CONCEPTUAL FRAMEWORK ON THE PATHOPHYSIOLOGY OF DIABETES MELLITUS TYPE 2

Destruction of alpha and beta cells of the pancreas Ineffecient to produce insulin Production of excess glucagons Increased elevated blood glucose Production of glucose acidosis acetone osmolarity protein and fat stores breath due to glucose Wasting of lean body mass fatigue Polydipsia Polyuria Polyphagia Weight loss

C. DISCUSSION OF THE PATHOPHYSIOLOGY Regardless of the cause, insulin deficiency produces generally predictable consequences. In the normal state, insulin (formed by the beta cells of the pancreas by the precursor proinsulin) acts to facilitate transport of glucose, some amino acids, and some fatty acids across cell membranes of tissue that are insulin sensitive, namely, liver, skeletal muscle and adipose tissue. In the liver, glucose is used as glucose or stored as glycogen. In the absence of sufficient insulin, excess glucose accumulates and circulates in the bloodstream (hyperglycemia) and spills into the urine (glucosuria). Muscle cells require insulin to incorporate amino acids into muscle protein. Insulin deficiencies cause withdrawal of amino acids and subsequent increases in serum amino acid levels. Finally, insulin is needed to facilitate transport of glucose into the cells to maintain a balance of lipolysis between stored triglycerides and esterification of fatty acids to triglycerides. In insulin, deprived states there is an increase in release of fatty acids and glycerol. The interference with glucose transported to the liver, muscle and adipose tissue, and resulting serum elevations of glucose, amino acids, fatty acids, and glycerol, precipitate further metabolic changes. There is hypertonic dehydration as water leaves the cells, osmotic diuresis brought about by glucosuria, and limited tubular re-absorption, causing polyuria and loss of electrolytes, notably sodium and potassium. Finally, fatty acids

breakdown into ketone bodies, acetoacetic acid, beta hydrobutyric acid, and acetone, causing a state of ketoacidosis. DIABETES MELLITUS Somatostatins are hormones secreted directly into the bloodstream, and together, they regulate the level of glucose in the blood. Insulin lowers the blood sugar level and increases the amount of glycogen (stored carbohydrate) in the liver; Diabetes mellitus is a metabolic disorder, specifically affecting carbohydrate metabolism. It is a disease characterized by persistent hyperglycemia (high glucose blood sugar). It is a metabolic disease that requires medical diagnosis, treatment and lifestyle changes. The World Health Organization recognizes three main forms of diabetes: type 1, type 2 and gestational diabetes (or type 3, occurring during pregnancy), although these three "types" of diabetes are more accurately considered patterns of pancreatic failure rather than single diseases. Type 1 is generally due to autoimmune destruction of the insulin-producing cells, while type 2 and gestational diabetes are due to insulin resistance by tissues. Type 2 may progress to destruction of the insulin-producing cells of the pancreas, but is still considered Type 2, even though insulin administration may be required. Since the first therapeutic use of insulin (1921) diabetes has been a treatable but chronic condition, and the main risks to health are its characteristic long-term complications. These include cardiovascular disease (doubled risk), chronic renal failure (it is the main cause for dialysis in developed world adults), retinal damage which can lead to blindness and is the most significant cause of adult blindness in the non-elderly in the developed world, nerve damage, erectile dysfunction (impotence) and gangrene with risk of amputation of toes, feet, and even legs. TYPE 1 DIABETES MELIITUS Type 1 diabetes mellitus formerly known as insulin-dependent diabetes (IDDM), childhood diabetes, or juvenile-onset diabetes - is characterized by loss of the insulin-producing beta cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. This type comprises up to 10% of total cases in North America and Europe, though this varies by geographical location. This type of diabetes can affect children or adults, but has traditionally been termed "juvenile diabetes" because it represents a majority of cases of diabetes affecting children. The most

common cause of beta cell loss leading to type 1 diabetes is autoimmune destruction, accompanied by antibodies directed against insulin and islet cell proteins. The principal treatment of type 1 diabetes, even from the earliest stages, is replacement of insulin. Without insulin, ketosis and diabetic ketoacidosis can develop and coma or death will result. Currently, type 1 diabetes can be treated only with insulin, with careful monitoring of blood glucose levels using blood testing monitors. Emphasis is also placed on lifestyle adjustments (diet and exercise). Apart from the common subcutaneous injections, it is also possible to deliver insulin via a pump, which allows infusion of insulin 24 hours a day at preset levels, and the ability to program a push dose (a bolus) of insulin as needed at meal times. This is at the expense of an indwelling subcutaneous catheter. It is also possible to deliver insulin via an inhaled powder. Type 1 treatment must be continued indefinitely at present. Treatment does not impair normal activities, if sufficient awareness, appropriate care, and discipline in testing and medication. The average glucose level for the type 1 patient should be as close to normal (80120 mg/dl, 46 mmol/l) as possible. Some physicians suggest up to 140150 mg/dl (7-7.5 mmol/l) for those having trouble with lower values, such as frequent hypoglycemic events. Values above 200 mg/dl (10 mmol/l) are often accompanied by discomfort and frequent urination leading to dehydration. Values above 300 mg/dl (15 mmol/l) usually require immediate treatment and may lead to ketoacidosis. Low levels of blood glucose, called hypoglycemia, may lead to seizures or episodes of unconsciousness. TYPE 2 DIABETES MELLITUS Type 2 diabetes mellitus is previously known as adult-onset diabetes, maturity-onset diabetes, or noninsulin dependent diabetes mellitus (NIDDM) - is due to a combination of defective insulin secretion and defective responsiveness to insulin (often termed insulin resistance or reduced insulin sensitivity), almost certainly involving the insulin receptor in cell membranes. In early stages, the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. In the early stages, hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver, but as the disease progresses the impairment of insulin secretion worsens and therapeutic replacement of insulin often becomes necessary. There are numerous theories as to the exact cause and mechanism for this resistance,

