HUMAN MEDICAL APPLICATIONS

Cellular metabolism describes a network of biochemical reactions that convert nutrients taken up from the environment into small molecules called metabolites. These metabolites serve as energy equivalents, RedOx co-factors, biomass building blocks, and substrates for DNA/RNA and protein modifications. The metabolism is involved in virtually any cellular process: proliferation and growth signaling, maintenance of ion gradients across membranes, epigenetic remodeling via DNA/protein modifications… Hence, metabolism is highly tissue specific, because it is optimized to the function and cellular processes of the different organs. Moreover, metabolism is tightly interconnected with the upstream signaling network to directly link it with the regulation of dependent cellular processes.

Any of the diseases or disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level, may be considered as a metabolic disease. Metabolic diseases will affect cell ability to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids). Thousands of enzymes participating in numerous interdependent metabolic pathways carry out this process.

In humans, disruption of normal metabolism is involved in various pathologies, from relatively benign to mostly severe ones. Among the most prevalent figure the following pathologies.

“Diabetes Mellitus”

It describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolisms resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs and is a major cause of heart disease and premature death (WHO 1999). The number of people with diabetes is rising worldwide. Between 35-40% of people in Europe will develop diabetes over their lifetime.

Two main types of diabetes are described:

Diabetes blood test

Type 1 diabetes (TDM1) usually develops in childhood and adolescence and patients require lifelong insulin injections for survival as their pancreas are unable to correctly synthetize then secrete insulin.

Type 2 diabetes (TDM2) usually develops in adulthood and is related to obesity, lack of physical activity, and unhealthy diets. This is the more common type of diabetes (representing 90% of diabetic cases worldwide) and treatment may involve lifestyle changes and weight loss alone, or oral medications or even insulin injections (Tangvarasittichai, 2015).

In the short term, hyperglycemia causes symptoms of increased thirst, increased urination, increased hunger, and weight loss. However, in the long-term, it causes damage to eyes (leading to blindness), kidneys (leading to renal failure), and nerves (leading to impotence and foot disorders/ possibly amputation). As well, it increases the risk of heart disease, stroke, and insufficiency in blood flow to legs. Many long-term studies have shown that a good metabolic control prevents or delays these complications.

Insuline-resistance and diabetes

Insulin-mediated glucose disposal varies widely in apparently healthy humans, and the more insulin resistant an individual, the more insulin he must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. These changes largely increase the risks of cardiovascular disease (CVD) (Polski et al, 2015).

Metabolic syndrome (MetS)

Metabolic syndrome is a disorder of energy utilization and storage, diagnosed by a co-occurrence of three out of five of the following medical conditions: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels. Its pathophysiology appears very complex and has been only partially elucidated. Most patients are elder, obese, sedentary, and have a degree of insulin resistance. Stress can also be a contributing factor. The most important factors are genetics, aging, diet (particularly sugar-sweetened beverage consumption), sedentary behavior, low physical activity, disrupted chronobiology/sleep, mood disorders/psychotropic medication use, and excessive alcohol use.

Its prevalence in elderly population varied from 11% to 43% (median 21%) according to the WHO. Obesity and hypertension are the most prevalent individual components (Bonomini et al, 2014).

MetS and CVD

MetS in elderly is a proven risk factor for cardiovascular morbidity, especially stroke and coronary heart disease (CHD), and mortality. Preventing and treating MetS would be useful in preventing disability and promoting normal aging.

MetS and neurodegenerative disorders

A growing body of epidemiological evidence suggested that MetS and Mets components (impaired glucose tolerance, abdominal or central obesity, hypertension, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol) may be important in the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), vascular dementia, and Alzheimer’s disease (AD). It may influence amyloid-beta (Abeta) peptide metabolism and tau protein hyperphosphorylation, the principal neuropathological hallmarks of AD (Hopps & Caimi, 2013). In AD, an age-related desynchronization of biological systems results, involving stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates (Yara et al, 2015) that precipitates an insulin resistant brain state (IRBS) with decreased glucose/energy metabolism and the increased formation of hyperphosphorylated tau protein and Abeta.

Cardiovascular diseases

Advanced age is associated with a disproportionate prevalence of CVD. Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD.

The biology of aging has not been fully clarified, but the free radical theory of aging is one of the strongest aging theories proposed to date (Sanz & Stefanatos, 2008). The free radical theory has been expanded to the oxidative stress theory, in which mitochondria play a central role in the development of the aging process because of their critical roles in bioenergetics, oxidant production, and regulation of cell death.

atherosclerosis US

Mitochondrial dysfunction is nowadays considered as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system (Indo et al, 2015). The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. A decline in cardiac mitochondrial function associated with the accumulation of oxidative damage might be responsible, at least in part, for the decline in cardiac performance with age (Shinmura, 2013).

