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DIABETES Also known as Diabetes Mellitus, it is a group of metabolic diseases in which a person has chronically high blood glucose levels (high blood sugar). This high blood sugar produces the symptoms of frequent urination, increased thirst and increased hunger. If left untreated or simply ignored, diabetes can cause many complications. Acute complications include ketoacidosis and coma. Long-term complications can include heart disease, kidney failure, and damage to the eyes and tissues at the extremities (mainly toes and feet). Diabetes is a result of either a lack of insulin production or under-production by the beta cells of the pancreas or because cells of the body lose sensitivity to the insulin that is produced. In both cases, the result is an excess of glucose in the blood as the body’s tissues are unable to transport glucose across the cell membrane for use as energy. There are three main types of diabetes mellitus: Type 1 DM results from the body's failure to produce insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes" because it is usually diagnosed in children. Type I Diabetes includes latent autoimmune diabetes in adults, which results when the T-Cells of a person’s immune system attack and damage or destroy the beta cells on the Islets of Langerhans of the pancreas. About 10% of people with diabetes are this type. Type I diabetes is partly inherited with multiple genes known to increase the risk. Onset can be triggered by one or more factors including viral infection or diet. Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes also with an absolute insulin deficiency. This form was previously referred to as non-insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes". Type 2 diabetes is due primarily to lifestyle factors and genetics. Obesity, lack of physical activity, poor diet and stress are the leading risk factors. In early stages, therapeutic drugs which improve insulin sensitivity of the body’s tissues or reduce glucose production by the liver can help to reduce hyperglycemia. Gestational diabetes, is the third main form and occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. While diabetes is a serious disease, identifying the symptoms early greatly increases the prospects for a healthy, relatively normal life for diabetic patients. Signs and symptoms in children include: Drinking and urinating more Bedwetting frequently than usual Lack of energy Other signs and symptoms include: Unusual thirst Frequent urination Sudden or unusual weight gain/loss Extreme fatigue/lack of energy Blurred vision Frequent or recurring infections Cuts and bruises that are slow to heal Tingling or numbness in hands and feet Blood sugar/blood glucose levels are typically used to test for pre-diabetes or diabetes. In general, blood glucose concentrations greater than 7.0mmol/L are higher than normal and cause for concern. Readings are normally taken after the person has fasted (nothing to eat or drink) for about 8 hours. This generally allows enough time for the body to convert excess glucose in the blood to glycogen for storage in the liver. Patients with undiagnosed or untreated diabetes may suffer from ketoacidosis, a condition which results from a shortage of insulin. Without glucose to power the cell’s metabolic processes, the cells will switch to metabolizing fatty acids. This produces acidic ketone bodies as metabolic waste products. Symptoms of ketoacidosis are nausea, vomiting, excessive thirst, panting or deep gasping breathing, excessive urine production and severe abdominal pain, along with severe hyperglycemia. A patient may have “ketone breath”, a fruity odour resulting from the volatile nature of ketones (they evaporate in air – which happens when blood saturated with ketones circulates through the lungs). Patients with ketoacidosis may also seem confused, lethargic or may fall unconscious. Diabetic ketoacidosis is a medical emergency and can lead to death if untreated. Diabetic ketoacidosis arises because of a lack of insulin in the body. The lack of insulin and corresponding elevation of glucagon leads to increased release of glucose by the liver (a process that is normally suppressed by insulin). High glucose levels spill over into the urine, taking water and dissolved sodium and potassium along with it in a process known as osmotic diuresis. This leads to dehydration, and extreme thirst. The absence of insulin also leads to the release of free fatty acids from adipose tissue which are converted, again in the liver, into ketone bodies. These can serve as an energy source in the absence of insulin-mediated glucose delivery and is a protective mechanism in case of starvation. The ketone bodies however, turn the blood acidic (metabolic acidosis). The body initially buffers the change with the bicarbonate buffering system, but this system is quickly overwhelmed and other mechanisms must work to compensate for the acidosis. One such mechanism is hyperventilation to lower the blood carbon dioxide levels. Untreated, ketoacidosis can cause cerebral edema (brain swelling) which can cause headache, coma, loss of the pupillary light reflex and death. Blood glucose levels in patients with ketoacidosis usually exceed 13.8mmol/L. Coma, or more specifically, hyperosmolar hyperglycemic coma results when high blood glucose levels result in extreme dehydration. The major difference between a patient in a hyperosmolic hyperglycemia