Cell Damage Caused by Diabetes

In addition, the breakdown of homocysteine is inhibited, causing an increase of cell inflammation leading to a buildup of plaque in the artery walls, which become rigid, thicker and more narrow -- a precursor to developing heart disease.

The red blood cells are glycated by the glucose attaching to the hemoglobin, as indicated by your hemoglobin A1C, producing advanced glycation endproducts, or AGEs.

Many cells in the body (for example, endothelial cells, smooth muscle, and cells of the immune system) from tissue such as lung, liver, kidney, and peripheral blood bear the Receptor for Advanced Glycation End-products (RAGE) that, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy, and neuropathy.
     
                                    
The process of formation and accumulation of AGEs play a major role among various biochemical pathways implicated in diabetic vascular complications, promoting the development and progression of cardiovascular disease. These compounds interact with receptors, such as RAGEs (receptors for advanced glycation end products), to induce oxidative stress, increase inflammation by promoting nuclear factor-êB (NFêB) activation, and enhance extracellular matrix accumulation.

The creation of "sharp, edgy" cells cause damage to the artery walls and small blood vessels, creating arterial plaque and increased cardiac fibrosis, with consequent effects on cardiac function. This causes damage throughout the body -- especially the small blood vessels that feed the eyes, kidneys, and feet. This leads to further damage that can eventually cause blindness, amputation, kidney failure, heart attack or stroke.

Disease and Cell/Tissue Damage
Disease processes may be incited or exacerbated by a variety of external and internal influences, including poor diet, drugs, trauma, infection, poisoning, loss of blood flow, autoimmunity, inherited or acquired genetic damage, or errors of development.

One common theme in pathology is the way in which the body's responses to cellular/tissue damage (i.e. injury), while evolved to protect health, can also contribute in some ways to disease processes.

Cells and tissues may respond to damage (or injury) and stress by specific mechanisms, which may vary according to the cell types and nature of the injury. In the short term, cells may activate specific genetic programs to protect their vital proteins and organelles from heat shock or hypoxia, and may activate DNA repair pathways to repair damage to chromosomes from radiation or chemicals.

Hyperplasia is a long-term adaptive response of cell division and multiplication, which can increase the ability of a tissue to compensate for an injury. For example, repeated irritation to the skin can cause a protective thickening due to hyperplasia of the epidermis.

Hypertrophy is an increase in the size of cells in a tissue in response to stress, an example being hypertrophy of muscle cells in the heart in response to increased resistance to blood flow as a result of narrowing of the heart's outflow valve. Metaplasia occurs when repeated damage to the cellular lining of an organ triggers its replacement by a different cell type.

Cell Death
Necrosis is the irreversible destruction of cells as a result of severe injury in a setting where the cell is unable to activate the needed metabolic pathways for survival or orderly degeneration. This is often due to external pathologic factors, such as toxins or loss of oxygen supply.
         

Milder stresses may lead to a process called reversible cell injury, which mimics the cell swelling and vacuolization seen early in the necrotic process, but in which the cell is able to adapt and survive.

In necrosis, the components of degenerating cells leak out, potentially contributing to inflammation and further damage. Apoptosis, in contrast, is a regulated, orderly degeneration of the cell which occurs in the settings of both injury and normal physiological processes.

Inflammation
Inflammation is a particularly important and complex reaction to tissue and cell damage (or injury), and is particularly important in fighting infection.

Acute inflammation is generally a non-specific response triggered by the injured tissue cells themselves, as well as specialized cells of the innate immune system and previously developed adaptive immune mechanisms. A localized acute inflammatory response triggers vascular changes in the injured area, recruits pathogen-fighting neutrophils, and begins the process of developing a new adaptive immune response.

Chronic inflammation occurs when the acute response fails to entirely clear the inciting factor. While chronic inflammation can lay a positive role in containing a continuing infectious hazard, it can also lead to progressive tissue damage, as well as predisposing (in some cases) to the development of cancer.

Tissue Repair
Tissue repair in the body is triggered by inflammation. The process may proceed through the formation of granulation tissue.

Healing involves the proliferation of connective tissue cells and blood vessel-forming cells as a result of hormonal growth signals. While healing is a critical adaptive response, an aberrant healing response can lead to progressive fibrosis, contractures, or other changes which can compromise function.

