Diabetes is a term that gets thrown around a lot these days. Whether you’re indulging in a sugary feast and a friend wryly comments on your risk of acquiring it, or you come across it in a headline, diabetes is one of the more prominent diseases of modern society. Over 20 million Americans suffer from diabetes and over 40 million have pre-diabetes . Most people know the rudimentary basis of the disease–a metabolic disorder of high blood sugar (hyperglycemia)–yet the actual pathogenesis and widespread symptoms are less well known and can be frustratingly obscure to research.
Background: Glucose & Insulin
Glucose is a sugar and carbohydrate that is absorbed directly into the bloodstream during digestion. It is one of the more important carbohydrates as it is the primary source of energy and metabolic intermediate for our cells. In cellular respiration (the process by which our cells gain biochemical energy from the food molecules we ingest), glucose is broken down to provide the energy used to create ATP. The ATP molecule is the molecular unit of currency which powers almost all of our cell processes; it is a bit like a mini battery. The average human body contains 250 grams worth of ATP which, considering its miniscule size is truly impressive. What is even more astonishing is that it is so essential to our functions that we recycle our entire body weight’s worth of ATP each day . Glucose is not the only molecule used to acquire energy and make ATP, but it is the primary one–especially in the brain.
Glucose and other carbohydrate levels in the blood are regulated by insulin, a protein hormone produced by specific cells called β-cells in the pancreas. Insulin secretion is triggered by high glucose levels in the blood. Once released, the hormone causes cells in the liver, muscle, and fat to absorb glucose from the blood and store it. This is crucial as hyperglycemia can have toxic effects. Insulin is also involved in a plethora of other functions including increasing amino acid uptake and consequently DNA replication and protein synthesis, decreasing protein degradation, decreasing production of glucose in the liver, decreasing degradation of damaged cell organelles, increasing potassium uptake in cells, increasing blood flow in arteries, and it also plays a role in memory formation [1,4,8].
In summary, not only does diabetes involve the primary source of metabolic energy for our cells, but it also involves glucose’s regulatory hormone insulin, which just so happens to have a finger in almost every pie, biologically speaking. Consequently, diabetes comes with a wide range of symptoms: damage and failure of organs, excess urination, weight loss, blurry vision, blindness, neurological effects, growth impairment, ketoacidosis, nerve damage, foot ulcers, gastrointestinal problems, sexual dysfunction, and cardiovascular symptoms .
To understand where all these symptoms are coming from, we need to take a closer look at the pathology of diabetes. The mechanisms and symptoms of the disease vary between types of diabetes (simply called Type 1 and Type 2). Both, however, are characterized by hyperglycemia because the body cannot move glucose into cells for energy storage, resulting in the high blood concentration. In Type 1 this is due to the pancreas not producing insulin because of autoimmune destruction of β-cells, while Type 2 is generally categorized by a resistance to insulin (cells do not respond to the hormone). The lines are not always clear, however; many cases of diabetes have a combination of β-cell loss and insulin resistance and fall between the lines of these two categories.
Type 1 has also been called Immune-Mediated, Juvenile-Onset (now obsolete), and Insulin-Dependent diabetes. In this scenario, the body makes very little to no insulin and patients require insulin injections to live. While the onset typically occurs in youth, it can occur at any age. Approximately 5-10% of diabetic cases are Type 1, and while the incidence varies enormously between populations across the world it is increasing in all of them. The cause of this type is unknown, and there is no known cure. It is generally accepted that a combination of genetic predispositions and environmental factors influence the susceptibility [1,3].
As previously mentioned, the deficiency of insulin in Type 1 is due to β-cell destruction. This occurs due to an autoimmune error: antibodies have been identified that mark β-cells for destruction after mistaking them as foreign cells. This is possibly due to a similarity between proteins used in β-cells and in invasive cells, although this theory has not been confirmed . The rate of cellular destruction varies between patients, and many are also prone to other autoimmune disorders suggesting there could be a broad, underlying problem.
Type 1 diabetes is treated by monitoring glucose levels and providing insulin when needed, although acute morbidity and mortality as well as chronic complications still result. Scientists have also created various altered forms of insulin that can be absorbed more rapidly and are faster acting. The closest treatment to a cure is a pancreas transplantation or islet (pancreatic cell) transplantation; unfortunately, donors and donor matches are rare and the transplantations require continued immunosuppression, which limits their use.
