone also decreases the levels of the cardio-protective HDL cholesterol. Therefore, the net effect of testosterone therapy on cardiovascular risk remains uncertain.
  • data have not shown evidence that testosterone causes prostate cancer, or that it makes subclinical prostate cancer grow
  • compared with otherwise healthy young men with organic androgen deficiency, there may be increased risks in older, obese men because of comorbidities and of decreased testosterone clearance
  • recent evidence that fat accumulation may be oestradiol-, rather than testosterone-dependent
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

Testosterone and metabolic syndrome Cunningham GR - Asian J Androl - 0 views

www.ajandrology.com/article.asp

Testosterone metabolic syndrome MetS TT total Testosterone SHBG men male hormone hormones Estradiol insulin resistance

shared by Nathan Goodyear on 02 Mar 15 - No Cached
  • The relationship of low testosterone to MetS often is considered to be bidirectional; however, the relationships probably are not direct
  • Many of the components of the MetS are recognized risk factors for the development of cardiovascular disease (CVD)
  • Multiple cross-sectional studies have found low TT and low sex hormone binding globulin (SHBG) levels in Caucasian and African-American men with the MetS, irrespective of age
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  • Low TT and SHBG levels also are prevalent in Chinese [7],[8] and Korean [9] men with the MetS
  • Normally 40%-50% of TT is bound to SHBG, so reducing SHBG levels will decrease TT.
  • Hyperinsulinism suppresses SHBG synthesis and secretion by the liver
  • significant increase in SHBG levels occurred after acutely lowering insulin levels in obese men
  • Estradiol levels are increased in men with the MetS, and they are positively correlated with the number of abnormal components of the MetS.
  • Although it is known that estrogen will increase SHBG levels, apparently the hyperinsulinism associated with obesity has a greater effect on SHBG levels
  • Estradiol also can inhibit luteinizing hormone (LH) secretion
  • Inflammatory cytokines are thought to have a direct effect on the pituitary to reduce LH secretion [15] and also a direct effect on Leydig cell secretion of testosterone
  • Low TT Levels have been shown to predict development of the MetS in men with normal BMI
  • Men in the lowest quartiles of serum TT, calculated free testosterone (cFT) and SHBG at baseline had the highest odds ratios for developing the MetS or DM during the 11 years follow-up
  • More recently, investigators conducting population-based studies have reported that only SHBG is associated with future development of the MetS
  • Additional evidence that low TT increases the risk of MetS comes from androgen deprivation treatment of prostate cancer
  • Low TT and low bioavailable testosterone (bT) were each significantly associated with elevated 20 years risk of CVD mortality in an older population in which cause-specific mortality was age, adiposity, and lifestyle-adjusted.
  • combination of low bT and ATP III-defined MetS is associated with increased cardiovascular mortality in men aged 40 years and above
  • in elderly men, testosterone may weakly protect against CVD. Alternatively, low TT may indicate poor general health
  • Muraleedharan and Jones [27] concluded that there is convincing evidence that low T is a biomarker for disease severity and mortality.
  • The evidence that TRT improves insulin sensitivity and glucose control is conflicted
  • It is widely recognized that testosterone treatment can reduce fat mass and increase lean body mass; however, until recently most reports have not been associated with much weight loss
  • Changes in body composition and weight loss are considered potential mechanisms by which testosterone treatment improves insulin sensitivity and glucose control in patients with diabetes. Effects on inflammatory cytokines [38] and changes in oxidative metabolism [39] also have been reported to improve glucose metabolism.
  • Testosterone replacement therapy has been reported to improve some or all of the components of the MetS.
  • Nathan Goodyear on 02 Mar 15
     
    To be read article on Testosterone and Metabolic Syndrome.
Nathan Goodyear

Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Lite... - 0 views

jaha.ahajournals.org/...e000272

low T Testosterone cardiovascular disease CAD CHF insulin resistance type II diabetes diabetes obesity men male hormone hormones therapy

shared by Nathan Goodyear on 13 May 14 - No Cached
  • Nathan Goodyear on 13 May 14
     