Note: Cell and tissue repair are slowed down or inhibited by diseases such as diabetes, i.e. high blood glucose levels. Consequently, maintaining consistent blood glucose levels in the normal range is key to helping a diabetic's body repair and heal over a period of time.

Neoplasia
Neoplasia, or "new growth," is a proliferation of cells which is independent of any physiological process. The most familiar examples of neoplasia are benign tumors and cancers. Neoplasia results from genetic changes which cause cells to activate genetic programs inappropriately.

Dysplasia is an early sign of a neoplastic process in a tissue, and is marked by persistence of immature, poorly differentiated cell forms. Interestingly, there are many similarities in the gene pathways activated in cancer cells, and those activated in cells involved in wound healing and inflammation.

Diabetes and Inflammation

Signs of systemic inflammation are elevated in both type 1 and type 2 diabetes. Systemic levels of TNF-α and IL-6 are elevated in diabetes and can directly promote insulin resistance (Senn et al., 2002; Borst, 2004).

                                      

Thus, elevated cytokine levels may not only serve as markers of diabetes, but also may play a causal role in the etiology of type 2 diabetes. The tendency of diabetics to have higher levels of inflammation has serious consequences (Nesto and Rutter, 2002). For example, 80% of individuals with type 2 diabetes die from coronary artery disease (Chiquette and Chilton, 2002).

 

There is circumstantial evidence in humans that microbial infections are an important risk factor for cardiovascular diseases, which has been linked to anaerobic bacteria, such as Chlamydia pneumoniae, a bacterium that causes respiratory infections (de Luis et al., 1998), Helicobacter pylori (Kusters and Kuipers, 1999), and periodontal pathogens (Beck et al., 1996; Amar and Han, 2003).

 

It is possible that diabetes renders individuals more susceptible to the systemic consequences of local infection. To address this issue, we examined the inflammatory response of the heart/aorta of diabetic db/db mice that develop type 2 diabetes (Lu et al., 2004). Subcutaneous inoculation of lipopolysaccharide stimulated an up-regulation of adhesion molecules, cytokines, and chemokines via an endotoxemia that was significantly more rapid and more pronounced in the cardiovascular tissue of the diabetic compared with normal mice.

Thus, diabetes may enhance the inflammatory response to bacteria at both the site of infection and also systemically through a greater response to endotoxemia or bacteremia.

 

Inflammatory Response to Bacteria
Given that diabetes affects oral health, and many oral health problems involve bacteria-induced inflammation, there has been considerable interest in determining whether diabetes alters the inflammatory response to oral pathogens. For example, human gingival crevicular fluid from type 1 diabetics with periodontal disease has higher levels of both PGE2 and IL-1β as compared with those in fluid from matched non-diabetics (Salvi et al., 1997b).

Furthermore, monocytes isolated from periodontal patients with type 1 diabetes produce significantly greater amounts of TNF-α, IL-1β, and PGE2 in response to lipopolysaccharide (LPS) compared with non-diabetics (Salvi et al., 1997a,b).

 

The impact of diabetes on the inflammatory response to P. gingivalis in a connective tissue setting (Naguib et al., 2004). Cytokine expression and formation of an inflammatory infiltrate were stimulated by P. gingivalis inoculation in the calvarial model. 
 

Moreover, this difference was not due to a deficit in bacterial killing in the diabetic group, since inoculation of fixed bacteria induced a similar persistent inflammation. That TNF played a central role in this process was established by reversal of prolonged chemokine expression, by the specific inhibition of TNF with etanercept (Naguib et al., 2004). Thus, cytokine dysregulation associated with prolonged TNF expression may represent an important mechanism through which diabetes alters the host response to bacterial challenge.

 

Diabetes leads to greater net periodontal bone loss and contributes to increased risk of tooth loss (Löe, 1993; Nishimura et al., 1998). It has been suggested that this occurs because diabetes increases periodontal tissue destruction (Ryan et al., 1999).

 

However, diabetes could also lead to a net loss of alveolar bone by impairing the cycle of bone formation that occurs after bone resorption. 
 

Thus, diabetes contributes to the net loss of bone, in part, because it suppresses the coupling of new bone formation that follows resorption.  Diabetes greatly prolonged P. gingivalis-induced apoptosis of these cells, which would diminish the capacity to form new bone.

