Chapter 5: Drugs for Diabetes Mellitus

According to the American Diabetes Association, approximately 18.2 million people in the United States have diabetes.¹ However, only a third of the individuals with diabetes actually know that they have the disease. It is estimated that 5 to 10 percent who are diagnosed with diabetes have type 1 diabetes and the remaining 90 to 95 percent have type 2 diabetes1 (Table 5–1). A third type, gestational diabetes, emerges during pregnancy and is usually reversible after delivery.

Diabetes is the sixth leading cause of death in the United States, with 213,000 individuals dying of complications of the disease in the year 2000 alone.¹ Complications include blindness, kidney disease, heart disease, stroke, impotence, and nontraumatic lower limb amputations (Box 5–1). Individuals from specific ethnic backgrounds, such as Latinos, African-Americans, Native Americans, Asian-Americans, and Pacific islanders, are at a higher risk of developing diabetes. Obesity is also a risk factor.

The cost of managing diabetes is increasing each year. In 2002, direct and indirect health-care expenditures of persons with diabetes totaled $132 billion.¹ In order to defray the costs of managing and treating diabetes and its complications, allied health-care professionals and athletic trainers must understand how to effectively treat individuals with the disease. Moreover, proper care and management will allow a person with diabetes to live a more functional lifestyle and decrease or diminish the extent of complications and reliance on insulin or oral antidiabetic agents.

If you have experience working with individuals with diabetes or know someone who has diabetes, you may be aware of the seriousness and restrictions this disease may impose. However, people with diabetes can live functional and active lives. In this chapter, we will explain the etiology of diabetes and common management techniques including blood glucose response and insulin and oral antidiabetic drug therapy. We will also discuss some of the common complications of diabetes and adverse affects of insulin and oral antidiabetic drug therapies.

The term diabetes mellitus stems from the Latin words diabetes, meaning "siphon," and mellitus, meaning "sweet." Diabetes mellitus is a condition in which the body cannot effectively regulate blood glucose, commonly called "blood sugar." The disease is characterized by hyperglycemia (high blood glucose) (Box 5–2). Physiologically, there are several mechanisms from which the disease develops, ranging from beta (β)-cell destruction in the pancreas to cellular insulin resistance. The specific type of diabetes depends on the mechanism of etiology. Type 1 diabetes results from the body's failure to produce insulin because of an autoimmune pathology. Type 2 diabetes arises from cell insulin resistance or failure of the pancreas to produce enough insulin. Additional information on the etiology of diabetes will be discussed in specific sections of this chapter.

During digestion, the body converts much of the food we eat into glucose to be used for energy. If glucose is not utilized at the time of digestion, it is stored in the form of glycogen in the liver and muscles. Insulin, produced by β cells of the pancreas, facilitates glucose transport into most cells for energy metabolism and storage, stimulates the uptake of amino acids, and facilitates amino acid conversion into proteins. Insulin also converts triglycerides into free fatty acids to be used as energy by the tissues. When the body's insulin supplies are insufficient, excess glucose accumulates in the blood and is then excreted in the urine. Because the cells cannot uptake glucose, the body is "starved" even though there is plenty of glucose available for energy. To produce the energy required for the body, muscles metabolize glycogen (stored glucose) and the liver metabolizes free fatty acids to form glucose.

Insulin, once it is released from the pancreas, binds with specific insulin receptors located on the cell membrane. Once they are bound, the receptors signal protein messengers (GLUT-4) found inside the cells of skeletal and cardiac muscles, liver, and adipose tissue. These protein messengers migrate to the cytoplasm of the cell membrane, bind with glucose, and allow passage through the cell by passive transport (Fig. 5–1).

Although most cells need insulin to actively transport glucose across cell membranes, some tissues are not dependent on insulin to receive circulating glucose. Because the brain requires a constant supply of glucose for its energy needs, it is freely permeable to glucose at all times. During exercise, skeletal muscles can readily uptake glucose into the cells without the presence of insulin. The liver is also non-insulin dependent, but insulin does enhance the metabolism of glucose.

