Handbook of Pathophysiology

Authors: Corwin, Elizabeth J.

Title: Handbook of Pathophysiology, 3rd Edition

Copyright 2008 Lippincott Williams & Wilkins

> Table of Contents > Unit V - Nutrition, Elimination, and reproductive function and dysfunction > Chapter 16 - The Pancreas and Diabetes Mellitus

Chapter 16

The Pancreas and Diabetes Mellitus

The pancreas is a large, diffuse abdominal organ that functions as both an exocrine and endocrine gland. In this chapter, both roles are presented, followed by a detailed description of diabetes mellitus, a condition in which the pancreatic hormone, insulin, is either ineffective or absent. Pancreatitis and pancreatic cancer are discussed briefly.

Physiologic Concepts

Exocrine Functions of the Pancreas

The exocrine functions of the pancreas involve the synthesis and release of digestive enzymes and sodium bicarbonate from specialized cells of the pancreas called acini cells. The acini cells release their contents into the pancreatic duct. From the pancreatic duct, the enzymes and bicarbonate solution travel through the sphincter of Oddi into the first section of the small intestine, the duodenum. The pancreatic enzymes and bicarbonate solution both play important roles in the digestion and absorption of food in the small intestine.

Secretion of Pancreatic Enzymes

The secretion of the various pancreatic enzymes occurs primarily as a result of stimulation of the pancreas by cholecystokinin (CCK), a hormone released from the small intestine. The stimulus for the release of CCK is the presence of a mixture of food particles entering the duodenum from the

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Secretion of Sodium Bicarbonate

Sodium bicarbonate is secreted from pancreatic ductal cells in response to a second small-intestine hormone, secretin. Secretin is released in response to the acidic chyme entering from the stomach. When delivered to the small intestine, sodium bicarbonate, which is a base, neutralizes acidic chyme. This function is essential because the digestive enzymes are inactivated in an acidic environment. Neutralization of the acid in the duodenum also protects this area against acid injury to the mucosal wall and subsequent ulcer development.

Endocrine Functions of the Pancreas

The endocrine functions of the pancreas involve the synthesis and release of the hormones insulin, glucagon, and somatostatin. These hormones are each produced by separate, specialized cells of the pancreas, called the islets of Langerhans.

Synthesis and Secretion of Insulin

The synthesis of insulin in the pancreas comes from the enzymatic cleavage of the molecule proinsulin, which itself is the cleavage product of an even larger preproinsulin molecule. Proinsulin is composed of an A peptide fragment connected to a B peptide fragment by a C peptide fragment and two disulfide bonds (Fig. 16-1). Enzymatic cleavage of the C peptide connections leaves the A and the B peptides connected to each other through only the two disulfide bonds. In this form, insulin circulates unbound in the plasma.

Insulin is released at a basal rate by the beta cells of the islets of Langerhans. A rise in blood glucose is the primary stimulus to increase insulin release above baseline. Fasting blood glucose level is normally 80 to 90 mg/100 mL of blood. When blood glucose increases to more than 100 mg/100 mL of blood, insulin secretion from the pancreas increases rapidly and then returns to baseline in 2 to 3 hours. Insulin is the main hormone of the absorptive stage of digestion that occurs immediately after a meal. Insulin levels are low between meals.

Insulin circulates in the plasma and acts by binding to insulin receptors present on most cells of the body. Once bound, insulin works through a protein kinase messenger system to cause an increase in the number of glucose-transporter molecules present on the outside of the cell

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Insulin release is also stimulated by amino acids and the hormones of digestion (i.e., CCK, secretin, and glucose-dependent insulinotropic polypeptide [GIP]; see Chapter 15). The autonomic nervous system also stimulates insulin release by means of parasympathetic nerves to the pancreas. Both the release of GIP and the activation of the autonomic nervous system occur when one starts eating, resulting in a release of insulin at the beginning of a meal, even before glucose is absorbed. Sympathetic stimulation to the pancreas decreases insulin release.

Insulin is the major anabolic (building) hormone of the body and has a variety of other effects besides stimulating glucose transport. It also increases amino acid transport into cells, stimulates protein synthesis, and inhibits the breakdown of fat, protein, and glycogen stores. Insulin also inhibits gluconeogenesis, the new synthesis of glucose, by the liver. In summary, insulin serves to provide glucose to our cells, build protein, and maintain low plasma glucose levels.

The Brain, Glucose, and Insulin

Unlike most other cells, brain cells do not require insulin for glucose entry. Also unlike other cells that may use free fatty acids or amino acids for energy, brain cells must use only glucose or glycogen to meet their

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Secretion of Glucagon

Glucagon is a protein hormone released from the alpha cells of the islets of Langerhans in response to low blood glucose levels and increased plasma amino acids. Glucagon is primarily a hormone of the postabsorptive stage of digestion that occurs during fasting periods in between meals. Its functions are mainly catabolic (breaking down). In most respects, glucagon works the opposite of insulin. For example, glucagon acts as an insulin antagonist by inhibiting glucose movement into cells. Glucagon also stimulates liver gluconeogenesis and causes the breakdown of stored glycogen to be used as an energy source instead of glucose. Glucagon stimulates the breakdown of fats and the release of free fatty acids into the bloodstream so they may be used as an energy source instead of glucose. These functions serve to increase blood glucose levels. The release of glucagon by the pancreas is stimulated by sympathetic nerves.

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Secretion of Somatostatin

Somatostatin is secreted by delta cells of the islets of Langerhans. Somatostatin is also called growth hormone inhibiting hormone and is released as well by the hypothalamus. Somatostatin from the hypothalamus inhibits the release of growth hormone from the anterior pituitary. Somatostatin from the pancreas appears to have a minimal effect on the release of growth hormone from the pituitary. Rather, it acts to control metabolism by inhibiting the secretion of insulin and glucagon. The exact function of somatostatin is otherwise unclear.

Tests of Pancreatic Function

Fasting Plasma Glucose

Measurement of plasma glucose above 126 mg/100 mL (corresponding to fasting blood glucose of 110 mg/100 mL) on more than one occasion is diagnostic of diabetes mellitus. Plasma glucose levels greater than 110 mg/100 mL indicate insulin resistance. Non-fasting plasma glucose of greater than 200 mg/100 mL with symptoms of polyurea, polydipsia, and polyphagia is also diagnostic of diabetes.

