A Metabolic Approach To Non Communicable Diseases - NCD

Monday, 31 January 2011 00:00

..scientists are even more understanding that many metabolic patho-mechanisms and many metabolic modulators are in common among Non Communicable Diseases…

Metabolism is not boring: writes L. Bryan Ray introducing a special issue of Science dedicated to the resurgence interest on metabolism (Science 2010; 330:1337). The focus on metabolism and on mitochondria and cellular energy fuel is raising new attention devoted to metabolic therapy, which seems to be a real therapeutic option in several conditions: e.g. in obesity, diabetes (see also metabolic surgery), or in some cardiovascular diseases such as heart failure. In those diseases appear even more studied mechanisms leading to energetic derangement which are suggesting new molecular targets for therapeutic intervention. Proof-of-principle clinical studies may use the phosphocreatine/ATP ratio to monitor the early energetic response of cells to metabolic therapy, and this method may provide a surrogate marker of long-term prognostic effects. Finally, large-scale clinical trials will have to prove or disprove the clinical efficacy of metabolic modulators. These therapies may improve the symptoms and prognosis of patients with the life-threatening illness of chronic heart failure (NEJM 2007; 356:1140-1151).

Shared metabolic mechanisms
Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells (Circ Res 2008; 102: 401-414). If nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species-ROS formation may have negative consequences such as, e.g., rate of mutagenesis and stimulation of pro-inflammatory processes. ROS formation is contributing with aging, reduced mitochondrial biogenesis, and genetic factors, to mitochondrial dysfunction. On the other side, interventions that improve mitochondrial function also reduce insulin resistance. That is a basis of an even more increased attention on the correlation between mitochondrial dysfunction and insulin resistance and associated complications (Circ Res 2008; 102: 401-414).
Mechanisms other than genetic ones are also involved in the pathophysiology of aging and disease. This applies for the non enzymatic post-translational modifications, which alter structural and biological properties of proteins in living organisms, and it is due to a wide range of chemical reactions that occur after the enzymatic processes of protein maturation, and may be considered hallmarks of protein molecular aging. They include oxidation, racemization, isomerization, deamidation, nitration, carbonylation, carbamylation, and glycation (or glycoxidation) (Exp Gerontol 2008; 43: 247-57). These cumulative and irreversible modifications occur progressively during aging but are amplified in various diseases such as diabetes mellitus, chronic renal failure, or atherosclerosis (Clin Chem 2010; 56: 1401-12).
Obesity is associated with increased serum levels of inflammatory factors and increased macrophage infiltration of adipose tissue. However experimental results suggest that adipose tissue inflammation may be secondary to weight gain induced by insulin resistance. The increased risk of diabetes associated with obesity may be caused by increased lipid deposits in skeletal muscle and liver, creating insulin resistance. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance (Eur Cytokine Netw. 2006 Mar;17(1):4-12). Leptin is a peptide hormone secreted by adipose tissue that has been associated with many processes. One of the target tissues of leptin is the hypothalamus where it can act to regulate feeding behavior and metabolism. Another leptin target is skeletal muscle. Activation of leptin signaling in skeletal muscle activates the AMP-activated protein kinase (AMP-kinase), known to play a key role in signaling in response to nutrients throughout evolution (J  Appl  Physiol 2001; 91: 1017-28 – no link; Diabetes 2002; 51: 144-151; Nature 2002; 415: 339-43). Leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity, leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cytokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes (Mol Cell Endocrinol. 2010 Mar 25;316(2):129-39). It is known that IL-6 plays a role in lipid metabolism and energy expenditure. The polymorphism found in point 174 (G174C) of a promoter region of IL-6 gene affects the level of interleukin-6 expression and, consequently, may lead to obesity and correlated conditions (Eur J Med Res. 2010 Nov 4;15 Suppl 2:123-7). In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised (J Clin Endocrinol Metab. 2010 Dec 29. [Epub ahead of print]) doi:10.1210/jc.2010-2253 - no link).
Insulin resistance is recognized since time (Diabetes Care 1999; 22: 562-568) as a characteristic of obesity, type 2 diabetes, and component of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease - CVD. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in non classic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Insulin resistance is not only a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome (Nutrition & Metabolism 2009; 6: 16-42; BMC Evolutionary Biology 2007; 7:61). Under an evolutionary biology point of view insulin resistance is likely to have evolved, beyond an energy homeostasis alone, as a switch in reproductive and sustenance strategies. The concept linked to an Insulin Resistance Syndrome is contributing to better understand the paradigm of common patho-physiology mechanisms among chronic diseases as obesity, diabetes, and cardiovascular disease. If the studies’ results will support the hypothesis, it can change the epidemiological thought and help scientists to better design the line of action for control of the disorders associated with the Insulin Resistance Syndrome. Insulin resistance syndrome is considered “a major cause of morbidity and death throughout the world today, and … (it) has the potential to revolutionize the line of prevention and treatment of the disorder, and it would be a valuable example of contribution of evolutionary biology to medicine” (BMC Evolutionary Biology 2007; 7:61).
Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle (Journal of Biomedicine and Biotechnology Volume 2010, Article ID 476279, 19 pages). Increased intra-myocellar fat content and fatty acid metabolites, for example, Fatty Acyl CoA and DiAcylGlycerol, (see also Journal of Nutrition 2000; 130: 299S-304S) seem to play a pivotal role in the development of insulin resistance in skeletal muscle. A mitochondrial defect in oxidative phosphorylation has been reported in insulin resistant individuals; however, the contribution of this mitochondrial defect to the intra-myocellar fat accumulation is not yet clear (Journal of Biomedicine and Biotechnology Volume 2010, Article ID 476279, 19 pages). Insulin resistance induced by a high fat diet caused an inability of intramuscularly injected insulin to diffuse throughout the interstitial space and cause glucose uptake, similar to insulin resistance induced by systemic intra-lipid. The interstitial insulin concentration shows that most cells were not exposed to insulin. Thus, skeletal muscle insulin resistance after fat feeding can be explained by impaired access of insulin to the tissue, independent of muscle cell insulin resistance (Obesity Journal 2009; 17: S72 88 - no link). Insulin resistance (measured by euglycaemic hyperinsulinaemic clamp) parallels the amount of obesity (Diabetes 1996; 45:337-341). Resistance is seen in the liver, adipose tissue, and skeletal muscle, as noted in type 2 diabetes, with 30% reduction in glucose disposal, higher endogenous glucose production, and increased non-etherified fatty acids concentrations in plasma compared with controls with normal glucose tolerance, matched for age, sex, and ethnic origin (JAMA 2008; 299: 2770-76).