Type 1 diabetes, formally known as insulin-dependent diabetes mellitus (IDDM) and previously called juvenile-onset diabetes, has the lower prevalence of the two types of diabetes. Usually children, teenagers, and young adults are diagnosed with this type of diabetes. It results from an autoimmune destruction of the pancreatic β cells.⁶ The β cells of the pancreas, under normal circumstances, produce enough insulin to metabolize fat, carbohydrates, and proteins in the foods that we eat. Destruction of the β cells limits the effectiveness of food metabolism, leading to hyperglycemia, ketoacidosis, and the need for exogenous insulin to sustain life.

The destruction of the β cells is variable, meaning that some individuals have a rapid rate of destruction and others have a slower rate of destruction.⁴⁹ Usually the process of cell destruction takes place over weeks, months, or even years. A virus, toxin, or some environmental condition is thought to stimulate the destruction of the β cells; however, the exact process is unclear.

Type 2 Diabetes Mellitus

The etiology of type 2 diabetes, formally known as non–insulin-dependent diabetes and previously called adult-onset diabetes, remains unclear but is thought to stem from insulin deficiency or resistance.^{13,35–36,44} Type 2 diabetes can occur at any age, including adolescence, but usually affects older individuals. Individuals diagnosed with type 2 diabetes can have elevated, reduced, or normal insulin levels, but all present with hyperglycemia. Insulin resistance, dysregulated hepatic glucose production, impaired glucose tolerance, and decreasing β-cell function are other factors that contribute to hyperglycemia.

Insulin resistance is thought to be caused by abnormal insulin antibodies, decreased insulin receptor numbers or affinity, postreceptor defects such as deficient GLUT transporters, or abnormal postreceptor signal transduction. With insulin resistance, insulin-sensitive tissues do not readily absorb glucose and serum levels of glucose begin to rise. The increased glucose levels stimulate the β cells of the pancreas to release more insulin. However, the increase in insulin secretion rarely alleviates the high glucose levels. Over time, the β cells become exhausted and fail to secrete insulin at appropriate levels. Autoimmune destruction of the beta cells usually does not occur in type 2 diabetes.

Type 2 diabetes often goes undiagnosed for years (Box 5–3). Hyperglycemia increases gradually, and individuals rarely notice symptoms before they realize they have the disease ^16,20,48 Most individuals with type 2 diabetes are obese, which has been shown to correlate with some form of insulin resistance.^9,29 Insulin resistance may improve with a combination of weight reduction, diet, exercise, and drug therapy to reduce hyperglycemia, but individuals rarely return to normal levels.^{15,24,39–40,45} The risk of developing type 2 diabetes increases with age, lack of exercise, and obesity,^19,48 and occurs more frequently in individuals with hypertension or dyslipidemia, members of certain racial and ethnic groups, and women who were previously diagnosed with gestational diabetes.^16,19,48 A strong genetic disposition plays a contributing role in developing type 2 diabetes, although the specific genetic link is not clearly known.^7,33

The primary goals for managing diabetes are glucose control through education, glucose monitoring, diet, exercise, oral drug therapy, and/or insulin therapy. With proper management, diabetes can be controlled and the complications associated with it can be minimized. Individuals who properly manage their disease can live long, productive, and active lives.

Glucose Monitoring

Individuals with type 1 and type 2 diabetes are strongly encouraged to monitor their blood glucose levels. Normal fasting plasma glucose (FPG) levels are less than 100 mg/Dl (Table 5–2). To determine if an individual has diabetes, a fasting plasma glucose test is advised. Values above 126 mg/dL may be indicative of diabetes mellitus and values between 100 mg/dL and 126 mg/dL are considered pre-diabetes (Box 5–2).