Urine Glucose Tests

Glucose in the urine may or may not be indicative of diabetes. Likewise, the absence of glucose in the urine cannot be used to discount diabetes. Under most conditions, however, glucose is not present in the urine of healthy, non-pregnant individuals.

Glycosylated Hemoglobin

Throughout the 120-day life span of the red blood cell, hemoglobin slowly and irreversibly becomes glycosylated (glucose bound). Normally, approximately 4 to 6% of red blood cell hemoglobin is glycosylated. If there is chronic hyperglycemia, the level of glycosylated hemoglobin increases. Poorly controlled diabetics show the highest level of glycosylated hemoglobin, which may be greater than 10%. The particular hemoglobin most often measured and reported is glycohemoglobin A1c (HbA1c). Measurement of HbA1c is important because it offers an indication of how well controlled the blood glucose has been over the previous 2 to 4 months.

Serum Amylase

Amylase is a pancreatic enzyme. Its increased concentration in the serum suggests pancreatic pathology.

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Pathophysiologic Concepts

Hypoglycemia

Hypoglycemia is a blood glucose level less than 50 mg/l00 mL of blood. Hypoglycemia can be caused by fasting or, especially, fasting coupled with exercise, because exercise increases the usage of glucose by skeletal muscle. Most commonly, hypoglycemia is caused by an insulin overdose in an insulin-dependent diabetic.

Because the brain relies on blood glucose as its main energy source, hypoglycemia results in many symptoms of altered central nervous system (CNS) functioning, including confusion, irritability, seizure, and coma. Hypoglycemia can cause headache, as a result of alteration of cerebral blood flow, and changes in water balance. Systemically, hypoglycemia causes activation of the sympathetic nervous system, stimulating hunger, nervousness, sweating, and tachycardia. Anxiety levels increase due to being shaky and agitated.

Hyperglycemia

Hyperglycemia is defined as plasma glucose higher than the normal, fasting range of 126 mg/100 mL of blood. Hyperglycemia is usually caused by insulin deficiency, as seen in type 1 diabetes, or as a result of decreased cellular responsiveness to insulin, as seen in type 2 diabetes (the types of diabetes are discussed in the following section of this chapter). Hypercortisolemia, which occurs in Cushing's syndrome and in response to chronic stress, can cause hyperglycemia by stimulation of liver gluconeogenesis. Acute conditions of elevated thyroid hormone, prolactin, and growth hormone all increase blood glucose as well. Prolonged high levels of these hormones, especially growth hormone, are considered diabetogenic (producing diabetes) because they overstimulate insulin release by beta cells of the pancreas, leading to an eventual decrease in the cellular response to insulin. Sympathetic nervous stimulation and epinephrine released from the adrenal gland also raise plasma glucose levels, especially during periods of stress. The catecholamines epinephrine and norepinephrine inhibit insulin secretion, increase the breakdown of stored fats, and promote the use of glycogen for energy. By these mechanisms, the catecholamines make a variety of alternative energy sources available for the body to use instead of glucose, thereby raising plasma glucose and increasing its availability for use by the brain.

Conditions of Disease or Injury

Diabetes Mellitus

Diabetes is a Greek word that means to siphon or pass through. Mellitus is a Latin word meaning honey or sweet. The disease diabetes mellitus is

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Tests used to diagnose diabetes include the fasting plasma glucose (FPG) test and the oral glucose tolerance test (OGTT). The American Diabetes Association recommends the FPG test because it is faster, easier to perform, and less expensive than the OGTT. A FPG level between 100 and 125 mg/dL is indicative of prediabetes, and a FPG level of 126 mg/dL or more is considered frank diabetes. For the OGTT, a person's blood glucose is measured after a fast and two hours after drinking a glucose rich beverage. A 2-hour OGTT between 140 and 199 mg/dL indicates prediabetes; a level of 200 mg/dL or higher indicates diabetes. Providing a range of values indicative of prediabetes allows for earlier intervention with patients at risk of developing frank diabetes. Early intervention is extremely important because, at the time of diagnosis of type 2 diabetes, 20% of patients already have retinal damage, 8% have renal dysfunction, and 9% have neurologic symptoms.

Types of Diabetes Mellitus

A 1997 consensus paper put forth by the American Diabetes Association's Expert Committee on the Diagnosis and Classification of Diabetes Mellitus outlined four major categories of diabetes: type 1, characterized by absolute lack of insulin; type 2, characterized by insulin resistance with an insulin secretory defect; type 3, other specific types; and type 4, gestational diabetes (Table 16-1). Types 1, 2, and 4 are discussed in the following sections. Other specific types of diabetes (type 3) include those due to pancreatic trauma, neoplasm, or diseases characterized by other endocrine disorders, for example, Cushing's disease (see Chapter 9).

Type 1 Diabetes Mellitus

Hyperglycemia caused by an absolute lack of insulin is known as type 1 diabetes mellitus. Previously, this type of diabetes has been referred to as insulin-dependent diabetes mellitus (IDDM) because individuals who have this disease must receive insulin replacement. Type 1 diabetes is most commonly seen in non-obese individuals less than 30 years old and occurs in a slightly higher proportion of males than females. Because the incidence of type 1 diabetes peaks in the early teens, in the past it was referred to as juvenile diabetes. However, type 1 diabetes mellitus can occur at any age. See page C12 for illustrations and further explanation.

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Causes of type 1 diabetes

Type 1 diabetes results from autoimmune destruction of the beta cells of the islets of Langerhans. It appears that individuals who have a genetic tendency to develop this disease experience an environmental trigger that initiates the autoimmune process. Examples of possible triggers include viral infections such as mumps, rubella, or chronic cytomegalovirus (CMV). It also has been suggested that exposure to certain drugs or toxins may trigger an attack. Because type 1 diabetes develops over several years, there is often no clear stimulating event. Antibodies to islets of Langerhans cells are present in most individuals at the time of diagnosis of type 1 diabetes.

Why an individual develops antibodies against the islet of Langerhans cells in response to a triggering event is unknown. One mechanism may be that the environmental agent antigenically changes the cells such that they stimulate the production of autoantibodies. It is also possible that individuals who develop type 1 diabetes mellitus share antigenic similarities between their pancreatic beta cells and certain triggering microorganisms or drugs. In the course of responding to a virus or drug, the immune system may fail to distinguish the pancreatic cells as self.

