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Nathan Goodyear

Testosterone restores insulin sensitivity in patients with diabetes and hypogonadism | ... - 0 views

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    This is the abstract from oral presentation at AACE in Las Vegas from May.  Small study finds reduction in fat mass, increase in muscle mass, increase in insulin sensitivity, and reduction in inflammation signaling with Testosterone therapy in men with low Testosterone.  These men were type 2 diabetics.  This is consistent with prior published literature.  However, men without diabetes, this association is hard to reproduce. The degree of glucose control also effects the response to Testosterone therapy i.e. the worse the glucose control, the more the response from Testosterone.   Also of note, those men with hypogonatrophic hypogonadism had decreased insulin receptor expression, decreased insulin sensitivity, and decreased GLUT-4 expression versus eugonadal men.  Remember from prior studies, it is the conversion of Testosterone to DHT that increases GLUT-4 transcription, translocation, and expression.
Nathan Goodyear

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders - 0 views

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    great review of Gluten sensitivity or Non-Celiac Gluten sensitivity.
Nathan Goodyear

Gluten Sensitivity and Celiac Disease - 0 views

  • cientists at the University of Maryland School of Medicine’s Center for Celiac Research have proven that gluten sensitivity is different from celiac disease at the molecular level and in the response it elicits from the immune system
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    Gluten sensitivity different than celiac disease proven
Nathan Goodyear

Fifty- two-Week Treatment With Diet and Exercise Plus Transdermal Testosterone Reverses... - 0 views

  • there appears to be a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance (Pitteloud et al, 2005), and this relationship is at least partially direct and not fully dependent on (changes in) elements of the MetS
  • supervised D&E alone led to significant improvements in testosterone concentrations, glycemic control, and components of the MetS
  • diet control, exercise, and testosterone supplementation may be beneficial in the management of men with T2D
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  • androgen-deprivation therapy in males with prostatic cancer may be associated with an increased risk for T2D, which may be caused by negative effects on insulin sensitivity
  • insulin sensitivity, measured by HOMA, improved in both groups and with a significantly greater degree when testosterone was added to supervised D&E
  • Fasting insulin concentrations, a good representative of insulin sensitivity, did show a significant correlation with changes in circulating androgen levels, an observation in support of Pitteloud et al (2005), who showed a direct relationship between insulin sensitivity and circulating testosterone concentrations using the hyper-insulinemic euglycemic clamp technique
  • 52 weeks of testosterone treatment also significantly improved circulation levels of adiponectin and hsCRP, key serum markers of insulin sensitivity and hepatic steatosis
  • The changes in both adiponectin and hsCRP were significantly correlated with the therapy-induced changes in bioavailable testosterone
  • a negative correlation was found between hsCRP levels and bioavailable testosterone
  • serum PSA concentrations did not differ between the 2 treatment groups, indicating that short-term testosterone administration appears to be acceptably safe
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    Study of men with metabolic syndrome and type II Diabetes finds that diet and exercise alone improved glucose control and metabolic syndrome components by 31%.  The addition of Testosterone therapy increased this % to 81%.
Nathan Goodyear