Patients with diabetes should monitor their glucose levels daily. Blood glucose levels are measured using self-monitored blood glucose (SMBG) equipment (Fig. 5–2), which can be used any time during the day as needed. Although most diabetes patients use SMBG equipment, clinicians and physicians usually assess glucose concentrations over time using glycosylated hemoglobin levels (HbA_1c). HbA_1c is an indicator of average glycemic control for a period of 2 to 3 months, and normal values for individuals without diabetes range from 4 to 6 percent. HbA_1c is the preferred test because it is least affected by daily fluctuations in blood glucose.¹⁰

Diet and Exercise

Individuals with type 2 diabetes should be encouraged to monitor their diet and exercise (Table 5–3). Regular exercise, along with diet management, can improve blood glucose control and insulin sensitivity, and possibly lower medication requirements.^{12,14,21,37–38,41–42} Exercise can also promote weight loss and reduce body fat,³ resulting in decreases in cholesterol and blood pressure.^{5,18,21,23,27} Exercise and diet may reduce the amount of oral antidiabetic medication or insulin needed for glucose control.³ In addition, exercise may prevent or delay the onset of type 2 diabetes.³

Type 1 diabetes patients should also be encouraged to exercise (Table 5–3) and to monitor their diet to control glucose responses. During rest, approximately 10 percent of muscle metabolic requirements come from glucose. During exercise, almost all metabolic requirements come from glucose, rapidly depleting muscle glycogen stores and increasing peripheral glucose utilization. As the demand for glucose increases, hepatic glycogenolysis and gluconeogenesis increases. If exercise commences when insulin levels are insufficient, hepatic glucose production will increase and peripheral utilization will decrease, causing hyperglycemia. After exercise, muscle cells need relatively little insulin to facilitate glucose uptake. This glucose uptake into the muscle cells can last for up to 10 to 12 hours after exercise. If adjustments are not made in diet and insulin therapy, individuals can become hypoglycemic.³²

People with diabetes who have glucose levels equal to or exceeding 250 to 300 mg/dL should delay exercising because high glucose levels indicate insulin deficiency. In contrast, excess insulin will enhance peripheral glucose utilization by muscles and suppress hepatic glucose output, resulting in hypoglycemia. Individuals who have glucose levels that are close to normal before exercise have a higher chance of developing hypoglycemia and should be instructed to either ingest 10 to 20 g of carbohydrates before exercise or decrease their dose of insulin.

Managing insulin levels during exercise can be difficult for athletes with both types of diabetes. These athletes have to experiment with their insulin and carbohydrate intake to participate safely in exercise. Type 1 and 2 diabetes patients must know the hormonal and metabolic responses of their body to exercising and need to avoid dangerous conditions such as hypoglycemia. To avoid hypoglycemia, type 1 diabetes patients must alter insulin therapy (time, location, dose). Type 2 diabetes patients must alter oral antidiabetic agents (time and dose) or ensure appropriate nutritional intake before or during exercise. In addition, both types 1 and 2 diabetes patients should monitor blood glucose and adjust for exercise intensity and dietary requirements. In many cases, these processes are managed not only by individuals but also by their health-care professionals, including their athletic trainer. Therefore it is the responsibility of the athletic trainer to become familiar with diet, exercise, insulin, and oral antidiabetic therapies.

Insulin Administration

Insulin is required to treat gestational diabetes, as well as type 1 and sometimes type 2 diabetes, when diet, exercise, and oral antidiabetic agents cannot control symptoms. Regardless of the type of diabetes, insulin dosage must be individualized and balanced with diet and exercise. Insulin was originally manufactured from the pancreases of pigs and cows but now is being replaced by human insulin synthesized using recombinant DNA techniques. With this new technology, a more purified insulin can be prepared biosynthetically that is structurally identical to human insulin and causes fewer allergic reactions (Fig. 5–3).

The absorption rate of insulin (and ultimately the patient's glucose control) can vary with the site of administration.²⁸ Most patients with diabetes use the upper arms, thighs, abdomen, and buttocks for insulin administration. It is now recommended that insulin be injected in the same anatomical region each day to control for insulin reactions⁴ and to ensure similar and consistent absorption (Fig. 5–4). Individuals who exercise should inject insulin into the abdomen to avoid accentuated absorption into exercising muscles.