Genetic tendency for type 1 diabetes mellitus

There appears to be a genetic tendency for individuals to develop type 1 diabetes mellitus. Certain individuals appear to have diabetogenic genes, meaning a genetic profile that predisposes them to type 1 diabetes (or possibly any autoimmune disease). Genetic loci that pass an inherited tendency for type 1 diabetes are part of the histocompatibility complex genes (see Chapter 5). The histocompatibility complex controls the recognition of self-antigens by the immune system; loss of self-tolerance is core to developing autoantibodies. The histocompatibility genes are primarily coded for on chromosome 6. Another specific insulin-related gene on chromosome 11 has been implicated in the development of type 1 diabetes through its effects on beta cell development and replication. Siblings of individuals who have type 1 diabetes and children of a parent

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Characteristics of type 1 diabetes

Individuals who have type 1 diabetes show normal glucose handling before disease onset. In the past it was thought that type 1 disease developed suddenly and with little warning. Currently, however, it is thought that type 1 diabetes usually develops slowly over the course of many years, with the presence of autoantibodies against the beta cells and their steady destruction occurring well in advance of diagnosis.

By the time type 1 diabetes is diagnosed, there is usually little or no insulin being secreted from the pancreas, and more than 80% of the pancreatic beta cells have been destroyed. Blood glucose levels increase because glucose cannot enter most cells of the body without insulin. At the same time, the liver begins to undertake gluconeogenesis (new glucose synthesis) using the available substrates of amino acids, fatty acids, and glycogen. These substrates are present in high concentrations in the circulation because the catabolic action of glucagon is unopposed by insulin. This results in functional cell starvation in the face of high glucose levels. Only the brain and red blood cells are spared glucose deprivation because they do not require insulin for glucose entry.

All other cells switch to the use of free fatty acids for energy. Metabolism of free fatty acids in the Krebs cycle (see Chapter 1) supplies cells with the adenosine triphosphate (ATP) necessary to run cell functions. Extensive reliance on fatty acids for energy production increases production of various ketones by the liver. Ketones are acids, which cause plasma pH to decrease.

Type 2 Diabetes Mellitus

Hyperglycemia caused by cellular insensitivity to insulin is called type 2 diabetes mellitus. In addition, there is a corresponding insulin secretory defect that results in the pancreas being incapable of secreting enough insulin to maintain normal plasma glucose. Although insulin levels may be only slightly reduced or even within the normal range, they are inappropriately low, considering the elevated level of plasma glucose. Because insulin is still produced by the pancreatic beta cells, type 2 diabetes mellitus was previously called non insulin-dependent diabetes mellitus (NIDDM), a misnomer because many individuals who have type 2 are treated with insulin. In type 2 diabetes mellitus, women are over-represented compared with men. A strong genetic predisposition and obvious environmental factors contribute to development of type 2 diabetes. See page C13 for illustrations and further explanation.

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Causes of type 2 diabetes

For most individuals, the number one risk factor for type 2 diabetes mellitus is obesity. In addition, the genetic tendency to develop the disease is strong. It is possible that an unidentified genetic trait causes the pancreas to secrete altered insulin or causes the insulin receptors or second messengers to fail to respond to insulin adequately. It is also possible that a genetic link is associated with obesity and prolonged stimulation of the insulin receptors. Prolonged stimulation of receptors may lead to a decrease in the number of receptors for insulin present on body cells. This decrease is called downregulation. It is also possible that individuals who develop type 2 diabetes produce insulin autoantibodies that bind to the insulin receptor, blocking insulin's access to the receptor, but do not stimulate carrier activity. Other studies suggest that a deficit in the hormone leptin, due to a lack of the leptin-producing gene or its dysfunction, may be responsible for type 2 diabetes in some individuals. Without the leptin gene, sometimes called the obesity gene, animals, perhaps including humans, fail to respond to satiety cues, and thus are more likely to become obese and develop insulin insensitivity.

Although obesity is the main risk factor for type 2 diabetes, there are certain individuals who develop type 2 diabetes at a young age and who are thin or of normal weight. One example of this type of disease is maturity-onset diabetes of the young (MODY), a condition related to a genetic defect in the pancreatic beta cell such that it is unable to produce insulin. In this circumstance and a few others, there appears to be an even stronger genetic link than in most types of type 2 diabetes.

ediatric Consideration

In the past, type 2 diabetes mellitus was referred to as adult-onset diabetes because it typically occurred in individuals older than 30 years of age. Unfortunately, this distinction is becoming less and less true as more teenagers and preteens are developing insulin resistance, most likely related to the increasing prevalence of obesity in childhood. Several studies suggest that over 20% of American children are obese, a finding with enormous implications for health and health care costs as these children reach adulthood and experience the complications of long-term hyperglycemia.

Characteristics of type 2 diabetes

An individual with type 2 diabetes still secretes insulin. However, there is often a delay in the initial secretion and a reduction in the total amount released. This trend worsens as a person ages. In addition, the cells of the body, especially muscle and adipose cells, show a resistance to the insulin that does circulate. As a result, the glucose carrier (the glut-4 glucose transporter) is inadequately present on cells, and glucose is not available for cells to use. As cells are starved for glucose, the liver initiates gluconeogenesis, further increasing blood glucose levels as well as stimulating the

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Gestational Diabetes

Type 4 diabetes mellitus, or gestational diabetes, is defined as diabetes that occurs in a previously non-diabetic pregnant woman. Although this type of diabetes often resolves after delivery, approximately 50% of affected women will not revert to the non-diabetic state after the pregnancy is over. Even in those who do, the risk of developing type 2 diabetes after about 5 years is higher than normal.

Causes of gestational diabetes

The increased energy demands during pregnancy and the continually high levels of estrogen and growth hormone are believed to be the causes of gestational diabetes. Growth hormone and estrogen stimulate insulin release and may result in an oversecretion of insulin, leading to decreased cellular responsiveness. Growth hormone also has some anti-insulin effects, for example, the stimulation of glycogenolysis, the breakdown of glycogen, and the breakdown of adipose tissue. Adinonectin, a plasma protein derived from adipose tissue, plays a role in regulating insulin concentration and resistance; reduced levels of this substance also may contribute to the impaired glucose metabolism and hyperglycemia seen in gestational diabetes. Women who develop gestational diabetes may have subclinical problems with glucose control even before diabetes develops.