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pa... - 0 views

  • WNT signaling
  • early colon cancers commonly display loss of function of the tumor suppressor Adenomatous polyposis coli (APC), a key component of the β-CATENIN destruction complex
  • Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas
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  • In normal embryogenesis and homeostasis, the canonical WNT pathway is activated by secreted WNT ligands produced in highly controlled context-dependent manners and in precise amounts. WNT activity is transduced in the cytoplasm, inactivates the APC destruction complex, and results in the translocation of activate β-CATENIN to the nucleus, where it cooperates with DNA-binding TCF/LEF factors to regulate WNT-TCF targets and the ensuing genomic response
  • beyond the loss of activity of the APC destruction complex, for instance throughAPC mutation, phosphorylation of β-CATENIN at C-terminal sites is required for the full activation of WNT-TCF signaling and the ensuing WNT-TCF responses in cancer.
  • The WNT-TCF response blockade that we describe for low doses of Ivermectin suggests an action independent to the deregulation of chloride channels
  • involve the repression of the levels of C-terminally phosphorylated β-CATENIN forms and of CYCLIN D1, a critical target that is an oncogene and positive cell cycle regulator.
  • the Avermectin single-molecule derivative Selamectin, a drug widely used in veterinarian medicine (Nolan & Lok, 2012), is ten times more potent acting in the nanomolar range
  • Ivermectin also diminished the protein levels of CYCLIN D1, a direct TCF target and oncogene, in both HT29 and H358 tumor cells
  • Activated Caspase3 was used as a marker of apoptosis by immunohistochemistry 48 h after drug treatment. Selamectin and Ivermectin induced up to a sevenfold increase in the number of activated Caspase3+ cells in two primary (CC14 and CC36) and two cell line (DLD1 and Ls174T) colon cancer cell types (Fig​(Fig2C).2C). All changes were significative
  • The strong downregulation of the expression of the intestinal stem cell genesASCL2 andLGR5 (van der Flieret al, 2009; Scheperset al, 2012; Zhuet al, 2012b) by Ivermectin and Selamectin (Fig​(Fig2D)2D) raised the possibility that these drugs could affect WNT-TCF-dependent colon cancer stem cell behavior
  • Pre-established H358 tumors responded to Ivermectin showing a ˜ 50% repression of growth
  • Ivermectin hasin vivo efficacy against human colon cancer xenografts sensitive to TCF inhibition with no discernable side effects
  • Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities
  • these drugs block WNT-TCF pathway responses, likely acting at the level of β-CATENIN/TCF function, affecting β-CATENIN phosphorylation status.
  • anti-WNT-TCF activities of Ivermectin and Selamectin
  • Ivermectin has a well-known anti-parasitic activity mediated via the deregulation of chloride channels, leading to paralysis and death (Hibbs & Gouaux, 2011; Lynagh & Lynch, 2012). The same mode of action has been suggested to underlie the toxicity of Ivermectin for liquid tumor cells and the potentiation or sensitization effect of Avermectin B1 on classical chemotherapeutics
  • the specificity of the blockade of WNT-TCF responses we document, at low micromolar doses for Ivermectin and low nanomolar doses for Selamectin, indicate that the blockade of WNT-TCF responses and chloride channel deregulation are distinct modes of action
  • What is key then is to find a dose and a context where the use of Ivermectin has beneficial effects in patients, paralleling our results with xenografts in mice.
  • Cell toxicity appears at doses greater (> 10 μM for 12 h or longer or > 5 μM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.
  • Our data point to a repression of WNT-β-CATENIN/TCF transcriptional responses by Ivermectin, Selamectin and related macrocylic lactones.
  • (i) The ability of Avermectin B1 to inhibit the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in our screen
  • (ii) The ability of Avermectin B1, Ivermectin, Doramectin, Moxidectin and Selamectin to parallel the modulation of WNT-TCF targets by dnTCF
  • (iii) The finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF
  • (iv) The repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by Ivermectin and Selamectin
  • (v) The specific inhibition ofin-vivo-TCF-dependent, but notin-vivo-TCF-independent cancer cells by Ivermectin in xenografts.
  • These results together with the reduction of the expression of the colon cancer stem cell markersASCL2 andLGR5 (e.g., Hirschet al, 2013; Ziskinet al, 2013) raise the possibility of an inhibitory effect of Ivermectin, Selamectin and related macrocyclic lactones on TCF-dependent cancer stem cells.
  • the capacity of cancer cells to form 3D spheroids in culture, as well as the growth of these, is also WNT-TCF-dependent (Kanwaret al, 2010) and they were also affected by Ivermectin treatment
  • If Ivermectin is specific, it should only block TCF-dependent tumor growth. Indeed, the sensitivity and insensitivity of DLD1 and CC14 xenografts to Ivermectin treatment, respectively, together with the desensitization to Ivermectin actionin vivo by constitutively active TCF provide evidence of the specificity of this drug to block an activated WNT-TCF pathway in human cancer.
  • Ivermectin has a good safety profile since onlyin-vivo-dnTCF-sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin-treated mice at the doses used
  • previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, 2012), that birth defects were not observed after exposure of pregnant mothers (Pacquéet al, 1990) and that this drug does not cross the blood–brain barrier (Kokozet al, 1999). Similarly, only dogs with mutantABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealeyet al, 2001; Orzechowskiet al, 2012)
  • Indications may include treatment for incurable β-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.
  • Ivermectin, Selamectin, or related macrocyclic lactones could also serve as topical agents for WNT-TCF-dependent skin lesions and tumors such as basal cell carcinomas
  • they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population
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    Ivermectin, a common anti-parasitic, found to inhibit WTF-TCF pathway and decrease c-terminal phosophorylaiton of Beta-CATENIN all resulting in increased aptosis and inhibition of cancer growth in colon cancer cell lines and lung cancer cell lines.
Nathan Goodyear

