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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

Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure

E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution

ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake

It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.

Both ERs have been identified in the ARC

Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.

Both ERs have been identified in the LH

both ERs have been identified in this nucleus

The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive

The VMH is ERα regulated

Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body

GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake

data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance

In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane

It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.

E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue

In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue

decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin

Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance

Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs

Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue

suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue

In adipocytes, cortisol inhibits lipid mobilization in the presence of insulin, thus leading to triglyceride accumulation and retention.

Since the density of GC receptors is higher in intra-abdominal (visceral) fat than in other fat depots, the activity of cortisol leading to accumulation of fat is accentuated in visceral adipose tissue (24, 158), providing a mechanism by which excessive endogenous or exogenous GC lead to abdominal obesity and IR

obese patients generally have normal or subnormal plasma cortisol concentrations

This may be explained by an increased intratissular/cellular concentration of cortisol in adipose tissues

Intracellular GC may be produced from recycling of GC metabolites such as cortisone in adipose tissues

Local GC recycling metabolism is mediated by 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2

Cortisol also increases 11β-HSD1 expression in human adipocytes

In humans, elevated 11β-HSD1 expression in visceral adipose tissue is also associated with obesity

even if obese patients generally have normal or subnormal plasma cortisol concentrations (131, 158), triglyceride accumulation in visceral adipose tissue may be due, at least in part, to the local production of GC in insulin- and GC-responsive organs such as adipose tissue, liver, and skeletal muscle

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

Hif-1α stabilization enhances aerobic fermentation

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

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

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

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

Previous studies showed that GBM survival and tumor growth was correlated with blood glucose levels

Evidence indicates that glioma cells cannot effectively use ketone bodies for energy due to defects in the number, structure, and function of their mitochondria

The accuracy of the GKI as a predictor for therapeutic efficacy, however, is better when ketone bodies are measured from the blood than when measured from the urine

A reduction of glucose-driven lactic acid fermentation would not only increase tumor cell apoptosis, but would also reduce inflammation and edema in the tumor microenvironment thus reducing tumor cell angiogenesis and invasion

Besides serving as a metabolic fuel for GBM, glutamine is also an essential metabolite for normal immune cells

therapies that inhibit glutamine availability and utilization must be strategically employed to avoid inadvertent impairment of immune cell functions

we used the non-toxic green tea extract, EGCG, and chloroquine in an attempt to limit glutamine availability to the tumor cells

EGCG is thought to target the glutamate dehydrogenase activity that facilitates glutamine metabolism in GBM cells

Chloroquine, on the other hand, will inhibit lysosomal digestion thus restricting fermentable amino acids and carbohydrates from phagocytosed materials in the tumor microenvironment

HBOT to increase oxidative stress in the tumor cells

As glucose and glutamine fermentation protect tumor cells from oxidative stress, reduced availability of these metabolites under ketosis could enhance the therapeutic action of HBOT, as we recently described

Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast

Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day

KD (increased to 1,500 kcal/day at day 22

the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA)

Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D

This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies

Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers

less than 20% of younger adults generally survive beyond 24 months

glucose and glutamine are the primary fuels that drive the rapid growth of most tumors including GBM

Glucose drives tumor growth through aerobic fermentation (Warburg effect), while glutamine drives tumor growth through glutaminolysis

The fermentation waste products of these molecules, i.e., lactic acid and succinic acid, respectively, acidify the tumor microenvironment thus contributing further to tumor progression

Glucose and glutamine metabolism is also responsible for the high antioxidant capacity of the tumor cells thus making them resistant to chemo- and radiotherapies

The reliance on glucose and glutamine for tumor cell malignancy comes largely from the documented defects in the number, structure, and function of mitochondria and mitochondrial-associated membranes

These abnormalities cause the neoplastic GBM cells to rely more heavily on substrate level phosphorylation than on oxidative phosphorylation for energy

dexamethasone not only increases blood glucose levels but also increases glutamine levels through its induction of glutamine synthetase activity

Calorie restriction and restricted KD are anti-angiogenic, anti-inflammatory, anti-invasive, and also kill tumor cells through a proapoptotic mechanism

Evidence also shows that therapeutic ketosis can act synergistically with several drugs and procedures to enhance cancer management improving both progression free and overall survival

hyperbaric oxygen therapy (HBOT) increases oxidative stress on tumor cells especially when used alongside therapies that reduce blood glucose and raise blood ketones

The glutamine dehydrogenase inhibitor, epigallocatechin gallate (EGCG) is also proposed to target glutamine metabolism