Consequences of gestational diabetes

Gestational diabetes can negatively affect the pregnancy by increasing the risk of congenital malformations, stillbirths, and large-for-date babies, which can result in problems during delivery. Gestational diabetes is routinely tested for during prenatal medical examinations. Good obstetrical outcomes are dependent on good maternal glycemic control as well as pre-pregnancy weight. Women who have gestational diabetes usually are treated with diet, insulin, or both, as necessary. The use of oral anti-hyperglycemic agents such as sulfonylurea (glyburide) instead of insulin for pregnant women unable to achieve glycemic control with diet alone has been investigated. Findings suggest glyburide may be as effective as insulin in reducing obstetric complications, without increasing the risk of congenital malformations, although further studies are required to ensure the safety of this or other agents.

The Role of Glucagon in Diabetes Mellitus

Glucagon appears to have a role in the development of diabetes mellitus. Although glucagon is not considered a cause of diabetes mellitus, slightly

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Clinical Manifestations

• Polyuria (increased urine output) as water follows glucose loss in the urine.

• Polydipsia (increased thirst) caused by the high urine volume and loss of water, leading to extracellular dehydration. Intracellular dehydration follows extracellular dehydration because intracellular water diffuses out of cells, down its concentration gradient, and into the hypertonic (highly concentrated) plasma. Intracellular dehydration stimulates anti-diuretic hormone (ADH; vasopressin) release and causes thirst.

• Fatigue and muscle weakness caused by catabolism of muscle protein and the inability of most cells to use glucose for energy. Poor blood flow seen in long-term diabetics also contributes to fatigue.

• Polyphagia (increased hunger) caused by the chronic catabolism of fat and protein, and relative cellular starvation. Weight loss frequently occurs without treatment.

• Type 1 diabetics may present with nausea and severe vomiting.

Although both type 1 and 2 diabetics may show the clinical manifestations outlined above, and both types may develop the symptoms and complications listed below, individuals who have type 2 diabetes frequently present with one or more non-specific symptoms, including:

• Increased rate of infections because of increased glucose concentration in mucus secretions, poor immune function, and reduced blood flow.

• Visual changes related to changes in water balance or, in more severe cases, retinal damage.

• Paresthesias, or abnormalities in sensation.

• Vaginal candidiasis (yeast infection), resulting from increased glucose levels in vaginal secretions and urine, and poor immune function. Candidiasis may lead to vaginal itching and discharge. Vaginal infections are a common presenting condition in women previously unsuspected of having diabetes.

• Muscle wasting may develop as muscle protein is broken down to meet the body's energy needs.

Diagnostic Tools

• In most cases, the suspicion of type 1 diabetes arises clearly with a history of polyuria, polydipsia, polyphagia, and weight loss. The individual may experience repeated vomiting and appear very sick. Type 1 disease is confirmed by plasma glucose testing.

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• Suspicion and testing for type 2 diabetes may be delayed, because symptomology is often non-specific. Type 2 diabetes is also confirmed by plasma glucose testing.

• Throughout pregnancy, women are tested for gestational diabetes by being screened for urine glucose, and at 28 weeks' gestation, their fasting plasma glucose or plasma glucose level after a glucose load (glucose tolerance test) is measured. Women who do not receive prenatal care will not be tested for gestational diabetes.

• Having a fasting plasma glucose level greater than 126 mg/100 mL on two separate occasions is diagnostic of diabetes mellitus. Fasting glucose is elevated because most cells cannot move glucose intracellularly without insulin, and gluconeogenesis is stimulated. Postprandial (after eating) glucose levels are elevated as well.

• Glucose present in the urine is suggestive of diabetes. Glucose handling in the kidney depends on carrier-mediated transport. As described in Chapter 18, glucose is freely filterable across the renal glomerular capillaries. In non-diabetics, all glucose that is filtered into the urine is actively transported back into the blood via stimulation of glucose carriers, resulting in a normal urine glucose of zero. When glucose levels are greater than approximately 180 mg/100 mL of blood, however, as can occur with moderate or severe diabetes mellitus, the renal carriers that move glucose out of the urine and back into the blood become saturated. This saturation means that they can carry no additional glucose and any excess is then lost in the urine (Fig. 16-3). Interestingly, long-term diabetics may have a slightly higher renal threshold for glucose excretion, as much as 200 mg/100 mL of blood, because the tubules

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  tend to adapt and reabsorb glucose more efficiently. Reabsorbing extra glucose, however, puts a strain on the kidneys. In addition, because glucose is osmotically active in the urine filtrate, water stays in the filtrate and is excreted in the urine with glucose, resulting in polyuria, a frequent symptom of diabetes. Although glucose in the urine is very common among diabetics, absence of urine glucose does not rule out diabetes.

  Figure 16-3. Urine glucose concentration as affected by blood glucose concentration. Note that no urine glucose is found until the blood glucose concentration exceeds a threshold value of 180 mg/10 mL.

• Ketones may be present in the urine. This is especially true for individuals who have poorly controlled type 1 diabetes.

• Elevated levels of glycosylated hemoglobin indicate poorly controlled diabetes. HbA1c levels maintained below 8% appear to be sufficient for the avoidance of most complications of diabetes. Levels less than 6% are considered in the normal range.

Acute Complications

• Diabetic Ketoacidosis: Almost always restricted to type 1 diabetics, diabetic ketoacidosis is an acute complication characterized by a worsening of all symptoms of diabetes. Diabetic ketoacidosis may occur after physical stress such as pregnancy or an acute illness or trauma. Sometimes it is the presenting symptom of type 1 diabetes.

  With diabetic ketoacidosis, blood glucose levels rise rapidly as a result of gluconeogenesis and a progressive increase in fat breakdown. Polyuria and dehydration follow. Ketone levels also rise (ketosis) as a result of the nearly total use of fatty acids to produce ATP. The ketones spill into the urine (ketonuria) and cause a recognizable fruity smell to the breath. With ketosis, pH decreases below 7.3. The low pH results in metabolic acidosis and stimulates hyperventilation, called Kussmaul's respiration, as the individual attempts to compensate for the acidosis by blowing off carbon dioxide (a volatile acid).

  A person with diabetic ketoacidosis frequently experiences nausea and abdominal pain. Vomiting may occur and may contribute to the extracellular and intracellular dehydration. Total body levels of potassium fall as a result of prolonged polyuria and vomiting.

  Diabetic ketoacidosis is life threatening and is treated by hospitalization and the correction of fluid and electrolyte balances. Administration of insulin is required for reversal of the hyperglycemia. Because insulin sensitivity increases with decreasing pH, the dose and rate of administration of insulin must be carefully monitored. Studies have shown that the fast-acting insulin analog called lispro (Humalog) is an effective and less costly treatment for diabetic ketoacidosis than other types of insulin.