When storing insulin, one should closely follow the manufacturer's guidelines. Insulin should generally be kept at room temperature; however, when not in use, it should be refrigerated (not frozen). If an individual is traveling for a long period of time in warm weather, insulin can be stored in an insulated container with a cooling agent. Extreme temperatures (<36° or >86°F) and agitation can produce clumping or precipitation (the separation of solids from a solution or suspension) of insulin and affect potency.

Visual inspection of insulin before administration is necessary. Clumping, frosting, precipitation, or color change may signify a loss of potency. If unsure about the potency of a vial, individuals should always substitute a new vial of the same type. Expiration dates stamped on each vial should remind the user to dispose of any expired insulin.

The type of syringe used to inject insulin is also important. Most manufacturers produce small syringes (27–30 gauge with a length of 5/16 or 1/2 inch) that can hold 1.0, 0.5, 0.25, or 0.3-mL. Syringe capacities of 0.25 mL and 0.3 mL are recommended for pediatric and insulin-sensitive patients who require less than 25 units of insulin before meals or snacks.

Most athletes with type 1 diabetes self-administer their own insulin as needed. However, there may be circumstances under which the athletic trainer may be required to inject insulin. To begin, first clean the injection site with alcohol, moving in a circular fashion outward. Grasp the skin around the injection site to elevate the subcutaneous tissue (about 1″ fat fold) (Fig. 5–5.) With the other hand, position the needle bevel up. Insert the needle at a 45° or 90° angle and release the skin. (Fig. 5–6) Inject the insulin and remove the needle gently at the same angle used for insertion. Cover the injection site with an alcohol sponge and check the site for any bleeding or bruising.

Insulin Injection Devices

Currently, there are several ways to deliver insulin: (1) drawing a dose from a vial with an insulin syringe and needle; (2) an insulin pump; or (3) prefilled insulin pens.

Insulin pumps are a more precise way to mimic normal insulin secretion. An insulin pump, which is a battery-operated device with an internal computer, delivers a predetermined amount of insulin, stored in a reservoir, to a subcutaneously inserted catheter or needle. Insulin pumps are designed to be portable and to deliver a basal amount of insulin throughout the day to replicate insulin secretion from the pancreas, as well as to deliver meal-related boluses (concentrated quantities administered rapidly). Individuals may regulate the amount of insulin pumped depending on their circumstances (e.g., time of meals and exercise). Intermittently, depending on individual habits and insulin responses, the pump's reservoir must be refilled.

Insulin pumps can also be implanted, delivering insulin continuously. Insulin is stored in a reservoir surgically located subcutaneously in the abdomen or the chest wall. However, there can be several complications, ranging from infection to catheter blockage. Currently, the widespread use of implantable pumps is limited.

Prefilled insulin pens are convenient for individuals who want to carry insulin discreetly. An insulin pen actually looks like a writing pen and has a cartridge that contains fixed amounts of insulin. Each end of an insulin pen has a specialized function. Located on one end of the insulin pen is a needle similar to the needle found on a syringe. There is a plunger on the other end. To use, the patient selects the desired amount of insulin (measured by a dial on the pen) and then uses the plunger to administer it through the skin. Insulin pens can be disposable or have replaceable cartridges (Fig. 5–7).

Insulin is available in different forms, categorized according to duration and onset of action (Table 5–4). Currently, there are four types of insulin: rapid acting, short acting, intermediate acting, and long acting. Patients with diabetes may combine different types of insulin for glucose management. However, when different types of insulin are mixed, physiochemical changes may occur and therapeutic responses may differ from those obtained by injecting insulin separately. Please consult the physician or pharmacist to ensure proper procedures and precautions for injecting mixed insulin. Injection techniques, site of injection, and patient response may also affect the onset, degree, and duration of insulin activity.

Rapid-acting Insulin

Insulin Lispro (Humalog)

The first available rapid-acting insulin that received United States Food and Drug Administration (FDA) approval (1996) was lispro (Humalog). Lispro is administered 0 to 15 minutes before meals because this type of insulin mimics the normal physiologic insulin secretion response after meals.²⁶ Because lispro has a short duration of action, users may be more susceptible to hyperglycemia and ketosis if insulin administration is inadvertently interrupted.

