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The starting period of the LeanBiome program includes a detoxification process that effectively removes any accumulated ree radicals, toxins, fand oxidative stress. This cleansing enables improved blood circulation, setting the stage for the body to initiate its own fat-burning mechanisms. To enhance metabolic activity, introducing the lean bacteria contained in LeanBiome to your gut microbiome is a beneficial approach. This activation triggers r
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Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
cancer is predicted to overtake heart disease as the leading cause of death in Western societies
cancer can also be recognized as a metabolic disease.
glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
Otto Warburg first proposed that all cancers arise from damage to cellular respiration
The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
Glucose and glutamine act synergistically for driving rapid tumor cell growth
Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
reason to eliminate glutamine in cancer patients and even GSH with cancer patients
It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
Ketone bodies and fats are non-fermentable fuels
Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
Apoptosis under energy stress is greater in tumor cells than in normal cells
A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
. This energy stress acts as a press disturbance
Drugs that target availability of glucose and glutamine would act as pulse disturbances
Hyperbaric oxygen therapy can also be considered another pulse disturbance
The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
Protein amino acids can be metabolized to glucose through the Cori cycle
The fats in KDs used clinically also contain more medium chain triglycerides
Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
GKI values of 1.0 or below are considered therapeutic
The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
Ketones are much more than energy adaptabilit, but actually are therapeutic.
ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
Ketone supplementation has also been shown to reduce anxiety behavior in animal models
This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
oxaloacetate is a glycolytic inhibitor, as is doxycycline, and IVC.
A synergistic interaction of the KD diet plus radiation was seen
It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
GBM and use glutamine as a major fuel
Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
Androgen deprivation therapy was found to decrease lean muscle mass and increase abdominal adipose tissue, not visceral. Significant change in body composition in men depleted of androgens in androgen deprivation therapy.
One advantage of FMI, as compared to the BMI concept, is that it amplifies the relative effect of aging on body fat
We believe that the definition of obesity based on relative body fat (ie percentage) remains of great value for the definition of obesity. However, in a situation in which a patient is losing weight without substantially changing his/her relative body fat (as is the case with crash diets), the calculation of FMI will quantitatively reveal the amount of body fat store lost.
high sensitivity of FMI (respectively FFMI) to a slight change of body fat stores
Sarcopenic obesity has been defined as a low FFM associated with a high body fat
relative FFM lower than 73% (ie a relative body fat greater than 27%) in men and a FFM lower than 62% (ie a body fat greater than 38%) in women.
FMIs greater than 8.2 kg/m2 in men and 11.8 kg/m2 in women would define the 'overfat' status (rather than the overweight range) in terms of fat mass
In young women, FMI averaged 5.5 kg/m2 (range 5th-95th percentile: 3.5-8.7 kg/m2) ie 38% higher than in males
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
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
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
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 TableT
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
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.
Abstract only available due to pre-release. Cysteine and glycine supplementation feed the glutathione pathways. In HIV men, this improved insulin sensitivity, body composition, and muscle strength.
Cochran review of 6 studies of only 164 women found lifestyle interventions improved body composition, mostly fat loss, decreased the hyperandrogen status and improved insulin resistance in women with PCOS.
The vast majority (88%) did not screen cardiac patients for TDS.
Testosterone deficiency has a prevalence of 7% in the general population, rising to 20% in elderly males
Males with CAD have lower testosterone levels than those with normal coronary angiograms of the same age,5 suggesting that the prevalence of testosterone deficiency is much higher in the CAD population
Men with hypertension, another established risk factor for CAD, have lower testosterone compared to normotensive men
Recent meta-analyses showed that testosterone levels are generally lower among patients with metabolic syndrome, regardless of the various definitions of metabolic syndrome that are used
Testosterone (total and bioavailable) and sex-hormone binding globulin (SHBG) are inversely associated with the prevalence of metabolic syndrome in men between the ages of 40 and 80, and this association persists across racial and ethnic backgrounds
ower levels of testosterone and SHBG predict a higher incidence of metabolic syndrome.