• Hyperosmolar Hyperglycemic Nonketotic Coma: Also called hyperosmolar non-acidotic diabetes, hyperosmolar hyperglycemic nonketotic coma is an acute complication seen in individuals with type 2 diabetes. This condition indicates a worsening of disease. Although not ketosis prone, type 2 diabetics may develop severe hyperglycemia, with blood glucose levels well in excess of over 300 mg/100 mL. This level of

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  hyperglycemia causes plasma osmolality, normally tightly controlled at 275 to 295 mOsm/L, to increase to more than 310 mOsm/L. As a result, liters of urine are lost, resulting in massive thirst, severe potassium deficit, and, in approximately 15 to 20% of patients, coma and death. Treatment is geared toward fluid and electrolyte replacement. Hyperosmolar hyperglycemic nonketotic coma is usually seen in elderly diabetics after consumption of a high-carbohydrate meal.

• Somogyi Effect: The Somogyi effect is an acute complication characterized by a fall in blood glucose levels during the night, followed by a rebound increase in the morning. The cause of the nighttime hypoglycemia is most likely related to the evening insulin injection. The resulting hypoglycemia in turn causes a reflex increase in glucagon, catecholamines, cortisol, and growth hormone. These hormones stimulate gluconeogenesis, leading to the morning hyperglycemia. Treatment of the Somogyi effect is aimed at manipulation of the evening insulin injection so as not to initiate hypoglycemia. Dietary interventions can also reduce the Somogyi effect. The Somogyi effect is most common in children.

• Dawn Phenomenon: Dawn phenomenon is an early-morning (between 5 A.M. and 9 A.M.) hyperglycemia that results from a circadian increase in glucose levels in the morning. It can be seen in type 1 or 2 diabetics. Hormones that show circadian variation in the morning include cortisol and growth hormone, both of which stimulate gluconeogenesis. In type 2 diabetics, a decrease in insulin sensitivity might also occur in the morning, either as a normal circadian variation of its own or in response to the circadian increases in growth hormone and cortisol.

• Hypoglycemia: Type 1 diabetics may experience the complication of hypoglycemia after an insulin injection. Symptoms may be light-headedness or loss of consciousness. Coma may develop if hypoglycemia is severe. Tightly controlled type 1 patients, that is, patients who perform multiple insulin injections throughout the day and maintain HbA1c levels equal to or less than 7%, are at increased risk of experiencing hypoglycemic events. For some, the benefits of excellent HbA1c levels must be balanced by the risks of hypoglycemia.

Long-Term Complications

Diabetes mellitus has many long-term complications. Most seem directly caused by high blood glucose concentration. All contribute to the morbidity and mortality of the disease. These complications affect almost all body organs.

• Cardiovascular System: Long-term diabetes mellitus has a severe effect on the cardiovascular system. Microvascular damage occurs to the small arterioles, the capillaries, and the venules. Macrovascular damage occurs to the large and medium arteries. All organs and tissues of the body suffer as a result of these microvascular and macrovascular injuries.

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  Microvascular complications arise from a thickening of the basement membrane of the small vessels. The cause of the thickening is unknown, but seems directly related to high blood glucose levels. Microvascular thickening leads to ischemia and a decreased passage of oxygen and nutrients to the tissues. In addition, glycosylated hemoglobin has an increased affinity for oxygen, resulting in the hemoglobin molecule binding more tightly to oxygen, making it less available to meet tissue needs. Acidosis causes a decrease in red blood cell 2,3-diphosphoglycerate (2,3-DPG), which also increases hemoglobin's affinity for oxygen, making it less likely that tissues will be adequately oxygenated.

  The resulting chronic hypoxia can directly damage or destroy cells. Chronic hypoxia also can lead to the development of hypertension by causing the heart to increase its cardiac output in an attempt to deliver more oxygen to ischemic tissues. The kidneys, retina, and peripheral nervous system, including both somatic motor and sensory neurons and the peripheral autonomic nerves, are severely affected by diabetic microvascular disease. Poor microvascular circulation impairs the immune and the inflammatory reactions because these depend on good tissue perfusion for delivery of immune cells and inflammatory mediators.

  Macrovascular complications primarily arise from the development of atherosclerosis (hardening of the arteries) and contribute to poor blood flow, long-term complications, and high mortality. Macrovascular damage can occur even without the presence of overt diabetes mellitus (plasma glucose levels less than 126 mg/100 mL).

  Damage to the endothelial layer of the arteries occurs in diabetes and may result directly from the high circulating levels of blood glucose, a glucose metabolite, or high levels of circulating fatty acids commonly seen in individuals who have diabetes. With injury, endothelial cell permeability increases, and lipid-laden molecules enter the artery. Damage to the endothelial cells initiates an immune and inflammatory reaction, leading to deposition of platelets, macrophages, and fibrous tissue. Smooth muscle cells proliferate. The thickened arterial wall leads to hypertension, which further damages the endothelial lining of the arteries by exerting increased shear forces on the cells. (Refer to Chapter 13 for a full discussion of atherosclerosis.) Vascular effects of long-term diabetes include coronary artery disease, stroke, and peripheral vascular disease. Diabetic patients who suffer a myocardial infarct have a poorer prognosis than do non-diabetics who suffer an infarct. Coronary artery disease is a main cause of morbidity and mortality in the diabetic population.

  Stroke, or a cerebral vascular accident, also is a common outcome of diabetes. This outcome is especially true for type 2 diabetes as a result of the combined risks of atherosclerosis of the cerebral vessels and hypertension, which weaken and may ultimately burst the vessels.

  Peripheral vascular disease also occurs from severe atherosclerosis. It contributes to the amputations and erectile dysfunction often experienced by long-term diabetics.

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• Vision Loss: A common long-term complication of diabetes is vision loss. The most serious threat to vision is retinopathy, or damage to the retina, resulting from the lack of oxygen. The retina is highly active metabolically, and with chronic hypoxia, it progressively demonstrates breakdown in capillary structure, microaneurysm formation, and spots of hemorrhage. Areas of infarcts (dead tissue) develop; neovascularization (new vessel formation) and sprouting of old vessels occur. Unfortunately, the new vessels and sproutings are thin walled and frequently hemorrhagic, leading to activation of the inflammatory system and to scarring of the retina. Interstitial edema occurs and intraocular pressure rises, leading to the collapse of the capillaries and the remaining nerves, and blindness may ensue. Diabetes is the number one cause of blindness in the United States. It also is associated with frequent development of cataracts and glaucoma.