The second type of diabetes is characterized by insulin resistance and relative insulin deficiency. It is the most prevalent type (incidentally, the highest prevalence of Type 2 is found in Saudi Arabia while the highest of Type 1 is Finland [3,10]) and is also rapidly increasing in prevalence due to increasing urbanization, aging populations, obesity, and falling levels of physical activity. While the mechanism of the cause is not completely understood (are you sensing a trend here?), in approximately 70-90% of the cases obesity is held responsible. Most people who are obese and relatively insulin resistant do not become diabetic, but instead compensate by increasing insulin secretion from the pancreas. However, when this compensatory mechanism fails, diabetes develops. Unfortunately, weight and diabetes is a vicious cycle: obesity increases the risk of diabetes and complications (coronary heart disease is responsible for 80% of deaths of people with diabetes), but most pharmacologic approaches to treat diabetes contribute to weight gain [1,2,6].
When the cells normally targeted by insulin (to jog your memory: muscle, liver, and fat cells) do not respond to standard concentrations of insulin, the body compensates by having the pancreatic β-cells secrete higher amounts of insulin. However, over time the high secretory demands cause cellular damage. This prevents the β-cells from maintaining the higher rate of insulin secretion, leading to a relative insulin deficiency and, consequently, diabetes . This is compounded by β-cells having a reduced volume in patients with Type 2 diabetes, possibly due to the aforementioned damage leading to cellular death in larger, more mature cells and leaving a younger, smaller population behind to deal with the problem .
Insulin resistance is where obesity comes into play: high amounts of free fatty acids, which are a symptom of obesity, could block insulin signaling . This, combined with the fact that mitochondria (the site of cellular respiration in our cells) in the skeletal muscles and neurons of diabetics are smaller with reduced activity compared to healthy individuals, could lead to increased cell death and insulin resistance . On the other hand, it could also be any number of structural or functional interferences in the signal pathway between the cell receptor for insulin and the genes that insulin triggers the transcription of. In any case, not all tissue cells become insulin resistant. As a result, higher levels of insulin can trigger exaggerated responses in sensitive tissues. For example, some nervous system cells can be hyperstimulated and cause hypertension, and increased ovarian androgen production can lead to polycystic ovary syndrome .
Type 2 diabetes can sometimes be reversible in the early stages by lifestyle changes or weight-loss surgery. Increased physical activity and weight loss slows the development of the disease and can reduce the risk in pre-diabetics by 58%. Thus, a healthy workout regime and diets involving specific types of carbs, high fiber, and low fat (rich in vegetables, fruits, and whole grain) are sometimes recommended for diabetics . Patients of Type 2 diabetes do not always need insulin treatment, and there are various drugs being explored and used to reduce insulin resistance, such as thiazolidinedione . Unfortunately, as mentioned, many treatments that help control glucose levels in the blood tend to increase weight which increases the risk and progression of the disease, forming a tradeoff between the protection against cell damage and increasing the risk of heart disease and chronic problems .
Symptom Pathology: Ketoacidosis
Ketoacidosis is a symptom found in all types of diabetes, although it occurs more frequently in Type 1 diabetes than Type 2. Due to the lack of glucose entering cells to be used for energy, more fatty acids are metabolized for energy to compensate. When fatty acids are broken down, keto acids are produced. These keto acids enter the bloodstream, where their levels are normally regulated by insulin (oh dear). As you might predict, this rapidly becomes a problem: accumulation of keto acids in the blood lowers the pH and makes the blood more acidic. This can cause gasping, breathing irregularities, and hyperventilation as the body tries to decrease the carbon dioxide levels in the blood to compensate for the acidity. Dehydration and a water shortage in the body can also result from the increased blood acidity, along with confusion and comatose states due to the blood acidity causing inflammation and decreased blood flow in the brain .
Symptom Pathology: Oxidative Stress
Oxidative stress is another severe problem in diabetes that can lead to cell death. It is caused by damage done by reactive oxygen species such as free radicals. These are atoms, molecules, or ions with an unpaired electron in the outermost orbit, which means that they are incredibly reactive. Free radicals will react with and damage proteins, lipids, and nucleic acids (DNA) leading to cell death. They are naturally produced during cellular processes, but are carefully detoxified using antioxidants. In diabetes, the production of free radicals is increased and the antioxidant defenses are reduced. As glucose oxidation is believed to be the main source of free radicals, increased glucose levels in the blood result in more glucose oxidation and, consequently, more free radicals. Glucose itself can also interact with proteins and enzymes, increasing free radical production. At the same time, there is some research to suggest that antioxidant levels (specific vitamins, minerals, and proteins which normally detoxify free radicals) are lower or less active in diabetics . This possibly contributes to cellular damage and death in nerve cells, which leads to diabetic neuropathies.