Low testosterone levels have been related to increased insulin resistance and cardiovascular mortality,12 even in the absence of overt type 2 diabetes mellitus.
testosterone levels (total and bioavailable) in middle-aged men are inversely correlated with insulin resistance
The Massachusetts Male Aging Study (MMAS) demonstrated that low levels of testosterone and SHBG are independent risk factors for the development of type 2 diabetes,
Andropausal men (age 58 ± 7 years) have a higher maximal carotid artery intima-media thickness
There is an inverse linear correlation between body mass index (BMI) and wait-to-hip ratio with testosterone and insulin-like growth factor-1 levels.
Testosterone supplementation for 1 year in hypogonadal men has been shown to cause a significant improvement in body weight, BMI, waist size, lipid profile, and C-reactive protein levels
TRT for 3 months in hypogonadal men with type 2 diabetes significantly improved fasting insulin sensitivity, fasting blood glucose and glycated hemoglobin.
Testosterone replacement can improve angina symptoms and delay the onset of cardiac ischemia, likely through a coronary vasodilator mechanism
ADT is associated with an increased risk of cardiovascular events, including myocardial infarction and cardiovascular mortality.
ADT significantly increases fat mass, decreases lean body mass,29,30 increases fasting plasma insulin and decreases insulin sensitivity31 and increases serum cholesterol and triglyceride levels
Startling study on the knowledge of Testosterone and cardiovascular disease in general practitioners and cardiologists in Canada. Eight-eight percent did not screen patients with cardiovascular disease for low Testosterone. A whopping 67% of physicians did not know that low T was a risk factor for cardiovascular disease, yet 62% believed Testosterone would increase exercise tolerance.
The lack of knowledge displayed by physicians today is staggering and is an indictment of the governing bodies. This was a survey conducted in Canada so there are obvious limitations to the strength/conclusion of this study.
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
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
Testosterone therapy in men with low Testosterone was found to improve insulin sensitivity, total cholesterol levels, LDL, Lpa, and sexual performance in men with low T, type II diabetes and/or metabolic syndrome. There is suggestion that muscle composition was improved as well.
It is important to note that, although the blood level of glucose drops, it still remains at a physiological level (23), which is maintained through gluconeogenesis involving glucogenic amino acids and also glycerol released from triglycerides
“physiological ketosis” where KB levels may rise to 7 to 8 mmol L-1 (but without any pH change). In “pathological diabetic ketoacidosis,” on the other hand, ketonemia can exceed 20 mmol L-1 and also cause lowering of blood pH
in the initial phase of KD, about 16% of glucose comes from glycerol (released from triglyceride hydrolysis) and the bulk (60–65 g) from proteins via gluconeogenesis (proteins may be of either dietary or endogenous origin
the protein supply consumed during a KD “preserves,” as demonstrated, lean body mass
The importance of glycerol as a glucose source increases progressively during ketosis; in fact, glycerol passes from supplying 16% of total glucose to an average of 60% after many days (>7 d) of complete fasting (from 38% in lean individual to 79% in the obese).
The possible reasons for the effectiveness of KD for weight loss may be listed as follows, in order of evidence, strongest first:
Figure 3Image Tools
1. Appetite reduction: protein satiety, effects on appetite-related hormones such as ghrelin, and possibly a sort of direct appetite-blocking effect of KB
2. Reduced lipogenesis and increased fat oxidation
3. A reduction in respiratory quotient may indicate a greater metabolic efficiency in fat oxidation
4. A thermic effect of proteins and increased energy usage by gluconeogenesis
all data regarding biochemical and molecular mechanisms suggest that it is very difficult to increase muscle mass during a KD; use of which really should be limited to the few days immediately before competition in bodybuilding.
a long-term KD can interfere with some muscle hypertrophy mechanisms and this could be counterproductive if the aim of the athlete is to gain muscle mass
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
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
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.
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
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