but central obesity (fat concentrated around the waist in relation to abdominal organs, not it seems, subcutaneous fat) is known to predispose for insulin resistance, possibly due to its secretion of adipokines (a group of hormones) that impair glucose tolerance. Abdominal fat is especially active hormonally. Obesity is found in approximately 90% of Developed world patients diagnosed with type 2 diabetes. Other factors may include aging and family history, although in the last decade it has increasingly begun to affect children and adolescents. Type 2 diabetes may go unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (e.g. lack of ketoacidotic episodes) and can be sporadic. However, severe complications can result from unnoticed type 2 diabetes, including renal failure, vascular disease (including coronary artery disease), vision damage, etc. Type 2 diabetes is usually first treated by changes in physical activity (usually increase), diet (generally decrease carbohydrate intake, especially glucose generating carbohydrates), and through weight loss. These can restore insulin sensitivity, even when the weight loss is modest, for example, around 5 kg (10 to 15 lb), most especially when it is in abdominal fat deposits. The next step, if necessary, is treatment with oral antidiabetic drugs. As insulin production is initially unimpaired, oral medication (often used in combination) can still be used that improves insulin production (eg, sulfonylureas) and regulate inappropriate release of glucose by the liver (and attenuate insulin resistance to some extent (eg, metformin), and substantially attenuate insulin resistance (eg, thiazolidinediones). If these fail, insulin therapy will be necessary to maintain normal or near normal glucose levels. A disciplined regimen of blood glucose checks is recommended in most cases, most particularly and necessarily when taking most of these medications. GESTATIONAL DIABETES Gestational diabetes, Type 3, also involves a combination of inadequate insulin secretion and responsiveness, resembling type 2 diabetes in several respects. It develops during pregnancy and may improve or disappear after delivery. Even though it may be transient, gestational diabetes may damage the health of the fetus or mother, and about 20%50% of women with gestational diabetes develop type 2 diabetes later in life. Gestational diabetes mellitus occurs in about 2%5% of all pregnancies. It is temporary, and fully treatable, but, if untreated, may cause problems with the pregnancy, including macrosomia (high birth weight) of the child. It requires careful medical supervision during the pregnancy.

D. SYMPTOMATOLOGY SIGNS AND SYMPTOMS OF DIABETES MELLITUS Type 2 diabetes almost always has a slow onset (often years), but in Type 1, particularly in children, onset may be quite fast (weeks or months). Early symptoms of Type 1 diabetes are often polyuria (frequent urination) and polydipsia (increased thirst and consequent increased fluid intake). There may also be weight loss (despite normal or increased eating), increased appetite, and unreduceable fatigue. These symptoms may also manifest in Type 2 diabetes, though this seldom happens for some years, and sometimes not at all. Clincally, it is most common in Type 2 patients who appear at the doctor with frank poorly controlled diabetes. Another common presenting symptom is altered vision. Prolonged high blood glucose causes changes in the shape of the lens in the eye, leading to blurred vision and, perhaps. All unexplained quick changes in eyesight should force a fasting blood glucose test. Especially dangerous symptoms in diabetics include the smell of acetone on the patient's breath (a sign of ketoacidosis), Kussmaul breathing (a rapid, deep breathing), and any altered state of consciousness or arousal (hostility and mania are both possible, as is confusion and lethargy). The most dangerous form of altered consciousness is the so-called "diabetic coma" which produces unconsciousness. Early symptoms of impending diabetic coma include polyuria, nausea, vomiting and abdominal pain, with lethargy and somnolence a later development, progressing to unconsciousness and death if untreated. Signs and symptoms of diabetes mellitus are due to the high amounts of sugar in the body. The signs and symptoms of Type 1 diabetes develop quicker and become more severe than those of Type 2 diabetes. However, the symptoms of Type 2 diabetes may not be noticed until a regular medical checkup. The more severe the diabetes is, the more sugar is in the blood and the longer high blood sugar levels last. The high amount of sugar in the blood means that more urine is needed to carry it out of the body. As a result, people with diabetes usually experience a strong urge to pee, high amounts of urination (peeing), and constant thirst. The strong urge to pee can occur at night and lead to low amounts of sleep. A high amount of peeing also leads to high amounts of water and electrolyte loss. Electrolytes are chemical substances that are able to conduct electricity after they are melted or dissolved in water.