Insulin Aspart (Novolog)

Insulin aspart (Novolog) is another type of rapid-acting insulin. It is similar to lispro, but its genetic composition differs. Like lispro, insulin aspart controls postprandial (after meals) glucose. It was approved by the FDA in June 2000. Insulin aspart should be administered 0 to 15 minutes before meals.

Short-acting Insulin

Regular

Regular (R) insulin has a slightly longer onset of action than rapid-acting insulin. The duration of action is approximately 5 to 10 hours. Of major concern for people using regular insulin is the proper timing of premeal administration because of the relatively longer onset of action.²⁵

Intermediate-acting Insulin

Isophane Insulin (NPH) and Insulin Zinc (Lente)

NPH and Lente are two similar, related intermediate-acting insulins. The insulin action is dependent on individual responses and glucose level. Fluctuations in absorption of intermediate-acting insulin may alter glucose responses.

Long-acting Insulin

Insulin Zinc Extended (Ultralente)

Ultralente is a long-acting insulin. Because of its delayed-action effects, Ultralente is not recommended for acute glucose control related to meals. Long-acting insulin is usually mixed with short-acting insulin to produce a basal level of insulin between meals. However, administrations are often required twice daily for continuous control of blood sugar throughout the entire day.

Insulin Glargine (Lantus)

Insulin glargine is indicated for children and adults who have type 1 diabetes and those who have type 2 diabetes and need basal insulin to control hyperglycemia. Glargine has no pronounced peak, but instead maintains a basal rate over a 24-hour period. Insulin glargine is administered usually once daily, at bedtime.

Combination Insulin Products

A variety of combination insulin products are also available. In such products, two different types of insulin, usually short and long acting, are dispensed already mixed in the same vial or insulin pen. This method requires fewer injections per day but still provides the control needed. Some examples include Humulin 50/50, Humulin 70/30, and Humalog 75/25.

An insulin regimen is developed after determining the total daily dose and types of insulin required. Because of the variability, there are a multitude of insulin regimens that a physician may prescribe. A common insulin regimen consists of a mixture of intermediate- and short-acting insulin injected twice daily, before breakfast and before dinner (Fig. 5–8). The morning injection of short-acting insulin is intended to control for glucose responses after the morning meal and the intermediate acting insulin controls glucose responses of the noon meal and provides a basal rate throughout the day. The second injection of insulin controls for the evening meal plus later snacks and also provides a basal rate until morning. This method is preferred for individuals who are newly diagnosed and are still secreting pancreatic insulin. Other individuals who need tighter glucose control may administer 3 to 4 injections over the course of the day, usually at meal times.

Athletes with diabetes who require insulin must closely monitor glucose utilization and insulin intake. In most cases, athletes with diabetes can decrease the amount of insulin administered before exercise because of the glucose uptake by the exercising muscles. In addition, athletes with diabetes may be required to snack frequently before or during competition to control glucose levels adequately.

Hypoglycemia

The most common adverse effect of insulin therapy is hypoglycemia, sometimes referred to as insulin shock. Hypoglycemia is a serious and potentially life-threatening condition, most commonly caused by an excess amount of insulin. Other causes of hypoglycemia associated with insulin therapy include a decrease in glycogen stores, skipping meals, or exercise. A person suffering from hypoglycemia may feel weak, drowsy, confused, hungry, or dizzy. Other signs and symptoms include pallor, headache, irritability, trembling, sweating, and tachycardia. In severe cases, the person can lose consciousness and lapse into a coma.

To avoid hypoglycemia, individuals should follow a strict meal regimen, monitor glucose levels regularly, eat snacks if necessary, and learn glucose responses to food and exercise. In addition, all insulin-dependent individuals should carry at least 15 to 20 g of carbohydrates to consume in the event of a hypoglycemic reaction. Some examples are chewable glucose tablets and glucose gel. Medical personnel, athletic trainers, roommates, family members, friends, or other involved persons should also be instructed to use a glucagon emergency kit for situations in which the individual cannot be given carbohydrates orally. Finally, all insulin-dependent individuals should wear a medical alert identification tag.