Update on Serologic Testing in Celiac Disease - 0 views

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    New clarification of celiac disease and the new gluten sensitivity. It has been many years that gluten sensitivity was frowned upon, but now clarification and validation comes.
Nathan Goodyear

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

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

Microbial Modulation of Insulin Sensitivity - 0 views

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    Gut microbiota effects insulin sensitivity.
Nathan Goodyear

Cambridge Journals Online - Abstract - Resveratrol improves insulin sensitivity, reduce... - 0 views

  • resveratrol improves insulin sensitivity in humans,
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    Resveratrol improves insulin sensitivity
Nathan Goodyear

Divergence of gut permeability and mucosal immune gene expression in two glut... - 0 views

  • GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.
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    Gluten sensitivity a result of the innate immunity
Nathan Goodyear

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders - 0 views

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    good discussion on non-Celiac gluten sensitivity.  The incidence sits at roughly 6% of the general population.  As research builds, our understanding will also increase.
Nathan Goodyear

Berberine Improves Insulin Sensitivity by Inhibiting Fat Store and Adjusting Adipokines... - 0 views

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    Berberine reduced BMI, improved insulin sensitivity, improved leptin sensitivity, and improved leptin:adiponectin ratio levels in people with metabolic syndrome after 3 months.
Nathan Goodyear

Vitamin D and diabetes - 0 views

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    vitamin D in those with vitamin D deficiency and insulin resistance have improved insulin sensitivity.  The doses used in the case studies presented are low.  This article highlights the fact that vitamin D outperforms metformin in improved insulin sensitivity.
Nathan Goodyear

Diabetes Care - 0 views

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    supplementation of Vitamin K2 in healthy men improved insulin sensitivity.  The question of whether it improves insulin sensitivity in unhealthy men and/or diabetes is not confirmed here.
Nathan Goodyear

Platinum Sensitivity in a BRCA1 Mutation Carrier with Advanced Breast Cancer - ScienceD... - 0 views

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    BRCA indicates increased platinum sensitivity and decreased doxorubicin sensitivity.
pharmacybiz

Avacta Halts Sale Of Covid-19 Rapid Antigen LFT - 0 views

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    Britain's biotech firm Avacta Group on Monday (January 10) announced halting sales of its Covid-19 rapid antigen lateral flow test AffiDX to replace antibodies in the device and increase its ability to diagnose the Omicron variant. The company stated that AffiDX is capable of detecting Omicron when the virus is present in high numbers in samples, but the sensitivity of the test reduces at lower viral loads. The performance of all rapid antigen tests came under scanner in wake of a large number of mutations in the Omicron variant. AffiDX contains both a proprietary Affimer reagent and a commercially available antibody. The Affimer reagent detects the Omicron variant with the same sensitivity as the Delta variant, and performance of the antibody is paired with the Affimer reagent in the test. This has been affected by the additional Omicron mutations, the firm said. Alastair Smith, chief executive of Avacta Group, said: "Our determination to only provide high quality, high performance diagnostic tests has led us to the correct decision to pause all marketing of the AffiDX® lateral flow antigen test. We have, of course, been unable to market the product in the UK since October 2021, as the product continues to await approval under the new CTDA regulatory process.
Nathan Goodyear

Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Functi... - 0 views

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    Testosterone and insulin resistance.  Testosterone improves insulin sensitivity and mitochondrial function.
Nathan Goodyear

The Association Between Sleep Duration, Insulin Sensitivity, and β-Cell Funct... - 0 views

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    sleep duration linearly associated with insulin sensitivity.
Nathan Goodyear

Non-Celiac Gluten Sensitivity | Molina-Infante | OmniaScience Monographs - 0 views

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    Only abstract available here.  Non-celiac gluten sensitivity review.  NCGS is an innate immune response rather than a humoral or autoimmune response.
Nathan Goodyear

American Journal of Gastroenterology - Abstract of article: Non-Celiac Wheat Sensitivit... - 0 views

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    Non-celiac gluten sensitivity.  Only abstract available here.
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