For people with diabetes mellitus, the urine smells sweet because the extra sugar comes out in the urine flow. Weakness and tiredness occur because the cells in the body are not able to store or use the sugar that they need for energy. Thus, the body is being starved of one its main energy sources. The body still gets some energy, however, from breaking down stored fat. The breaking down of stored fat, in turn, leads to weight loss. Although people with diabetes mellitus can break down stored fat for energy, the body has a difficult time doing so. People with diabetes mellitus also have a difficult time breaking down proteins. The difficulty in breaking down fats, especially when the body does not produce insulin, can lead to the production of acids and poisonous chemical substances called ketones. This condition is known as ketoacidosis. Ketoacidosis is a medical emergency because it can cause coma, severe loss of body fluids, and even death. A coma is a state of deep unconsciousness in which there are no voluntary movements, no responses to pain, and no verbal speech. The signs and symptoms of ketoacidosis are nausea, vomiting, abdominal pain, confusion, deep breathing, and foul-smelling breath. The foul-smelling breath smells like nail polish remover. Emergency treatment for ketoacidosis includes giving the person fluids to correct for fluid loss and to bring back a normal chemical balance in the blood. Insulin injections are also given to allow cells to better absorb glucose from the blood. Ketoacidosis can occur in people with Type 1 and Type 2 diabetes. The difficulty with breaking down fats is especially true for people with Type 1 diabetes (see two sections down for a description) if they miss several doses of insulin or develop another disease. The reason for this is that developing another disease increases the body's use of insulin. Other symptoms of diabetes mellitus are blurry vision, increased hunger, boils, as well as tingling and loss of sensation in the feet and hands. Boils are inflamed, pus-filled areas of the skin. Pus is a yellow or green creamy substance sometimes found at the site of infections.

Diabetes Mellitus 1 is caused by an auto immune destruction of the beta cells in the pancreas, which leads to an absolute insulin deficiency that occurs mainly in younger adults and teenage years. This occurs by a genetic predisposition, environmental stress, active autoimmunity, progressive cell destruction and often develops because of acute illnesses or infection, poor insulin compliance and precipitated by medications that affect carbohydrate metabolism such as anti-hypertensive, antihistamines, tricyclic antidepressants, alcohol, cocaine and ecstasy. The stressors provoke an excessive release of counterregulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone

and the elevation of pro-inflammatory cytokines. In this fight or flight stress response energy stores from fat, protein, and glycogen are mobilized and new glucose is produced. Hyperglycemia occurs when there is insulin deficiency that leads to glucose in the blood as glucose cannot enter the cells. Normally insulin suppresses glucose production and lipolysis in the liver. Therefore insulin deficiency leads to hepatic glucose over production. Counterregulatory hormones increases the glucose level through gluconeogenesis (formation of new glucose) and

glycogenolysis(breakdown of complex glycogen into simple glucose). The process of gluconeogenesis driven by high availability of all the precursors: amino acids(from protein breakdown), lactate (from muscle glycogenolysis) and glycerol (from increased lipolysis). When serum osmolality is high, even less insulin is produced and insulin resistance increases. Thus further difficulty of glucose uptake for tissue occurs, as a result, hyperglycemia worsens. Hyperglycemia raises extracellular fluid osmolality. Water is drawn from the cell into the extracellular compartment and intracellular dehydration and acid overload contributes to altered mental status that later on lead to coma. The development of total body dehydration and sodium depletion is the result of increased urinary output and electrolyte losses. With marked hyperglycemia the serum glucose threshold fro glucose reabsorption in the kidneys is exceeded and glucose is excreted in the urine (glycosuria) that causes obligatory loss of water and electrolytes such as sodium, potassium, magnesium, calcium, and phosphate (osmotic diuresis). Excretion of ketone anions contribute to osmotic dieresis that causes additional obligatory lossess of urinary cations (sodium, potassium and ammonium salts). Insulin deficiency also contribute to renal losses of water and electrolytes since it stimulates salt and water reabsorption by nephron and phosphate reabsorption in the proximal tubule. Acidosis causes nausea and vomiting that leads to further fluid loss. There is increased sensible fluid loss through Kussmaul respiration. Severe dehydration reduces the renal blood flow and decreases glomerular filtration, and may progress to hypovolemic shock. Insulin deficiency and release of counterregulatory hormones promote lipolysis in adipose tissue inhibiting lipogenesis leading to increased relase of fatty acids and glycerol. Glucagon stimulates the liver to oxidize free fatty acids to ketone bodies such as beta-hydroxybutyrate and acetotrexate. The production of ketone bodies exceeds the ability of the tissues to utilize them, resulting in ketonaemia. Ketone bodies fully dissociate ketone ions into hydrogen ions. The body attempts to maintain extracellular pH by binding hydrogen ions with bicarbonate ion thus depleting its alkali reserves, thus acidosis develop.

The respiratory system compensates for acidosis by increasing the depth of breathing to exhale more carbon dioxide (Kussmaul respiration). The breath has a fruity odor because acetone ketones are exhaled.