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Nathan Goodyear

Testosterone and glucose metabolism in men: current concepts and controversies - 1 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

Homocysteine and Endothelial Dysfunction: A Link with Cardiovascular Disease - 0 views

jn.nutrition.org/...369.full.pdf+html

homocysteine CVD endothelial dysfunction cardiovascular disease ROS reactive oxygen species

shared by Nathan Goodyear on 25 Sep 12 - No Cached
  • Nathan Goodyear on 25 Sep 12
     
    No surprise that homocysteine is associated with vascular dysfunction, when elevated;  But the mechanism is elucidated here through ROS generation.
Nathan Goodyear

European Journal of Clinical Nutrition - C-reactive protein concentration and concentra... - 0 views

www.nature.com/...1601667a.html

IV vitamin C intravenous IV vitamin C antioxidants CRP ROS vitamins

shared by Nathan Goodyear on 10 Dec 12 - No Cached
  • Nathan Goodyear on 10 Dec 12
     
    This study shows that inflammation, CRP in this study, was inversely associated with low antioxidants ie. vitamin C.  This makes since as ROS are known to stimulate inflammation.  Vitamin C should be considered as a therapeutic option in those with inflammation.
Nathan Goodyear

Human C-reactive protein and the metabolic syndrome - 0 views

www.ncbi.nlm.nih.gov/...PMC2921825

CRP metabolic syndrome cardiovascular disease

shared by Nathan Goodyear on 15 Jan 13 - No Cached
  • Nathan Goodyear on 15 Jan 13
     
    CRP and metabolic syndrome
Nathan Goodyear

C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events - 0 views

circ.ahajournals.org/...391.full

CRP metabolic syndrome cardiovascular events cardiovascular disease

shared by Nathan Goodyear on 15 Jan 13 - No Cached
  • Nathan Goodyear on 15 Jan 13
     
    CRP is prognostic for metabolic syndrome.
Nathan Goodyear

A Preliminary Study of Daily Interpersonal Stress and C-Reactive Protein Levels Among A... - 0 views

www.ncbi.nlm.nih.gov/...PMC2715831

stress inflammation

shared by Nathan Goodyear on 18 Mar 13 - No Cached
  • Nathan Goodyear on 18 Mar 13
     
    stress increases inflammation
Nathan Goodyear

α-Lipoic Acid and Cardiovascular Disease - 0 views

jn.nutrition.org/...3327.full

cardiovascular disease CVD alpha alpha lipoic acid ALA antioxidant antioxidants ROS reactive oxygen species

shared by Nathan Goodyear on 20 Feb 13 - No Cached
  • Nathan Goodyear on 20 Feb 13
     
    Great read for anyone interested in the antioxidant properties of ALA.  
Nathan Goodyear

C-Reactive Protein in Healthy Subjects: Associations With Obesity, Insulin Resistance, ... - 0 views

atvb.ahajournals.org/...972.full

inflammation insulin resistance obesity GLUT4 receptor IL-1B TNF-alpha NF-KappaB

shared by Nathan Goodyear on 17 Oct 12 - No Cached
  • Nathan Goodyear on 17 Oct 12
     
    The summary statement of this article says it all: "chronic inflammatory state may induce insulin resistance and endothelial dysfunction..."  Inflammation causes insulin dysfunction. And in fact, we know this to be true.  We know that IL-1B and TNF-alpha stimulated by NF-KappaB actually inhibits insulin action via disruption of the GLUT4 receptor.
Nathan Goodyear

C-reactive protein levels and ageing male symptoms in hypogonadal men treated with test... - 0 views

onlinelibrary.wiley.com/...abstract

low t low Testosterone Testosterone Testosterone therapy men male hormones hormones CRP inflammation hsCRP

shared by Nathan Goodyear on 29 Sep 16 - No Cached
  • Nathan Goodyear on 29 Sep 16
     
    Testosterone therapy in older men with low T found a reduction in CRP.
Nathan Goodyear

The effect of testosterone replacement therapy on adipocytokines and C-reactive protein... - 0 views

www.eje-online.org/...595.full

low T testosterone IL-6 CRP inflammation men male diabetes

shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    low testosterone correlated with elevated IL-6 and CRP in this study.  Translation: low Testosterone = inflammation
Nathan Goodyear

Prognostic Influence of Increased Fibrinogen and C-Reactive Protein Levels in Unstable ... - 0 views

circ.ahajournals.org/...4204.full

fibrinogen CRP CAD coronary artery disease

shared by Nathan Goodyear on 28 Apr 12 - No Cached
  • Nathan Goodyear on 28 Apr 12
     
    fibrinogen and CRP associated with poor outcome in those individuals with CAD.
Nathan Goodyear

The CD16-CD56bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by ... - 0 views

www.jimmunol.org/...4513.long

NK cells CD56

shared by Nathan Goodyear on 01 May 12 - No Cached
  • Nathan Goodyear on 01 May 12
     
    Good discussion of CD 56 (bright) and CD 56 (dim) NK cells.
Nathan Goodyear

Elevated C-Reactive Protein Levels in Overweight and Obese Adults - 0 views

jama.ama-assn.org/...2131.full.pdf

CRP overweight obese inflammation

shared by Nathan Goodyear on 15 Mar 12 - No Cached
  • Nathan Goodyear on 15 Mar 12
     
    Overweight and obese adults, irregardless of age, were associated with elevated CRP. This indicates inflammation and creates the link between adipose induced inflammation and a direct contribution to CVD and other associated disease of aging.
Nathan Goodyear

International Journal of Obesity - Obesity is the major determinant of elevated C-react... - 0 views

www.nature.com/...0802609a.html

inflammation adipose tissue obesity overweight CRP metabolic syndrome

shared by Nathan Goodyear on 15 Mar 12 - No Cached
  • Nathan Goodyear on 15 Mar 12
     
    another study showing the link between obesity and increased CRP.  In this article, the elevated CRP was associated/linked with metabolic syndrome.  Again, suggesting adipose tissue as the source of inflammation.
Nathan Goodyear

Weight Loss Reduces C-Reactive Protein Levels in Obese Postmenopausal Women - 0 views

circ.ahajournals.org/...564.full

weight loss weight loss obesity postmenopausal women CRP inflammation cardiovascular disease

shared by Nathan Goodyear on 30 Mar 12 - No Cached
  • Nathan Goodyear on 30 Mar 12
     
    Weight loss in postmenopausal women reduces crp levels.  Translated: weight loss reduces fat induced inflammation and thus Cardiovascular disease.
Nathan Goodyear

Effect of chronic stress associated with unemployment on salivary cortisol: overall cor... - 0 views

www.psychosomaticmedicine.org/...460.abstract

stress saliva salivary cortisol test testing hormone hormones evaluation

shared by Nathan Goodyear on 28 Nov 11 - No Cached
  • Nathan Goodyear on 28 Nov 11
     
    salivary cortisol used to assess reactions to daily stressors.  
Nathan Goodyear

Inflammation (Chronic Inflammation) - Elevated C-Reactive Protein, Glycation - Life Ext... - 0 views

www.lef.org/...prtcl-146.shtml

inflammation aging CRP IL-6

shared by Nathan Goodyear on 23 Jan 12 - No Cached
  • Nathan Goodyear on 23 Jan 12
     
    good review of chronic inflammation and the systemic detrimental effects of it: aging.  
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