  

Impact of AGES on Periodontitis and Wound Healing
Advanced glycation end-products (AGEs) form under normal conditions and accumulate in aged individuals. With chronic hyperglycemia, AGE accumulation is greatly accelerated. AGEs form spontaneously from abnormally elevated levels of sugars and oxidized lipids in the blood.

                      

 

AGEs contribute significantly to many complications of diabetes, including kidney fibrosis, atherosclerosis, enhanced periodontal disease, and diminished bone formation (Lalla et al., 2000; Vlassara and Palace, 2002; Santana et al., 2003). 
 

For other AGE-associated pathologies, there may be other receptors that are more important (Vlassara and Palace, 2002). There are several mechanisms through which AGEs may affect cell behavior, such as enhancing inflammation, stimulating apoptosis, or affecting production of extracellular matrix (Owen et al., 1998; Vlassara and Palace, 2002).

 

Enhanced inflammation through advanced glycation end-products (AGEs) has been implicated in P. gingivalis-induced bone loss in a murine periodontal model (Lalla et al., 2000).
 

These findings link AGEs with an exaggerated inflammatory response to P. gingivalis in diabetes-enhanced periodontal disease. 
 

Bone repair in diabetes is characterized by decreased expression of genes that induce osteoblast differentiation, decreased growth factor production, and diminished extracellular matrix production (Bouillon, 1991; Kawaguchi et al., 1994; Lu et al., 2003). Osseous healing in diabetics may be limited by the effect of AGEs (Santana et al., 2003).

  

Another mechanism by which AGEs may delay wound-healing is through the induced apoptosis of extracellular-matrix-producing cells. Enhanced apoptosis would reduce the number of osteoblasts that could participate in the repair of resorbed bone.

 

Diabetes and Apoptosis
Apoptosis is programmed cell death that can be triggered by various signals and is characterized by well-defined morphologic changes (Nagata, 1997; Li et al., 1998). Apoptosis is important as a critical mechanism for removing unwanted cells during development, as a means of preventing autoimmunity, and as part of a response to protect the host from cells that have been infected or have become tumorigenic.

 

Apoptosis occurs rapidly, within an hour of effector caspase activation. Although the percentage of cells that are apoptotic at any given point in time may seem low, the cumulative effect over a 24-hour period can be quite high. Since adequate healing requires a sufficient number of cells to repair wounds, enhanced apoptosis of matrix-producing cells could reduce tissue formation (Darby et al., 1997; Slomiany and Slomiany, 2002; Carlson et al., 2003).

 

When diabetic mice are treated with curcumin, there is reduced apoptosis of fibroblasts and accelerated wound-healing, suggesting that reduced expression of pro-apoptotic factors enhances the repair process (Sidhu et al., 1999). The opposite is also true: Conditions that promote apoptosis impair healing (Darby et al., 1997; Gastman et al., 2003). Thus, enhanced apoptosis associated with diabetes may contribute to altered healing.

 

A body of evidence is emerging that apoptosis plays an important role in several diabetic complications. These include apoptosis of neuronal cells in diabetic neuropathy (Li et al., 2002), diabetes-enhanced myocardial apoptosis, which plays a role in cardiac pathogenesis (Cai et al., 2002), and apoptosis of mesangial cells that occurs in diabetic nephropathy (Makino et al., 2000; Yamagishi et al., 2002a).

 

There are several aspects to diabetes that could enhance apoptosis. Diabetes is associated with activation of the polyol pathway, leading to the formation of AGEs and phospholipase C activation, higher levels of TNF-α expression, enhanced protein kinase C activation, and greater oxidative stress (Vlassara, 1997; Koya and King, 1998; Asnaghi et al., 2003; Du et al, 2003).

The formation of reactive oxygen species (ROS), TNF, and AGEs could potentially affect oral healing or the response to bacteria-induced periodontitis by direct effects on osteoblastic or fibroblastic cells, such as reduced expression of collagen, or indirectly through promoting inflammation and apoptosis of these matrix-producing cells. Thus, by enhancing the production of ROS, TNF, and AGEs, diabetes may impair the healing response or progression of periodontal disease.

 

Diabetes enhances apoptosis of fibroblasts and osteoblasts following Porphyromonas gingivalis infection (He et al., 2004; Liu et al., 2004). In the calvarial model, P. gingivalis induces inflammation and injury, which is repaired by fibroblasts. Following P. gingivalis-induced injury, diabetic mice have significantly elevated fibroblast apoptosis and reduced fibroblast density (Liu et al., 2004).