Other metabolic issues
The pathophysiology of ketosis-prone atypical diabetes is linked to a specific insulin-secretion defect that reduces the insulin action. Ketosis-prone atypical diabetes affects individuals in all age-groups, with clear male preponderance; half are overweight or obese at presentation (Diabetes Metab 2002; 28: 5-12). Up to 15% of new cases of diabetes in hospital populations in sub-Saharan African could have the phenotype of ketosis-prone atypical diabetes (Diabetes Metab 2002; 28: 5-12; Diabetes 2004; 53: 645-53).Viral infections could contribute to the acute initial presentation of ketosis-prone atypical diabetes. The association between ketosis-prone atypical diabetes and human herpesvirus 8 infection was strengthened by presence of viraemia at acute ketotic onset of disease (JAMA 2008; 299: 2770-76). Additional factors, such as reduced protection against oxidative stress, might have a role, especially through glucose-6-phosphate dehydrogenase deficiency (J Clin Endocrinol Metab 2005; 90: 4446-51).
Increased levels of urea - long considered to have negligible toxicity in patients with chronic renal failure-CRF can cause insulin resistance in vitro and in vivo as a consequence of increased Reactive oxygen species-ROS generation. Treatment with a superoxide dismutase - SOD/catalase mimetic normalizes insulin resistance and glucose intolerance in mice with CRF. Urea infusion in normal animals induces insulin resistance and elevates insulin resistance–associated adipokines, and treatment with a SOD/catalase mimetic prevents these urea-induced abnormalities. Because insulin resistance is an important independent cardiovascular risk factor, novel therapeutics that directly target urea-induced ROS and insulin resistance may potentially help reduce the high morbidity and mortality caused by End-stage renal disease – ESRD (J Clin Invest 2010; 120: 203-213).