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is frequently seen in people with type 1 diabetes, with rare occurrences in non–insulin-dependent individuals. DKA results from a shift in metabolism from glucose to nonglucose sources (fatty acids from adipose tissue) for use as energy as a result of insulin deficiency. Glucose levels rise as a result of decreased glucose uptake by the cells. Therefore fatty acids are metabolized and used by the cells as an alternate energy source.

The byproducts of fat metabolism are ketones. As ketones accumulate in the blood, the blood becomes more acidic than the body tissues. The increase in acidity results in the condition called ketoacidosis. Signs and symptoms of DKA include hyperglycemia, thirst, excess urination, fatigue, blurred vision, fruity breath, nausea, muscular stiffness, and difficulty breathing. Other signs are a flushed face, dry skin and mouth, a rapid and weak pulse, and low blood pressure. If the person is not given fluids and insulin immediately, ketoacidosis can lead to coma and potentially death. Individuals who display the symptoms described should check for ketones in the urine, drink fluids, continue with insulin therapy, and contact a physician immediately.

Lipohypertrophy

Lumpy or bumpy appearances on the surfaces of injection sites are thought to be from the lipogenic (fat-producing) effects of insulin. Lipohypertrophy usually results after months to years of repeated injections in the same region. In some cases, the injection site even becomes anesthetized from the constant use of the needle. Proper rotation of the injection region may limit development of lipohypertrophy. If it develops, surgical excision may be necessary.

Lipoatrophy

Lipoatrophy is the breakdown of adipose tissue at the injection site. This causes skin depression and may delay the effects of insulin absorption. Causes of lipoatrophy include an immune response or using less pure insulin, such as animal- derived insulin.

Local Skin Reactions

The prevalence of skin reactions, including pain, swelling, erythema, and itching, has decreased since the development of more purified insulin (insulin made by recombinant DNA technology). Zinc and protamine (additives to increase the duration of action) are thought to be the cause of skin reactions. Skin reactions usually occur in four forms: (1) an immediate flare reaction, (2) as an immediate reaction followed by 4 to 8 hours of erythema, (3) a delayed reaction up to 12 or 24 hours, and (4) a severe inflammatory local reaction.³⁴ Most individuals become desensitized after the first vial of insulin. For resistant cases, oral antihistamines or a glucocorticoid steroid mixed within the syringe can be tried.³⁰

Initial treatment for individuals newly diagnosed with type 2 diabetes is a diet and exercise program to help them gain control of their high glucose levels and lose weight. If, after a period of time, these modifications are unsuccessful, oral antidiabetic agents may be prescribed.

Until 1995, oral antidiabetic agents were limited strictly to a specific drug class known as sulfonylureas. Now several newer oral medications have been developed to control glucose levels at different sites of the body (Fig. 5–9). The combination of oral antidiabetic medications with a regimen of diet and exercise allows people with diabetes to better manage hyperglycemia. Only if these systems fail is insulin prescribed to control hyperglycemia. The next section will describe the type and pharmacology of oral drugs available for diabetes. For an overview of these oral agents, please refer to Table 5–5.

Alpha-Glucosidase Inhibitors

Alpha (α)-glucosidase inhibitors currently include two specific drugs, acarbose (Precose) and miglitol (Glyset). These drugs target the enzymes of the mucosa of the small intestine by inhibiting the breakdown of complex polysaccharides and sucrose into monosaccharides, which are more easily absorbed into the bloodstream. This action results in a slower rate of digestion and lowers the postprandial blood glucose concentrations by up to 25 to 50 mg/dL. Although α-glucosidase inhibitors decrease the mean HbA_1c levels up to 0.5 to 1.0 percent, these effects occur only when they are taken with a complex carbohydrate meal.^31,46

The most common adverse effects of α-glucosidase inhibitors are flatulence, diarrhea, and abdominal pain. Because α-glucosidase inhibitors delay carbohydrate digestion in the gastrointestinal (GI) tract, they may affect the absorption of other drugs if taken concurrently. Additionally, acarbose and miglitol are not recommended for individuals with inflammatory bowel disease or intestinal obstruction. As with any antidiabetic agent, α-glucosidase inhibitors may produce hypoglycemia.