   

Advanced glycation end-products may also promote apoptosis of critical matrix-producing cells (Alikhani et al., 2005a). Enhanced apoptosis of these cells is associated with diabetic complications such as retinopathy, neuropathy, nephropathy, and accelerated vasculopathy (Huang et al., 2001; Yamagishi et al., 2002b; Kaji et al., 2003).

 

There are several mechanisms by which AGEs can enhance apoptosis: the direct activation of caspase activity, as well as indirect pathways that increase oxidative stress, or the expression of pro-apoptotic genes that regulate apoptosis (Kasper et al., 2000; Yamagishi et al., 2002b; Kaji et al., 2003; Alikhani et al., 2005b).

 

The periodontium is well-equipped for repair following infection. In periodontitis, there is a net loss of connective tissue attachment to the tooth that does not repair sufficiently to prevent epithelial down-growth. There is also a net loss of bone, which is pathologic, since bone is a tissue that is particularly well-suited for regeneration.

 

Thus, the central issue may center not around the breakdown of tissue, but rather on the failure of adequate repair. One mechanism that might explain inadequate repair is loss of matrix-producing cells. This is supported by a high rate of fibroblast apoptosis in patients with periodontitis, particularly in areas where inflammatory cells have been recruited (Koulouri et al., 1999). We propose that infection induces an inflammatory response that is exaggerated in diabetic individuals and leads to apoptosis of fibroblastic and osteoblastic cells.

 

This, in turn, contributes to the greater net loss of hard and soft connective tissue that occurs in diabetic individuals. Consistent with this principle are findings that reduced apoptosis during wound-repair is associated with qualitative and quantitative improvements in healing (Ono et al., 2004; Al-Mashat et al., 2006).

 

In contrast, conditions that enhance apoptosis are associated with impaired healing (Qu et al., 2003). It is also striking that inhibition of osteoblast apoptosis may be one of the mechanisms through which intermittent exogenous PTH treatment increases bone mass (Jilka et al., 1999; Stanislaus et al., 2000).

 

Thus, apoptosis of matrix-producing cells may be a critical factor in the repair of soft and hard connective tissue and may represent an important mechanism through which diabetes has a negative effect on the periodontium.
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Cell Division

Cell division is the process by which a parent cell divides into two or more daughter cells. Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort of cell division in prokaryotes is known as binary fission. In another type of cell division present only in eukaryotes, called meiosis, a cell is permanently transformed into a gamete and cannot divide again until fertilization. Right before the parent cell splits, it undergoes DNA replication.

                                

Cell division enables a sexually reproducing organisms to develop from the one-celled zygote, which itself was produced by cell division from gametes. And after growth, cell division allows for continual construction and repair of the organism. A human being's body experiences about 10,000 trillion cell divisions in a lifetime.

The primary concern of cell division is the maintenance of the original cell's genome. Before division can occur, the genomic information which is stored in chromosomes must be replicated, and the duplicated genome separated cleanly between cells. A great deal of cellular infrastructure is involved in keeping genomic information consistent between "generations".

Multicellular organisms replace worn-out cells through cell division. In some animals, however, cell division eventually halts. In humans this occurs on average, after 52 divisions, known as the Hayflick limit. The cell is then referred to as senescent. Cells stop dividing because the telomeres, protective bits of DNA on the end of a chromosome required for replication, shorten with each copy, eventually being consumed, as described in the article on telomere shortening.

Note: Cancer cells, on the other hand, are not thought to degrade in this way, if at all. An enzyme called telomerase, present in large quantities in cancerous cells, rebuilds the telomeres, allowing division to continue indefinitely.

Healing & Repair

• By repair: injured tissue is replaced with scar tissue.

In order for an injury  to be healed by regeneration, the cell type that was destroyed must be able to replicate. Most cells have this ability, although it is believed that cardiac muscle cells and neurons are two important exceptions.
          

Cells also need a collagen framework along which to grow. Alongside most cells there is either a basement membrane or a collagenous network made by fibroblasts that will guide the cells' growth. Since ischaemia and most toxins do not destroy collagen, it will continue to exist even when the cells around it are dead.

