The Cascade of Inflammatory Signaling

Inflammation is the physiological response to biological, mechanical, or chemical stressors. In people with diabetes, increased risk of cardiovascular disease, kidney disease, peripheral vascular disease, autoimmune disorders, obesity, and cancer as well as neurological disorders like Alzheimer's and Parkinson's disease are triggered at least in part from the inflammatory signaling that is chronically upregulated. The inflammatory state is closely related to obesity and insulin resistance, yet other vectors may lead to chronic inflammation, including chronic stress, gut-brain miscommunication, neu-roendocrine-immune shifts, dietary choices (including artificial sweeteners), exercise frequency, drug use (prescription, non-prescription, and recreational), and environmental stressors (such as heavy metals and chemical preservatives in foods). Population-based studies have reported strong relationship between inflammatory markers and metabolic disturbances, obesity, atherosclerosis, and inflammation has been considered a 'common thread' between these conditions and type 2 diabetes [2, 3].

Cells are regularly exposed to stress, which mainly consists of inflammatory stress and metabolic stress. Inflammatory stress is exerted by cytokines that are released in large quantities by immune cells in response to invading microorganisms or other pathophysiological signals. The main cytokines involved in the pathogenesis of type 2 diabetes are interleukin (IL)-ip, tumor necrosis factor-a (TNF-a), NF-kB, and IL-6, IL-18 and adipokines, which are considered as the main regulators of inflammation; leptin, more recently introduced, and several others, such as monocyte chemoattrac-tant protein-1, suppressors of cytokine signaling proteins, resistin, angiotensinogen, and aromatase also are present with deleterious effects in diabetic pathogenesis. The characterization of these molecules helps to identify targeted diabetes treatment beyond the conventional interventions (lifestyle changes and pharmaceutical agents), and move toward the controlling of specific molecular pathways to greatly reduce inflammation.

Chronic stress has negative effects on inflammatory signaling, serum glucose, serum cortisol levels, serum thyroid hormone levels, and body weight. Chronic stress, through hyperexcitation of the hypothalamic-pituitary-adrenal axis and microglial cell activation of the immune system, directly affects fat storage and weight gain in stressed individuals. Elevated serum cortisol is associated with diabetes and its complications as well as being a known initiator of insulin resistance. This could be the clue to why so many type 2 diabetics have evidence of autoimmunity. Elevations of cortisol and depletion of dehydroepiandosterone (DHEA) pools are associated with memory loss and atrophy of the hippocampus combined with the known defect in glucose utilization in Alzheimer's disease could offer an important insight into neurodegeneration found in individuals with type 2 diabetes.

Oxidative stress in the diabetic, due to depleted levels of nitric oxide, can increase the pathways that lead to inflammatory signaling by upregulation of peroxyl nitrite free radicals. These processes accelerate pathological changes in endothelial tissues. Another vector associated with inflammatory signaling is obstructive sleep apnea syndrome. Sleep apnea produces more inflammatory signaling, which leads to more accumulation of visceral fat - cycles of the downward metabolic spiral. Surgical removal of visceral fat can reverse sleep apnea in a substantial number of patients, demonstrating the role played by adipokines in this disorder. Even restricted sleep can induce insulin resistance and progression toward type 2 diabetes. Alterations in leptin, ghrelin, growth hormone, and body mass index have been found with sleep deprivation (approx. 4-5 h per night).

The quality of an individual's adaptive immune system can be evaluated through the balance of inflammatory cytokines it is producing. A healthy immune system is both balanced and dynamic - it should be balanced between Th1 and Th2 activity, switching back and forth between the two as needed. A failure of the Th1 arm of the immune system and an overactive Th2 arm is implicated in a wide variety of chronic illnesses, including autoimmune conditions, acquired immunodeficiency syndrome, chronic fatigue syndrome, candidiasis, allergies, multiple chemical sensitivities, blood sugar regulatory problems (including diabetes), and cancer. Likewise, overexpression of Th1- and cell-specific immunity can occur, leading to a subset of autoimmune disturbances.

Exposure to environmental chemicals, such as pesticides and heavy metals, may also disrupt the neuroendocrine-immune system, leading to upregulation of inflammatory signaling. Endocrine disruptors include dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and plasticizers such as phtha-lates and bisphenol A (BPA). Endocrine disruptors may be found in many everyday products - including plastic bottles, metal food cans, detergents, flame retardants, food, toys, cosmetics, and pesticides and have been linked to insulin resistance. Exposure to BPA has been found to cause biological effects, and its mode of action appears to mimic that of the female hormone, estrogen. Studies have found that BPA does increase the risk of developing cancer [4]. Phthalates are another compound commonly found in cosmetics and personal care items such as shampoos. Phthalates are reported to also affect neuroendocrine-immune balance. A recent study reported that approximately 75% of the US population has measurable levels of phthalates in their bodies [5]. Chronic heavy metal exposure, including lead, mercury, aluminum, and cadmium, may lead to the upregulation of inflammatory signaling pathways. Mercury, commonly found in dental amalgam fillings, can cause microglial activation and lead to localized flora disturbances and immune activation in the gut. Mercury, commonly found in dental amalgam fillings, may leak into the gut, causing imbalances in the natural gut flora. This may lead to and increase in inflammatory signaling and neuroendocrine-immune imbalances. Similarly, chronic lead exposure can damage the neuroendocrine-immune system, leading to inflammatory signaling.

A disturbed gastrointestinal terrain can serve as an unseen 'motor' of inflammation, leading to a cycle of inflammatory signaling. There is a complex balance that exists between the indigenous flora and the adjacent immune system of the gut mucosa and liver. Evidence supports that impairment of normal gut barrier function, through environmental stressors (such as heavy metals and chemical preservatives), poor dietary habits (such as high in refined sugars and fructose), food allergies, various drug therapies, and chronic stress, results in the loss of the counterinflammatory flora balance and leads to the expression of uncontrolled inflammation [6]. Food and bacterial proteins, such as dairy lectins, can act together to damage the gut and allow toxic protein complexes to get through the tight junction glycoprotein and toll receptor network that is normally supposed to be resistant to such a breach - termed 'leaky gut. When there is an imbalance in the natural flora of the gut, bacterial lipopolysaccharide released by increasing populations of pathogenic bacteria, such as Escherichia coli and Candida sp., causing oxidation that leads to gut ischemia. Downregulation of immunologic activation is an active, energy-requiring process, therefore gut ischemia may impair this normal anti-inflammatory function, and promote a state of systemic inflammation.

Symptoms such as gas and bloating, abdominal pain and diarrhea, can occur with imbalances in gut flora. As these imbalances continue they can progress to more profound symptoms such as headaches, nerve pain, skin rashes, and joint pain. The disorders that result or could be aggravated by an unhealthy gut include are celiac disease, Crohn's disease and irritable bowel syndrome, multiple sclerosis, migraines, attention deficit, autism, depression, eczema, acne, rheumatoid arthritis, fibromyalgia, diabetes, chronic fatigue, and others. Many people are being diagnosed with multiple conditions, including type 2 diabetes, without the obvious connection of the overload in inflammatory signaling of the gut with certain foods that may be a driving force in the disease process in many of these illnesses.

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