Biguanides

The biguanide class of oral antidiabetic agents consists of one agent, metformin (Glucophage). Metformin lowers glucose concentration but does not cause hypoglycemia in people who do not have diabetes. Metformin is able to decrease hepatic glucose production, decrease glucose intestinal absorption, and improve insulin sensitivity by increasing peripheral glucose uptake and utilization. The specific mechanism to lower blood glucose is thought to occur by decreasing gluconeogenesis,^11,43 but research is still unclear as to whether this actually occurs.⁸ Metformin can reduce HbA_1c levels up to 1.7 percent and fasting plasma glucose levels by 50 to 70 mg/dL. Usually metformin is administered with meals two or three times daily.

The biguanides can cause diarrhea, abdominal discomfort, metallic taste, nausea, and anorexia. These GI adverse effects are usually dose related and should subside over time. Individuals with renal impairment, hepatic disease, or a history of lactic acidosis should refrain from therapy.

Meglitinides

Meglitinides are a new class of nonsulfonylurea agents that stimulate insulin secretion. Two drugs comprise this class; repaglinide (Prandin) and nateglinide (Starlix). Meglitinides work by closing ATP-sensitive potassium channels in the β cell, leading to depolarization and an influx of Ca⁺⁺, which stimulates the release of insulin. This class of drugs has a rapid onset of action and a short duration of action, and must be given with meals to enhance postprandial glucose utilization. If used separately, repaglinide decreases fasting plasma glucose levels by 61 mg/dL and HbA_1c by 1.7 percent. If it is combined with metformin, fasting blood glucose levels decrease by approximately 40 mg/dL.

Meglitinides can cause mild hypoglycemia, particularly if not taken with food. Weight gain of up to 3 percent can occur in some individuals. In addition, meglitinides should not be used by people with type 1 diabetes and a nonfunctioning pancreas.

Thiazolidinediones

Troglitazone (Rezulin) was the first thiazolidinedione approved by the FDA in 1997. Since then, two others have joined this class of drugs, rosiglitazone (Avandia) and pioglitazone (Actos). In 2001, troglitazone was withdrawn from the market because of hepatotoxic effects. Thiazolidinediones are still very effective and are classified as insulin sensitizers, meaning that these drugs decrease insulin resistance in the liver and stimulate glucose uptake by muscle tissues. However, to exert their effects on hyperglycemia, insulin must be present in the body to facilitate glucose uptake. When combined with other antidiabetic agents for poorly controlled type 2 diabetes, thiazolidinediones can decrease HbA_1c levels by an average of 1 percent.

Thiazolidinediones can cause hepatotoxicity in some individuals, usually in the first few months of therapy, and caution should be advised. Liver function tests are advised before starting therapy, every 2 months for the first year of therapy, and periodically afterward. Thiazolidinediones may also lower hemoglobin and hematocrit levels.²² Individuals may exhibit increases in plasma volume, and use in patients with heart failure should be cautious. Patients may see an increase in HDL cholesterol levels and an increase in total and LDL cholesterol levels.

Sulfonylureas

There are several types of sulfonylureas available. Categorized by their chemical structure, these include four first-generation sulfonylureas and three second-generation sulfonylureas. Second-generation sulfonylureas are approximately 100 times more potent than first-generation sulfonylureas based on a milligram-for-milligram comparison, but there is no evidence of differences in clinical effectiveness between them. As a group, sulfonylureas decrease fasting plasma glucose levels by 50 to 70 percent and HbA_1c levels by 1.5 to 1.7 percent.