    Some startling statistics in this 2013 review on Testosterone in men.  Studies reflect an inverse relationship between Testosterone and CAD severity.  That is, the lower the Testosterone levels, the increase in severity of CAD. This same association was also found with CHF.  Low Testosterone is common in those with CAD, CHF, type II diabetes, increased IMT in carotids and aorta, and obesity when compared to "healthy" individuals.  Testosterone therapy in those with CAD found benefits: prolongation of ST segment depression, coronary vasodilation, improved exercise capacity in those with CHF, shift to type I muscle fibers, shorten the QTc interval.  Testosterone therapy has been shown to improve insulin resistance, improve HgbA1c and decrease waist circumference and fat loss in obese individuals.  Otherwise, a good review of the association between a declining Testosterone and cardiovascular disease.
Nathan Goodyear

Effect of Testosterone Treatment on Glucose Metabolism in Men With Type 2 Diabetes: A R... - 0 views

care.diabetesjournals.org/...2098.abstract

Testosterone treatment low subcutaneous fat visceral fat T glucose insulin resistance metabolism obesity diabetes men male hormone hormones

shared by Nathan Goodyear on 29 Jul 14 - No Cached
  • Nathan Goodyear on 29 Jul 14
     
    Only the abstract available in this publication.  Good study design.  No improvement in insulin resistance, glycemic control or visceral adiposity in obese men with type II diabetes.  The levels of inclusion were TT < 346, which would not meet the criteria put forth by other studies.  This study appeared to look at border line "low T" men with obesity and type II diabetes and found no direct glycemic control improvement.  An increase in lean muscle mass and decrease in subcutaneous fat was found.
Nathan Goodyear

Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes - 0 views

www.ncbi.nlm.nih.gov/...PMC2886982

obesity insulin resistance diabetes inflammation adipocyte dysfunction adipose tissue

shared by Nathan Goodyear on 22 Dec 11 - No Cached
  • Nathan Goodyear on 22 Dec 11
     
    Great explanation of current understanding of how adipocyte dysfunction leads to inflammation, increase FFA, insulin resistance, obesity, and associated inflammatory conditions such as diabetes
Nathan Goodyear

Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome - 0 views

www.ncbi.nlm.nih.gov/...PMC3099529

TLR toll-like receptors toll-like receptors fatty acids fat metabolic syndrome obesity overweight inflammation dietary

shared by Nathan Goodyear on 08 Oct 12 - No Cached
  • Activation of the innate immune system controls macronutrient metabolism
  • the innate immune response is the first line of defense against invading pathogens, wherein highly conserved pathogen-associated molecular patterns (PAMPs) are recognized by cognate pattern recognition receptors (PRRs
  • many studies have supported the idea that cytokine signaling directly promotes insulin resistance
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  • innate immune system may be causally linked to obesity
  • adipose tissue contains a substantial population of macrophages, and macrophage-driven adipose inflammation contributes significantly to the pathogenesis of obesity
  • Collectively, activation of the innate immune system is strongly associated with ASCVD, insulin resistance, and obesity, and recent evidence suggests that much of this association can be traced to a unique family of PRRs known as TLRs
  • TLRs are a family of type I transmembrane receptors, currently thought to comprise at least 13 members in mammals, that specifically recognize a variety of microbial PAMPs and trigger host cellular responses
  • Free SFAs have indeed been demonstrated to elicit TLR4-dependent and TLR2-dependent responses in several cell types.
  • Endogenous SFAs released from adipocytes activate cocultured macrophages via TLR4 [18], indicating the potential for cellular crosstalk in adipose tissue. Collectively, there is a growing body of evidence that SFAs promote, whereas long chain PUFA antagonize, TLR4-dependent and TLR2-dependent signaling in multiple cell models
  • In an elegant study, Shi et al. [16] demonstrated that SFAs activate TLR4-dependent signaling in both macrophages and adipocytes, and mice lacking TLR4 are protected against insulin resistance driven by intravenous lipid infusion
  • In addition to effects in macrophages and adipocytes, SFAs can activate TLR4 in the hypothalamus, which triggers a central inflammatory response that results in resistance to anorexigenic signals
  • endogenous SFAs can indeed promote innate immunity and inflammatory disease
  • This finding strongly supports the work of Hwang and coworkers [19–22] demonstrating that ω-3 PUFAs can effectively counteract SFA-induced TLR4 activation in cultured macrophages and dendritic cells.
  • Nathan Goodyear on 08 Oct 12
     
    high dietary fatty acids linked to metabolic syndrome through TLR.
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