Type 2 Diabetes Mellitus Primarily Originates in the Target Tissue

Type 2 diabetes mellitus results primarily from impaired ability of target tissues to respond to insulin. There are multiple forms of the disease, each with a different etiology. In some cases, it is a permanent, lifelong disorder,- in others, it results from the secretion of counterregulatory hormones in a normal (e.g., pregnant) or pathophysiological (e.g., Cushing's disease) state. Gestational diabetes occurs in 2 to 5% of all pregnancies but usually disappears after delivery. Women who have had gestational diabetes have an increased risk of developing type 2 diabetes later in life.

Insulin Resistance in Type 2 Diabetes. In most cases of type 2 diabetes, normal or higher-than-normal amounts of insulin are present in the circulation. Therefore, there is no impairment in the secretory capacity of pancreatic beta cells but only in the ability of target cells to respond to insulin. In some instances, it has been demonstrated that the fundamental defect is in the insulin receptor. In most cases, however, receptor function appears normal, and the impairment in insulin action is ascribed to a postreceptor defect. Since the exact mechanism of insulin action has not been determined, it is difficult to explore the causes of insulin resistance in much greater depth.

Genetics, Environment, and Type 2 Diabetes. As with type 1 diabetes, key information on the influence of genetics and environmental factors in type 2 diabetes comes from studies of identical twins. These studies indicate that there is a strong genetic component to the development of type 2 diabetes and that environmental factors, including diet, play a considerably lesser role. If one identical twin develops type 2 diabetes, chances are nearly 100% that the second will as well, even if they are raised apart under entirely different conditions.

Many persons with type 2 diabetes are overweight, and often the severity of their disease can be lessened simply by weight loss. However, no strict cause-and-effect relationship between these two conditions has been established. Clearly, not all persons with type 2 diabetes are obese, and not all obese individuals develop diabetes.

Treatment Options for Type 2 Diabetes. In milder forms of type 2 diabetes, dietary restriction leading to weight loss may be the only treatment necessary. Commonly, however, dietary restriction is supplemented by treatment with one of several orally active agents, most often of the sulfonylurea class. These drugs appear to act in two ways. First, they promote insulin action in target cells, lessening insulin resistance in tissues. Second, they correct or reverse a somewhat sluggish response of pancreatic beta cells often seen in type 2 diabetes, normalizing insulin secretory responses to glucose. The exact mechanisms of these effects are unknown. In some cases, persons with type 2 diabetes may also be treated with insulin, although in the most of cases a regimen of oral agents and dietary manipulation is sufficient.

Diabetes Mellitus Complications Present Major Health Problems

If left untreated or if glycemic control is poor, diabetes leads to acute complications that may prove fatal. However, even with reasonably good control of blood glucose, over a period of years, most diabetics develop secondary complications of the disease that result in tissue damage, primarily involving the cardiovascular and nervous systems.

Acute Complications of Diabetes. The nature of acute complications that develop in type 1 and type 2 diabetics differs. Persons with poorly controlled type 1 diabetes often exhibit hyperglycemia, glucosuria, dehydration, and diabetic ketoacidosis. As blood glucose becomes elevated above the renal plasma threshold, glucose appears in the urine. As a result of osmotic effects, water follows glucose, leading to polyuria, excessive loss of fluid from the body, and dehydration. With fluid loss, the circulating blood volume is reduced, compromising cardiovascular function, which may lead to circulatory failure.

Excessive ketone formation leads to acidosis and electrolyte imbalances in persons with type 1 diabetes. If uncontrolled, ketones may be elevated in the blood to such an extent that the odor of acetone (one of the ketones) is noticeable on the breath. Production of the primary ketones, P-hydroxybutyric acid and acetoacetic acid, results in the generation of excess hydrogen ions and a metabolic acidosis. Ketones may accumulate in the blood to such a degree that they exceed renal transport capacities and appear in the urine. As a result of osmotic effects, water is also lost in the urine. In addition, the pK of ketones is such that, even with the most acidic urine, a normal kidney can produce about half of the excreted ketones in the salt (or base) form. To ensure electrical neutrality, these must be accompanied by a cation, usually either sodium or potassium. The loss of ke-tones in the urine, therefore, also results in a loss of impor tant electrolytes. Excessive ketone production in type 1 diabetes results in acidosis, a loss of cations, and a loss of fluids. Emergency department procedures are directed toward immediate correction of these acute problems and usually involve the administration of base, fluids, and insulin.

The complex sequence of events that can result from uncontrolled type 1 diabetes is shown in Figure 35.10. If left unchecked, many of these complications can have an additive effect to further the severity of the disease state.

Persons with type 2 diabetes are generally not ketotic and do not develop acidosis or the electrolyte imbalances characteristic of type 1 diabetes. Hyperglycemia leads to fluid loss and dehydration. Severe cases may result in hyperosmolar coma as a result of excessive fluid loss. The initial objective of treatment in these individuals is the administration of fluids to restore fluid volumes to normal and eliminate the hyperosmolar state.

Chronic Secondary Complications of Diabetes. With good control of their disease, most persons with diabetes can avoid the acute complications described above; however, it is rare that they will not suffer from some of the chronic secondary complications of the disease. In most instances, such complications will ultimately lead to reduced life expectancy.

Most lesions occur in the circulatory system, although the nervous system is also often affected. Large vessels often show changes similar to those in atherosclerosis, with the deposition of large fatty plaques in arteries. However, most of the circulatory complications in diabetes occur in microvessels. The common finding in affected vessels is a

Acute Complications Diabetes Mellitus

Events resulting from acute deficiency in type 1 diabetes mellitus. If left untreated, insulin deficiency may lead to several complications, which may have additive or confounding effects that may ultimately result in death.

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