• Renal Damage: Long-term diabetes resulting in renal damage is extremely common, and diabetic nephropathy is the number one cause of kidney failure in the United States and in other Western nations. In the kidney, damage to the glomerular capillaries from hypertension and high plasma glucose causes thickening of the basement membrane and glomerular enlargement. Nodular, sclerotic lesions, called Kimmelstiel-Wilson nodules, develop among the glomeruli, blocking blood flow and further damaging the nephrons.

  With glomerular enlargement, patients who have diabetes, especially type 1, begin to spill protein into the urine. Although the initial amount of protein lost in the urine may be small (microproteinuria), the damage continues, and progresses in a positive-feedback cycle: protein leakage across the glomeruli further damages the nephron, leading to more protein leakage. Eventually, marked proteinuria develops. This occurrence is associated with a predictable decrease in kidney function and life expectancy.

  The loss of plasma proteins in the urine also causes a decrease in capillary osmotic pressure, leading to a decrease in the reabsorption of fluid from the interstitial space. With net filtration of plasma into the interstitial space, generalized edema, called anasarca, occurs. This leads to compression of small capillaries and nerves and to further tissue hypoxia and nerve damage throughout the body, including in the kidney. The kidneys begin to deteriorate rapidly, and fluid overload and severe hypertension develop. With kidney deterioration, the ability to secrete hydrogen ions into the urine decreases, causing metabolic acidosis. Decreased renal production of vitamin D leads to bone breakdown, and decreased renal production of erythropoietin leads to red blood cell deficiency and anemia. Glomerular filtration decreases progressively, and renal failure may develop. Diabetics account for over 30% of renal dialysis transplant patients in the U.S. For a full description of renal failure, see Chapter 18.

• Peripheral Nervous System: Diabetes mellitus damages the peripheral nervous system, including sensory and motor components of both the

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  somatic and autonomic divisions. Neural disease related to diabetes mellitus is called diabetic neuropathy. Diabetic neuropathy is caused by chronic hypoxia of the nerve cells as well as by the effects of hyperglycemia, including hyperglycosylation of proteins involved in neural function. It also appears that nerve support cells, in particular the Schwann cells, begin to use alternative methods to handle the chronically high glucose load, which eventually results in segmental demyelination of the peripheral nerves. Some components of diabetic neuropathy are reversible or preventable with good glucose control; others are not. This suggests that unknown mechanisms of injury in diabetes besides those related to high blood glucose also occur. A seven-year European Diabetes Prospective Complications Study reported neuropathy in 23.5% of patients with type 1 diabetes. The risk of neuropathy was positively correlated with the duration of diabetes and inversely with glycemic control. Increased body mass index and smoking were associated with increased rates of neuropathy as well.

  Demyelination causes slowing of nerve conduction and loss of feeling. Loss of temperature and pain sensation predisposes an individual to severe and often unnoticed injury. Such injuries, coupled with poor blood flow and an impaired immune system, are responsible for the fact that the number one cause of foot amputations in the United States, other than trauma, is diabetes mellitus.

  Damage to the peripheral autonomic nerves can lead to postural hypotension; changes in gastrointestinal function; impaired bladder emptying, with resultant urinary tract infection; and, in men, erectile dysfunction.

• Metabolic Syndrome: Metabolic syndrome describes a combination of cardiovascular and metabolic characteristics often associated with type 2 diabetes and macro- and microvascular pathology. According to the World Health Organization (WHO), a diagnosis of the disorder is based on a combination of insulin resistance plus two other factors that may include hypertension, high plasma triglycerides, low levels of HDL cholesterol, central (or apple-shaped) obesity, microalbuminuria, or high urinary albumin-to-creatinine ratio. From the year 2000 census, it is estimated that 47 million U. S. residents meet the criteria for metabolic syndrome. The consequences of the syndrome are severe and include atherosclerosis, cerebrovascular disease, myocardial infarction, renal failure, and other disorders related to vascular impairment.

• Gestational diabetes is associated with increased risks of congenital malformation and obstetrical complications.

Treatment

• The most important goal of those who study or treat diabetes mellitus is prevention. Although there is no known mechanism to prevent type 1 diabetes, attempts are underway to identify individuals at high risk of developing type 1 diabetes (e.g., siblings of affected individuals) by

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  monitoring for anti beta-cell antibodies and to devise interventions. Different experimental protocols (e.g., providing insulin injections before the demonstration of any symptoms of type 1 with the expectation that antibody development against the beta cells may be prevented) are being tried with this population. For type 2 diabetes, prevention of obesity, especially childhood obesity, is imperative for reducing the incidence of the disease. For those who have gestational diabetes, early identification of risk factors and prompt dietary intervention or other treatments can minimize infant and maternal morbidity and mortality.

• If diabetes mellitus does occur, the goal of treatment becomes consistent normalization of blood glucose levels with minimum day-to-day, hour-to-hour variability. Recent studies demonstrate that keeping blood glucose levels as normal as possible as often as possible can successfully reduce the morbidity and mortality of diabetes mellitus. This goal is accomplished by different means, each suited precisely to the individual and the type of diabetes he or she has.

• Insulin: Type 1 diabetics require insulin therapy. Different types of insulin with different origins and purity are available. Today, human insulin is most commonly used and is associated with the fewest side effects and complications. Insulin preparations vary in terms of time to onset of action, peak time of action, and duration of action. Insulin injections are typically given subcutaneously 1 to 4 times a day after baseline blood glucose levels are measured. With studies showing the definite advantage of more frequent insulin injections, it is recommended that individuals test their plasma glucose levels frequently and use at least 3 to 4 injections per day. More frequent testing is required if there is a change in activity, during periods of growth, in pregnancy, or if an individual becomes ill.

  Other means of administration include subcutaneous insulin pumps that can be programmed to release a given amount of insulin at given times of the day. More or less than a usual amount of insulin may be programmed to be released if changes in routine (activity or diet) are planned or during times of illness. Insulin pumps have the advantage that injections need not be administered, which is an important consideration for all diabetics and especially children. Disadvantages to the pump involve mistakes in programming, which can cause hypoglycemia or hyperglycemia, and pump failures, which can result in death. In addition, infection is a danger with the implant, especially given the poor blood flow and compromised immune system of most diabetics. In addition, the pumps are expensive.