Inflammation as a shared patho-mechanism of multifactorial diseases
Several studies have demonstrated that inflammatory response represents the "common soil" of the multifactorial diseases, encompassing both chronic inflammatory rheumatic disorders and a wide variety of conditions including type 2 diabetes, cardiovascular and neurodegenerative diseases, obesity, cancer, asthma, and ageing (Autoimmun Rev. 2010 Dec 30. [Epub ahead of print]  doi:10.1016/j.autrev.2010.12.006 - no link). Recent studies on the relation between mitochondrium and inflammation are posing new intriguing questions on the meaning of cellular fuel production in systemic inflammatory response syndrome, myocardial infarction, cerebral ischemia, and systemic and organ autoimmunity (NEJM 2010; 362: 2132-4 and Nature 2010; 464: 104-107). Mitochondrial molecules share several characteristics with microbial molecules. Mitochondrial structures released by injured cells possibly prompt inflammation during heart, kidney, or brain ischemia-reperfusion injuries, in which local neutrophil activation and further tissue damage occur when the blood flow is restored. Inflammation takes place even in patients with sterile tissue injuries such as trauma and ischemia – reperfusion. In short, the immune system recognizes mitochondria released from dying tissues as the bacteria they (the mitochondria) once were, and it mobilizes its destructive potential to limit their proliferation and arrest an unlikely invasion. Mitochondrial constituents selectively activate an inflammasome that regulates the processing and secretion of Il-1 and Il-18, suggesting a possible link with other sterile inflammatory conditions such auto-inflammatory disease (NEJM 2010; 362: 2132-4). As inflammasome is defined a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta (Mol Cell. 2002;10(2):417-26).


Questions on Metabolic Disorders in Alzheimer's Disease and Vascular Dementia
There is an increasing number of studies focused on the relationship between dementia and metabolic disorders such as diabetes, obesity, hypertension and dyslipidemia. The interactive effects of classic pathological agents such as β amyloidal deposition and vascular injury in brain are requiring studies to better understand the boundaries of development of Alzheimer's disease – AD and vascular dementia VD. A careful attention to the measurement and characterization of the insulin resistance syndrome is expected do better answer to questions on patho-genetic mechanisms induced by those disorders at midlife, and on diagnostic and clinical approach to the AD or VD patients (Arch Neurol 2009; 66 (33): 300-305). Diet-induced metabolic disturbances, independent of diabetes, are associated with decreased expression of genes involved in oxidative phosphorylation and decreased expression of genes involved in mitochondria biogenesis (Circ Res 2007; 100: 795-806). Other studies report on  reduced mitochondrial biogenesis occurring in response to a high fat diet as well as during diabetes with promote pronounced effects on the function of mitochondria, and their function, essential to brain homeostasis. Consequently questions are raising on deleterious changes induced by not correct diet in mitochondrial homeostasis within the brain during brain aging or age-related neurodegeneration (Clin Interv Aging 2007; 2: 347-359). The fact that in the pre-diabetic state the effects of a western diet are partially or even fully reversible increase the necessity to better understand the role of diet in the genesis of brain disease, and extensively in the daily food choice (Biochim Biophys Acta 2009; 1792 (5): 417-422).

Metabolism patterns in cancer cells
New study approaches are revamping what Otto Warburg  demonstrated already in 1926 on cancer cells metabolism: they do not metabolize glucose in the same way as the normal, adult differentiated cells do (Science 1956; 123:309). The rapidly dividing cancer cells take up large quantity of glucose, and the high concentration of glucose within the cells is observed by positron emission tomography (PET) scans of radioactive F-19-2-deoxyglucose . It is described (Science 2010; 330:1340-44), that the oncogenes myc, nuclear factor kB (NF-kB), Akt, and the tyrosine kinase receptors (epidermal growth factor, EGF; insulin-like growth factor 1, IGF-1; Her-2; etc.), which turn on Ras, RAF–mitogen-activated protein kinase (MAP kinase), and the phosphatidylinositol 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) pathways along with hypoxia-induced factor (HIF), can stimulate the transcription of a number of genes that encode the proteins that mediate the glycolysis and glutaminolysis pathways. The connections among chronic inflammatory responses of the immune system, with the activation of NF-kB and its associated metabolic changes (Warburg effect) and PET scan–positive cells, and the formation of cancers of those cells are well established (FASEB J 2010; 24: 3643-52). From epidemiological studies, obesity appears to be associated to the formation of some cancers, such as the one of the oesophagus, colon, pancreas, breast (post-menopausal), endometrium, and kidney. In the UK approximately 5% of all cancers are attributable to overweight and obesity (Proc Nutr Soc. 2010 Feb;69(1):86-90). Increase in BMI by 5 kg/m2 was strongly associated with esophageal adenocarcinoma (RR 1.52, p<0.0001) and with thyroid (1.33, p=0.02), colon (1.24, p<0.0001), and renal (1.24, p <0.0001) cancers. In women, it has been recorded a strong associations between a 5 kg/m2 increase in BMI and endometrial (1.59, p<0.0001), gallbladder (1.59, p=0.04), esophageal adenocarcinoma (1.51, p<0.0001), and renal (1.34, p<0.0001) cancers. Associations were stronger in men than in women for colon (p<0.0001), (Lancet 2008;37:569-78 - no link - see also Colorectal Dis. 2009;11547-63). Data support some suggestions that uncontrolled genetic or early shared environmental factors may affect risk estimates in studies of anthropometric measures and cancer risk, but do not explain observations of increased cancer risks related to BMI or height (Int J Cancer 2007; 121: 810-8).