Symptom Pathology: Neuropathies
Diabetic peripheral neuropathy is a frequent complication of diabetes–in fact, diabetes is the leading cause of neuropathy (nerve damage) in the western world. This affects the sensory, autonomic, and motor systems of the peripheral nervous systems, which basically means every type of nerve fiber in the body is vulnerable and, consequently, every organ system that relies upon such nerve activation for function is also at risk. The pathology of diabetic neuropathy stems from cellular death and impairment of repair mechanisms. Blood vessels require neural regulation to control blood flow, and neurons depend on small blood vessels called capillaries for nutrients. As neither of these tissues require insulin to trigger the uptake of glucose, the high blood glucose levels have toxic effects on the nerve cells as they absorb excess glucose. This extra glucose contributes to oxidative stress, which was previously discussed (the exact mechanism and contribution to neuropathy is not well understood) and can alter protein structure and function. The altered proteins in the nerve cell impact various pathways of cellular action and cause nerve damage, death, and dysfunction. While the body can normally regenerate nerves to some extent, such repairs are inhibited in diabetics, possibly because the impact on blood glucose levels and blood vessels reducing the support needed for nerve growth [9,13].
There are several different types of neuropathy that occur in diabetes. In cardiac autonomic neuropathy, nerve damage occurs in nerves that stimulate the heart and coronary vessels, which can lead to an irregular heartbeat, myocardial infarction, and death. Gastrointestinal autonomic neuropathy occurs when nerves innervating the gastrointestinal tract (anywhere from the esophagus to your colon) are damaged. This can result in a loss of appetite, anorexia, cramping, bloating, nausea, vomiting, and heartburn. Genitourinary autonomic neuropathy causes sexual dysfunction and bladder problems. In over 50% of diabetic men over the age of 50 (and 75% over the age of 60), this presents as erectile dysfunction due to nerve damaged and death in the nerves that stimulate the muscle contraction required for penile erection. In females, this presents as a diminished libido, vaginal dryness, and pain during intercourse. Both genders may experience bladder enlargement, urinary retention, and overflow incontinence (the delicate way of describing urine leakage) .
Finally, there is also sensorymotor neuropathy. In this presentation, sensory (afferent) nerves become damaged or die resulting in a range of effects including pain, paresthesia (pins and needles), and sensory loss. This is also the symptom that leads to the infamous periphery amputations that are sometimes required for diabetics. Sensorymotor neuropathy progresses inward from the fingers and toes in a symmetric pattern, leading to both positive and negative symptoms. Positive symptoms are a gain of sensation: pain, abnormal sensations, pins and needles, aching, cold, numbness all result from nerve damage. Pain is the least common symptom, occurring in 11-32% of neuropathy patients. On the other hand, the negative symptoms include the inability to feel and identify small objects, loss of temperature sensation, and an inability to perceive painful stimuli. This last symptom presents a major problem when combined with the other effects of nerve damage in the feet, which can cause the foot muscles to atrophy. The atrophied muscles cause deformities that can lead to callus and ulcer development, and without the ability to sense pain these ulcers and other wounds can develop infections that may rage undetected and require amputations .
Other Forms of Diabetes
Diabetes can also be caused by genetic defects in the DNA encoding essential functions of β-cells, such as impaired insulin secretion. Mutations that influence insulin receptors themselves are another genetic form of diabetes, and both of these forms are hereditary in a dominant fashion (one mutated gene from one parent can cause the illness). Diabetes can also be acquired by an injury to the pancreas, either from trauma, an infection, or cancer that damages or inhibits β-cells function. There are a number of viruses (such as rubella) that target β-cells and can cause diabetes, as well as various drugs which may impair insulin secretion as a side effect. People suffering from endocrinopathies (hormonal diseases) may have excess amounts of hormones that reduce insulin efficiency. Finally, during pregnancy a woman may gain a glucose intolerance (likely due to hormonal issues similar to endocrinopathies) which will cause a form of diabetes. This is usually resolved upon delivery, although in some cases it persists .
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