As granulation tissue matures, the fibroblasts produce less collagen and become more spindly in appearance. They begin to produce the much stronger type I collagen. Some of the fibroblasts mature into myofibroblasts which contain the same type of actin found in smooth muscle, which enables them to contract and reduce the size of the wound.

During the maturation phase of wound healing, unnecessary vessels formed in granulation tissue are removed by apoptosis, and type III collagen is largely replaced by type I. Collagen which was originally disorganized is cross-linked and aligned along tension lines. This phase can last a year or longer. Ultimately a scar made of collagen, containing a small number of fibroblasts is left.

The process of healing a common incision involves an orchestrated sequence of events in standardized time, beginning with a clot at 0 hours, neutrophil invasion at 3 to 24 hours, and mitoses in epithelial bases at 24 to 48 hours. After this point, healing follows the previously mentioned procedure.

               

1. An irreversible state of dormancy, known as senescence
2. Cell suicide, also known as apoptosis or programmed cell death
3. Unregulated cell division, which can lead to the formation of a tumor that is cancerous

Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome  (but cells remain superficially functional when so-called "non-essential" genes are missing or damaged).

Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translation synthesis as a last resort.

Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.

How to Help Repair and Heal the Body                      

• Key micronutrients include Vitamin C, CoQ10, alpha lipoic acid, ribose, chlorophyll, Omega-3 EFAs, zinc, lysine, other amino acids, antioxidants, etc. But, the majority of  these micronutrients should be obtained via plant-based foods, not man-made supplements. For more details, refer to a program such as the Death to Diabetes Super Meal Program.
• For people with a disease such as diabetes, it takes time for the repair and healing processes to undo all the damage caused by abusing the body for so many years. Consequently, people struggling with a major disease need to be patient and vigilant if they want to overcome the ill effects of disease such as diabetes.
• For people who want to accelerate the body's repair process, read The Power of Raw Juicing web page.
• There are various factors  that determine how fast and how much repair of the body will occur, i.e. age, severity of disease, length of time with disease, type of nutritional program, use of multiple therapies, financial resources, motivation, spiritual health, lifestyle, emotional support, etc. Refer to the Death to Diabetes book and this web page for more details.

Key Macronutrients and Micronutrients
Specific super foods will promote an overall effect upon your health and help repair the damage caused by a disease such as diabetes.
 
                      
 
We need adequate Carbohydrates from green and bright-colored vegetables and dark-colored fruits to generate the energy for your cells to do their job. 

• Calcium: To keep your skeleton strong you need to make sure to get enough of this bone-nourishing mineral on a daily basis.  Leading Food Sources of calcium: Broccoli, Bok choy, Amaranth, Milk, Kale, Beans, dried, Cheese, fresh, Tofu, Soybeans, Salmon, Yogurt
• Complex carbohydrates: provide fuel and, as they take longer to digest than simple carbohydrates, are useful for sustained energy, and they are also a good source of fiber which assists in weight loss.  Leading Food Sources of complex carbohydrates: Broccoli, Blackberries, Brown Rice, Winter Squash
• Magnesium: assists in the use of vitamin D, which the body needs for calcium, and it also helps the muscles to relax. Leading Food Sources of magnesium: Spinach, Almonds, Quinoa, Avocados, Chocolate, Pumpkin seeds, Oysters, Sunflower seeds, Brazil nuts, Buckwheat, Amaranth, Barley
• Omega-3 fatty acids: help to reduce inflammation, and preliminary studies indicate that they may also assist in the repair of damaged ligaments. Leading Food Sources of omega-3 fatty acids: Salmon, Trout, Tuna
• Vitamin C: is helpful in keeping collagen, ligaments and tendons strong, and it helps to repair tissue and promote proper healing. Leading Food Sources of vitamin C: Cabbage, red, Potatoes, Strawberries, Oranges, Kiwi fruit, Tangerines & other mandarins, Peppers
• Vitamin D: regulates blood levels of calcium and phosphorus. Without vitamin D we wouldn’t be able to properly use calcium. Leading Food Sources of vitamin D: Milk, Tuna, Salmon  
• Zinc: promotes wound and tissue repair and is essential for bone health. It may also enhance mineral absorption. Leading Food Sources of zinc: Barley, Crab, Oysters, Wheat, Beef, Lamb, Chicken, Turkey