Metabolic reactions to exposoma
The risks to develop chronic diseases are attributed to both genetic and environmental factors (NEJM 2000; 343: 78-85; Proc Natl Acad Sci USA 2009; 106: 9362-5; Science 2002; 296: 695-8). The attention of epidemiologists on genome is increasing and a more comprehensive and quantitative view of environmental exposure is needed to better discover the major causes of chronic diseases. To better understand the toxic or harming effects by environment it is suggested to take into consideration that those effects are mediated through chemicals that alter critical molecules, cells, and physiological processes inside the body. Thus, it would be expected to consider the “environment” as the body’s internal chemical environment and “exposures” as the amounts of biologically active chemicals in this internal environment (Science 2010; 330:460-461). Exposures are not just chemicals entering from air, water, or food, into the body, but also include chemicals derived by metabolic reactions to them such as by inflammation, oxidative stress, lipid peroxidation, infections, gut flora etc (Clin Chem 2006; 52: 601-23; Chem Res Toxicol 2008; 21: 117-28).( On gut flora and microbiota see also Science 2010; 330: 1768-73). The term exposome comprehends internal and external environment plus exposures. The exposome is continually modulated during life, because of internal and external changes or stimuli such as ageing, life style, nutrition, physical exercise, jobs, stress, psychosocial factors, indoor and outdoor pollution, and preexisting diseases (Science 2010; 330:460-461). (See also multiple risk factors in INTERHEART studies (Lancet 2004; 364: 953-62)). To investigate diseases,  Exposomewide association studies (EWAS) are desired alongside  the recently established approach of  Genomewide association studies (GWAS) (Science 2010; 330: 1768-73). A recent example of GWAS is given by the identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in presence of coronary atherosclerosis (Lancet 2011;377:383-92).
Among the exposures smoking is playing one of the main roles. Active smoking was responsible of 5.1 million deaths in 2004, and passive smoking was responsible in the same year of 603 000 deaths worldwide. Passive smoking has produced 379.000 deaths from ischemic heart disease, 162.000 deaths for lower respiratory infections, 36.900 deaths from asthma, and 21.400 deaths from lung cancers. Of the 10.9 million DALYs due to passive smoking, 61% of DALYs were in children. The largest disease burdens in non smokers were from lower respiratory infections in children younger than 5 years (5.939.000), ischemic heart disease in adults (2.836.000), and asthma in adults (1.246. 000) and children (651.000). Absolute number of deaths is higher in women than in men: the number of female non-smokers (thus susceptible to be exposed to secondhand smoke by definition) is about 60% higher than that of male non-smokers (Lancet 2011; 377: 139-46)

Summary
It should not be surprising to observe such a central role of metabolic processes and the integration of metabolic pathways with many diverse signal transduction pathways in NCD. A better understanding the shared, by the mentioned diseases, metabolic pathways might support a global approach to their prevention and treatment. This approach could also help strategic policies to tackle the diseases burden and to develop Action Plan for the Global Strategy for the Prevention and Control of non-communicable Diseases with the aim to work in partnership to prevent and control the 4 non-communicable diseases — cardiovascular diseases, diabetes, cancers and chronic respiratory diseases - and the 4 shared risk factors: tobacco use, physical inactivity, unhealthy diets and the harmful use of alcohol. 4 risk factors that are heavily impacting on the body metabolic mechanism.

January, 2011

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