Lifelong caloric restriction can attenuate functional decline with age, delay the onset of morbidity, and extend lifespan in various species. The effect of caloric restriction appears to be related to a reduction in cellular damage induced by reactive oxygen species.

Cancer

Clinical and epidemiological studies have linked cancer and other chronic medical conditions. For example, patients diagnosed with metS, inflammatory diseases, and autoimmune conditions show increased incidence and aggressiveness of tumor formation (Giovannucci, 2007; Mantovani et al., 2008). Conversely, diabetics treated with metformin to lower insulin levels have reduced levels of cancer in comparison to untreated individuals. Smoking is linked not only to lung cancer, but also to cardiovascular and other diseases. In general, the molecular bases of these links among diseases are poorly understood.

prostate inflammation

Inflammation is commonly associated with cancer formation and progression, and it is estimated that 15%–20% of all cancer related deaths can be attributed to inflammation and underlying infections (Mantovani et al., 2008). Inflammatory molecules are elevated in many forms of cancer, and they provide growth signals that promote the proliferation of malignant cells. Constitutively active NF-kB, the key transcription factor that mediates the inflammatory response, occurs in many types of cancer, and mouse models provide evidence for a causative role of NF-kB in malignant conversion and progression.

Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer (Chen et al, 2015) . Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival.

Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes (Marzetti et al, 2013).

Increased cancer risk is associated with obesity, type II diabetes, high cholesterol, and atherosclerosis, which are components of MetS. Mechanistically, the link between metabolic diseases and cancer is less understood than the connection to inflammation. However, a pathway consisting of AMP-activated protein kinase, an fundamental energy sensor, Akt, and PI3 kinase that are crucial for tumor development plays a critical role in diabetes and other metabolic diseases (Hardie, 2008). In addition, fatty acid synthase also plays an important role in cancer pathogenesis, and inhibitors against this enzyme are being tested as anti-cancer drugs (Menendez and Lupu, 2007).

Neurodegeneration

Neurodegenerative diseases (NDDs) are traditionally defined as disorders with selective loss of neurons and distinct involvement of functional systems defining clinical presentation.

Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. Actually, over 200 disorders are described, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders (Vernon, 2015).

Nevertheless, metabolism dysfunction can not only affect childs but also be a starter for neurodegenerescence in adults that becomes a primary health problem. In 2013, 5.2 million Americans are estimated to be living with Alzheimer’s disease. By 2050, the number of people age 65 and older with the disease is projected to be nearly 14 million. An estimated 1 million Americans currently live with Parkinson’s disease, and the prevalence of the disease is expected to increase substantially in the next 20 years due to the aging of the population.

Alzheimers brain

The human brain has the highest energy demands of any organ in the body, consuming more than 20% of the body’s glucose and oxygen, despite comprising only 2% of total body mass. The majority of this energy is used to support functional processes.  Numerous studies have reported that metabolic rates of glucose and oxygen decline with age, and in an accelerated manner in Alzheimer senile dementia (AD). The metabolic rate reductions have been considered as major contributors to brain structural alteration (gray matter and white matter atrophy) and cognitive impairment later in life.

CNS functions strongly depend on efficient mitochondrial function, because brain tissue has a high energy demand. Mutations in the mitochondrial genome, defects in mitochondrial dynamics, generation and presence of ROS, protein aggregate-associated dysfunctions and environmental factors may alter energy metabolism and in many cases are associated with neurodegenerative diseases (Hameed & Hsiung, 2011; Giordano et al, 2014).

Aside direct involvement of mitochondrial dysfunction, accumulating evidence indicates that insulin plays an important role in the regulation of brain glucose homeostasis in the central nervous system and has trophic effects on neurons. Thus, insulin metabolism dysfunction in diabetes may contribute directly to AD, likely via the accelerated formation of advanced glycation end products (AGEs) in the brain (Sridhar et al, 2015). Defective insulin secretion and insulin resistance in the tissues means too much glucose in the blood and also in the brain. This presence can lead to an increased oxidative stress. AGEs, along with other signs of oxidative damage, have been found lurking inside the pathology of many other adult-onset neurodegenerative disorders, including Pick’s disease, Parkinson’s, Progressive Supranuclear Palsy, Lewy Body Dementia, and ALS (Nowotny et al, 2015) . Each of these involves a progressive decline in neurological function with deficits that may include dementia, movement disorders, seizures, muscle weakness…, that can be tightly associated with pathological expression of protein aggregates that can be seen microscopically in the nervous tissue. Brain accumulation of senile Aβ plaques and hyperphosphorylated tau (neurofibrillary tangles) in the medial temporal lobe (MTL) and cortical areas of the brain of a patient with mild cognitive impairment is associated with a high risk of developing AD. This precipitation of modified protein forming aggregates can be related to the protein side-chains modifications either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation (Jomova & Valko, 2011).