Sulfonylureas work by stimulating the release of insulin from the β cell of the pancreas and enhancing β-cell sensitivity to glucose. Sulfonylureas are believed to inhibit the potassium ion channel found on the β cell, lower the membrane potential, and cause depolarization. Calcium channels are then opened, increasing the intracellular calcium concentration. The increase in calcium concentration stimulates the release of insulin.^26,47 This class of drugs can also normalize hepatic glucose production and partially reverse peripheral insulin resistance in persons with type 2 diabetes.¹⁷

Sulfonylureas primarily produce hypoglycemia and weight gain. It is not uncommon for individuals to gain between 2 and 5 kg during the course of therapy. Other adverse effects of sulfonylurea administration include headache, dizziness, and nausea.

Early detection and treatment of diabetes is crucial to control the various complications associated with the disease. As allied health-care professionals, athletic trainers must thoroughly understand the type of insulin and oral therapies available and how these therapies affect the individual with diabetes, especially in the athletic setting. Athletes with diabetes normally manage their own condition, but circumstances exist in which the athletic trainer may intervene.

There are several factors that an athletic trainer can follow to assist the athlete with diabetes. The first course of action is to review medical files to determine if any athletes have diabetes and to ensure that proper medical examinations have been conducted. The second step is to discuss with the individual with diabetes his or her specific condition and the primary course of action to take if complications arise, including which equipment is necessary to have readily available at practices and games (glucagon kits, carbohydrates, glucose-monitoring devices, etc) and procedures for contacting medical personnel. The athletic trainer must also recognize the signs and symptoms of emergency complications of diabetes and how to handle and prevent these situations.

The athletic trainer should remind athletes to check their blood glucose levels before and after meals and practices and at other appropriate times. The athlete should also be reminded to eat properly and take proper doses of insulin or oral antidiabetic agents in accordance with their physician's instructions. It is also strongly recommended that the athletic trainer periodically inquire about the athlete's condition during games and practices to determine glucose regulation.

1. Insulin is released from this type of pancreas cell after stimulation from a meal:

   1. Alpha

   2. Beta

   3. Delta

   4. Theta

2. Which of the following is not a cause of type 2 diabetes mellitus?

   1. Insulin deficiency

   2. Hypoglycemia

   3. Glucose intolerance

   4. Insulin resistance

3. Treatment for type 2 diabetes mellitus can include:

   1. Diet and exercise

   2. Oral hypoglycemic agents

   3. Insulin

   4. All of the above

   5. Only 2 of the above

4. An individual with type 1 diabetes mellitus should follow these guidelines when exercising:

   1. Eat carbohydrates during peak insulin levels.

   2. Monitor glucose in the morning and evening only.

   3. Refrain from contact sports.

   4. Exercise only in the early morning when glucose is high.

5. If stored at room temperature, insulin has a shelf-life of:

   1. 1 year

   2. 90 days

   3. 1 week

   4. 30 days

6. Which of the following is the recommended insulin injection site when exercising?

   1. Arms

   2. Thigh

   3. Abdomen

   4. Buttock

7. This type of insulin is usually injected 3–4 times a day to control for postmeal glucose elevations:

   1. NPH

   2. Lantus

   3. Lente

   4. Humalog

8. Which of the following is not a sign and symptom of ketoacidosis?

   1. Hypoglycemia

   2. Hyperglycemia

   3. Excessive urination

   4. Difficulty breathing

9. Which type of oral antidiabetic agent targets the enzyme of the intestinal mucosa to inhibit carbohydrate catabolism?

   1. Biguanides

   2. Meglitinides

   3. Alpha-glucosidase inhibitors

   4. Thiazolidinediones

10. What is the normal preprandial glucose value of whole blood?

    1. <100 mg/dL

    2. 6 percent

    3. <110 mg/dL

    4. <180 mg/dL

11. What is a desired HbA_1c level?

    1. <12

    2. <10

    3. <8

    4. <6

12. Which of the following types of oral antidiabetic agent controls hypoglycemia at the muscle?

    1. Metformin

    2. Meglitinides

    3. Sulfonylureas

    4. Thiazolidinediones