state (HHS) and ketoacidosis is that blood glucose levels in HHS are extremely high, greater than 40-50mmol/L. The increasing glucose concentration and resulting volume depletion due to excess kidney function may result in: Altered mental status Sensory or motor impairment Increased thirst Tremors or depressed reflexes Heart attack or stroke Death All forms of diabetes increase the risk of long-term complications. These complications typically develop after many years (10–20), but may be the first signs or symptoms in those who have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood vessels. These complications can be grouped into microvascular disease (damage to small blood vessels) and macrovascular disease (damage to larger arteries). The primary microvascular complications of diabetes include damage to the eyes, kidneys, and nerves. Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and potentially blindness. Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant. Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes. The symptoms can include numbness, tingling, pain, and altered pain sensation, which can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation. The primary macrovascular complications of diabetes include coronary artery disease (angina and myocardial infarction), stroke, and peripheral vascular disease. About 75% of deaths in diabetics are due to coronary artery disease. The HPA axis is an integral part of the neuroendocrine system with an important role in maintaining homeostasis under varying physical and psychological stresses encountered by the body. The HPA axis regulates the production and release of glucocorticoid (GR) hormones by the adrenal glands. Under normal conditions, the activity of the HPA axis is regulated by the day/night cycles of the body’s circadian rhythms. It’s a complex web of interaction in which the hypothalamus secretes CRF and vasopressin which then stimulates the pituitary gland to release ACTH, which in turn activates glucocorticoid production in the adrenal cortex. Besides being regulated by circadian rhythm, the HPA Axis is also the major system that responds to stress. It’s part of the homeostatic control mechanism that provides resistance to changes in the body’s environment. When subjected to stress, affected regions of the brain activate the amygdala (a key component of the limbic system that coordinates negative emotional responses to threatening stimulus) which triggers the hypothalamus, leading to HPA axis activation and glucocorticoid production. Glucocorticoids affect energy metabolism and cardiovascular responses by preparing tissues for the physical needs that may be needed for the body to respond to stress. They can also suppress immune and neurological function. HPA axis activity is regulated by a glucocorticoid(GR) negative feedback mechanism involving the hypothalamus and pituitary gland. GR acts on the hypothalamus to suppress CRF and ACTH production which should restore homeostasis. However in situations in which there is long-term stress, the HPA axis can become “hyperactivated”, overwhelming the feedback mechanism and disrupting metabolic systems in similar ways as with diabetes. Patients with Type I diabetes typically present increased activity of the HPA axis, resulting in increased levels of glucocorticoids and other complications related to diabetes including hypertension, immune suppression and increased risk of depression. One explanation for the hyperactivity of the HPA axis in diabetics is the chronic effect of hyperglycemia-induced stress as chronically high blood glucose levels induce an increase in glucocorticoid production. A reduction in insulin levels characterizes Type 1 diabetes and diabetes also increases glucagon levels as the body tries to reduce blood glucose. However, increased glucagon levels also activate the HPA axis. As a result, increased levels of glucagon in diabetic patients can also contribute to the overproduction of glucocorticoids which culminate in the development or aggravation of diabetic complications. Resources: 1. http://www.diabetes.ca/ 2. http://en.wikipedia.org/wiki/Diabetes_mellitus 3. http://omicsonline.org/from-type-1-diabetes-hpa-axis-to-the-disease-complications-21556156.S12-002.pdf QUESTIONS: 1. What types of cells on the pancreas are responsible for insulin production? Where, exactly are they located? 2. What causes Type 1 diabetes? 3. What are the most common symptoms of diabetes? 4. If left untreated, diabetic hyperglycemia can result in two progressively more severe conditions. What are they? How is each characterized? 5. What is the approximate blood glucose level that defines diabetes? 6. What long-term complications can result from diabetes? 7. What is the danger of chronic glucocorticoid overproduction? How is this linked to diabetes? 8. The connection between diabetes, the stress response and the HPA Axis has only very recently been identified. A disease called Cushing Syndrome has also been linked to both HPA dysfunction and diabetes. Using your textbook, find out what Cushing Disease/Cushing Syndrome is. 9. Using the internet at home, research Cushing Syndrome/Cushing Disease more thoroughly and identify the signs, symptoms, tests and treatments for the disease. 10. Investigate the connection between long-term exposure to stress and dysfunctional HPA axis. Are there any similarities between the effects of diabetes and long-term stress on the HPA axis?