• The first stage of treatment for type 2 diabetics is usually the improvement of insulin sensitivity and secretion by diet, weight loss, and exercise. Studies have shown that with modification of diet and the initiation of an exercise program, many type 2 diabetics can normalize their blood sugar. If glucose normalization cannot be achieved by diet and exercise alone, or if patients cannot follow the regimen required, many type 2 diabetics benefit from oral hypoglycemic drugs. These drugs (e.g.,

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  biguanide, sulfonylurea) work by stimulating the beta cells of the pancreas to increase insulin secretion and/or by inhibiting hepatic gluconeogenesis. They also appear to increase the sensitivity of cells to insulin. For this type of drug to work, there must be some residual insulin secretion by the pancreas. Other drugs effective for type 2 diabetes work by stimulating the production of the glut-4 glucose transporters directly. By increasing the glucose transporters, these agents increase the cellular response to insulin. Specific oral hypoglycemic drugs differ in time to onset of action, time to peak onset, and duration of action. Some are contraindicated in individuals who have renal disease. Often combinations of different types of drugs are more effective than a single drug alone.

• Type 2 diabetics, although considered non insulin-dependent, also may benefit from insulin therapy. In type 2 diabetes, release of insulin may be deficient or the insulin produced may be subtly altered to be less effective than normal. In the latter case, exogenous insulin may be more effective than that which patients naturally produce. Some studies suggest that with provision of insulin exogenously, the course of type 2 diabetes may be slowed because of the elimination of stress on the pancreatic beta cells.

• Dietary Plans: Dietary regimens are individually calculated, depending on growth needs, weight-loss goals (usually for type 2 diabetics), and activity levels. Distribution of calories is generally 50 to 60% from complex carbohydrates, 20% from protein, and 30% from fat. Fiber, vitamins, and minerals are included. It is especially important for children who have type 1 diabetes to ingest adequate calories and minerals to ensure optimum growth.

• Exercise: An exercise program coupled with weight loss has been shown to increase insulin sensitivity and to reduce the need for pharmacologic intervention. For both types of diabetes, exercise has been demonstrated to increase cellular glucose utilization, thereby reducing blood glucose levels.

  Type 1 diabetics must be careful while exercising because the exercise-induced decrease in blood glucose may precipitate hypoglycemia. This is especially true if insulin administration is not matched to the exercise regimen.

• For diabetic ketoacidosis, the most important aspect of care is prevention. Prevention consists of careful monitoring of blood glucose levels and diet, especially in times of added stress or during a viral illness. If diabetic ketoacidosis occurs, it is treated with carefully administered insulin and interventions to balance fluid and electrolytes. Hospitalization is required.

• For hyperosmolar hyperglycemic nonketotic coma, care is centered upon fluid replacement and slow correction of potassium deficits. It can be prevented with good dietary control.

• Other Pharmacologic Interventions: Antihypertensive medications are among the pharmacologic interventions considered for all diabetics. For

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  patients with diabetes, blood pressure recommendations are lower than for the non-diabetic population, with systolic blood pressures above 115 mmHg considered elevated. Antihypertensives, especially the angiotensin II converting enzyme inhibitors (ACE inhibitors) or the angiotensin receptor blockers (ARBs), have been shown to reduce blood pressure in patients with diabetes and to delay the onset of renal disease. Even patients who do not have clinical hypertension or clinically obvious renal disease appear to develop less renal pathology when placed on ACE inhibitors. The addition of an ACE inhibitor should be considered in the care plan of all patients with diabetes. Although traditional beta blockers have been shown to worsen glycemic control, third-generation beta blockers added on top of an ACE inhibitor may prove beneficial for patients with refractory hypertension.

• Pancreatic transplantation has the potential to normalize glucose homeostasis. It also appears to reverse some of the established complications of diabetes, including improving diabetic neuropathy (but not diabetic retinopathy). Although clearly of benefit in normalizing plasma glucose levels, pancreatic transplantation carries with it the risks of surgery, the risks of rejection, and the necessity for lifelong immunosuppressive therapy.

• Advances in pancreatic islet cell replacement techniques have resulted in several thousand individuals worldwide being treated with islet cell transplantations. This treatment offers a significant hope for a diabetes cure in the future. At present, however, only 20% or so of patients become completely insulin-free, and immunosuppression is required. This approach is less invasive than total pancreatic transplantation.

• Experiments designed to allow for the insertion of the gene coding for insulin in individuals who have type 1 diabetes are underway. This procedure would offer a cure for diabetes rather than drug therapy.

• Eighty percent of obese patients who undergo bariatric (gastric bypass) surgery demonstrate a dramatic recovery from diabetes within days to weeks. The mechanism by which diabetes so rapidly remits is unclear, although it appears there is a significant improvement in insulin sensitivity that may be mediated by gut hormones. For example, glucagon-like peptide-1 (GLP-1), a hormone released from the small intestine in response to the rapid passage of food from the stomach, appears to increase insulin release and sensitivity; GLP-1 may be excessively stimulated after gastric bypass. Besides diabetes, two-year rates of recovery from hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, hypercholesterolemia, and hypertension were more favorable in patients who underwent gastric bypass surgery versus a comparable group who did not, although 10-year benefits were less clear. Gastric bypass surgery itself, however, carries significant risks, including bleeding, embolism, thrombosis, infection, and other complications. In addition, hypertrophy of pancreatic beta cells, a condition known as nesidioblastosis, may develop and result in serious postprandial hypoglycemia.

ediatric Consideration

Common childhood illnesses, especially viral infection, may precipitate ketoacidosis in a child with type 1 diabetes. A child is sometimes diagnosed for the first time as diabetic when he or she presents critically ill with ketoacidosis. Diabetic ketoacidosis, hypoglycemia, and the Somogyi effect are more common in children than adults because of especially labile glucose levels.

Treatment of a toddler or young child who has diabetes is extremely demanding and difficult for parents. Encouragement, and often counseling for the entire family, is needed. Older children and teens may rebel against strict carbohydrate control and frequent insulin injections as expressions of normal developmental stages of independence and autonomy. Providers and parents who encourage and allow the older child and teen to make as many decisions as possible regarding his or her care may be able to defuse some of these demonstrations of independence. In addition, girls or boys trying to be as thin as possible may skip or reduce their insulin injections; this manifestation is in some ways similar to an eating disorder.

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Acute Pancreatitis

Acute pancreatitis is an inflammation of the pancreas characterized by autodigestion of the pancreas by pancreatic enzymes. Pancreatic cells are injured or killed, leading to areas of cell necrosis and hemorrhage. Stimulation of the immune and inflammatory systems contributes to the swelling and edema of the organ.

Causes of Pancreatitis

Pancreatitis may occur as a result of blockage of the pancreatic duct, usually caused by a gallstone in the common bile duct. Hyperlipidemia is a risk factor for the development of pancreatitis. Hyperlipidemia may overstimulate the release of pancreatic enzymes, or it may contribute to the development of gallstones. Chronic alcoholism is associated with pancreatitis, perhaps because of stimulation of pancreatic enzyme release or because of damage caused to the sphincter of Oddi at the opening of the small intestine from the common bile duct.

Clinical Manifestations

• Pain, often in the epigastric area and radiating to the back, after a large meal or excess alcohol consumption is the usual presenting symptom. Pain is caused by the swelling and stretching of the pancreatic duct. Pain may be severe.

• Vomiting and nausea may accompany an attack of pancreatitis. The patient appears ill.

Diagnostic Tools

• Blood analysis typically demonstrates elevated levels of serum amylase and lipase.

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• Hyperglycemia and hyperlipidemia are common during an acute attack.

• Increased white blood cell count occurs with the inflammation and rises further with infection.

Complications

• Decreased blood pressure and cardiovascular shock may develop with a severe attack as a result of the systemic release of inflammatory mediators.

• A pancreatic abscess may occur if the pancreas becomes infected. Necrosis of the tissue may be widespread. Hemorrhage, circulatory collapse, and sepsis may follow.

Treatment

• Withholding of food and fluids reduces pancreatic secretions.

• Fluids are given intravenously to maintain blood volume and pressure.

• Narcotics, usually meperidine (Demerol), are administered to relieve pain. Morphine, which may cause spasm of the sphincter of Oddi, is not used.

Pancreatic Cancer

Pancreatic cancer is a relatively common cancer in the U. S. The cause of pancreatic cancer is unknown, but it may develop from either exocrine or endocrine cells. Cancers of the exocrine cells of the small pancreatic ducts are most common and lead to blockage of the ducts.

These tumors frequently penetrate the pancreas and invade surrounding tissue. Metastasis via the portal vein or lymphatic system is common and rapid.

Clinical Manifestations

• Pancreatic cancer may be asymptomatic (until advanced) or may be associated with vague complaints of aversion to food. Pain may be an early complaint or may occur only with advanced disease.

• Advanced disease is associated with jaundice, severe pain, and pronounced weight loss. Metastases to the brain and lung are common. Mortality is nearly 100% within less than 5 years.

Diagnostic Tools

• Laparotomy (penetration of the abdomen with a fiberoptic tool for visualization and sampling) can confirm the diagnosis.

• Ultrasound and computed tomography (CT scan) may be used.

Treatment

• Surgery to relieve pain may include bypass of the blocked ducts.

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Selected Bibliography

American Diabetes Association. (2005). All about diabetes. Retrieved on September 13, 2005 from http://www.diabetes.org/about-diabetes.jsp.

Bakris, G.L., Fonseca, V., Katholi, R.E., McGill, J.B., Messerli, F.H., Phillips, R.A., et al. (2004). Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. Journal of the American Medical Association 292, 2227 2236.

Barr, R.G., Nathan, D.M., Meigs, J.B., & Singer, D.E. (2002). Tests of glycemia for the diagnosis of type 2 diabetes mellitus. Annals of Internal Medicine 137, 263 272.

Colagiuri, S., Borch-Johnsen, K., Glumer, C., & Vistisen, D. (2005). There really is an epidemic of type 2 diabetes. Diabetologia 48, 1459 1463.

Colagiuri, S., Cull, C.A., Holman, R.R., & UKPDS Group. (2002). Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes? U.K. prospective diabetes study 61. Diabetes Care 25, 1410 1417.

Cummings, D.E. (2005). Gastric bypass and nesidioblastosis Too much of a good thing for islets? New England Journal of Medicine 353, 300 302.

Forsbach-Sanchez, G., Tamez-Perez, H.E., & Vazquez-Lara, J. (2005). Diabetes and pregnancy. Archives of Medical Research 36, 291 9.

Guyton, A.C., & Hall, J. (2006). Textbook of medical physiology (11th ed.). Philadelphia: W.B. Saunders.

Jacobson, G.F., Ramos, G.A., Ching, J.Y., Kirby, R.S., Ferrara, A., & Field, D.R. (2005). Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. American Journal of Obstetrics and Gynecology 193, 118 124.

Laaksonen, D.E., Lindstrom, J., Lakka, T.A., Eriksson, J.G., Niskanen, L., Wikstrom, K., et al. (2005). Physical activity in the prevention of type 2 diabetes: The Finnish diabetes prevention study. Diabetes 54, 158 65.

Lakka, H.M., Laaksonen, D.E., Lakka, T.A., Niskanen, L.K., Kumpusalo, E., Tuomilehto, J., & Salonen, J.T. (2002). The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Journal of the American Medical Association 288, 2709 2716.

Peters, A.L., & Schriger, D.L. (1998). The new diagnostic criteria for diabetes: The impact on management of diabetes and macrovascular risk factors. American Journal of Medicine 105(1A), 15S 19S.

Porth, C.M. (2005). Pathophysiology: Concepts of altered health states (7th ed.). Philadelphia: Lippincott Williams & Wilkins.

Sjostrom, L., Lindroos, A.-K., Peltonen, M., Torgerson, J., Bouchard, C., Carlsson, B., et al. (2004). Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. New England Journal of Medicine 351, 2683 2693.

Tesfaye, S., Chaturvedi, N., Eaton, S.E.M., Ward, J.D., Manes, C., Ionescu-Tirgoviste, C., et al. (2005). Vascular risk factors and diabetic neuropathy. New England Journal of Medicine 352, 341 350.

Umpierrez, G.E., Latif, K., Stoever, J., Cuervo, R, Park, L, Freire, A.X.E., et al. (2004). Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. American Journal of Medicine 117, 291 296, 2004.

World Health Organization. (1999). Definition, diagnosis, and classification of diabetes mellitus and its complications, Part 1: Diagnosis and classification of diabetes mellitus. Report of a WHO consultation. Geneva: WHO.

Resources

American Diabetes Association, 1660 Duke St., Alexandria, VA 22314. Phone: (800) 232 3472.