Intensive Management Of Type 1 Diabetes

Teaching and persuading patients to maintain tight glycemic control is clearly necessary, but it can seem far easier said than done. This review of insulin management basics provides the foundation for designing an individualized regimen.

By Jeff Unger, MD

Dr. Unger is the director of the Chino Medical Group Diabetes Intervention Center and an assistant professor of family medicine at Loma Linda University School of Medicine in Chino, California.

Diabetes is the sixth leading cause of death in the United States. Of the nation's estimated 16 million people living with this metabolic disease, 10% have type 1 diabetes, requiring exogenous insulin for glycemic control and survival. Unfortunately, the number of patients with type 1 disease who comply with treatment is probably fewer than 1 in 10. For some patients, the mere thought of using insulin, performing frequent home blood glucose monitoring, regulating dietary intake, undertaking lifestyle modifications, and enduring all the inconvenience that these tasks may entail can be depressing and frightening.

Patients with type 1 diabetes are often educated about the disease by nurse educators and dietitians. Responsibility for establishing the basic treatment regimen, however, belongs to the physician, and a regimen that conflicts or is poorly integrated with the patient's lifestyle will not achieve the degree of glycemic control that we now know to be necessary for these patients. The Diabetes Control and Complications Trial (DCCT) investigators recommended that hemoglobin A1c levels be maintained below 7.2%. Currently, the average hemoglobin A1c level among Americans with either type of diabetes is 8.5%-9.0%.

Primary care practitioners with no special training in diabetes or endocrinology manage 90% of patients with diabetes. Unfortunately, the variety of options and pharmacokinetic considerations in formulating an insulin regimen can be nearly as confusing to a medical professional as it is to patients, and for that reason physicians may hesitate to initiate a program of tight glycemic control. The purpose of this article is to review and clarify fundamentals of insulin therapy as they apply to most patients seen in primary care offices.

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Insulin Pharmacokinetics

In normal metabolism, insulin is secreted both basally and in a meal-stimulated bolus phase. The function of basal insulin secretion is to restrain hepatic glucose production from glycogen in the post-absorptive (fasting) state. The insulin bolus at mealtime promotes disposal of ingested nutrients, principally carbohydrates, into the peripheral adipose and muscle tissues. As soon as postprandial blood glucose levels normalize (within 2 to 4 hours of eating), circulating insulin returns to the basal range.

To review the pharmacologic features of the most commonly prescribed insulins and two new formulations, see the table below.

NPH and lente are intermediate-acting insulins with absorption rates that can vary by as much as 52% per day depending on dose and injection site. More predictable absorption can be accomplished by lowering the dose of the NPH or lente insulin used and by placing patients on twice-daily intermediate-acting insulin, injected before breakfast and at bedtime. Two smaller doses of intermediate-acting insulin are absorbed more predictably than a single large injection. Patients using intermediate-acting insulins should be aware that hypoglycemic events may occur 3 to 8 hours after receiving an insulin dose due to the erratic absorption of the drug. Intermediate-acting insulins are considered basal insulins because they suppress hepatic glucose production in the fasting state.

Ultralente is a peakless long-acting insulin that can be prescribed once daily (before dinner or at bedtime) in conjunction with regular or lispro insulin taken with meals. Ultralente can be challenging to work with. Like lente and NPH, its duration is quite variable, and it may not provide 24 hours basal insulin for many patients. In others it may have a duration of action longer than 24 hours, which may increase the risk of developing hypoglycemia long after the original dose is injected.

A new insulin analog, glargine (Lantus), is also a long-acting and peakless basal insulin with a 24-hour duration of action. Glargine's two genetically engineered human insulin modifications make the insulin less soluble at the physiologic pH of subcutaneous tissue, thereby delaying the absorption of the compound from the injection site. A single dose of glargine has been shown to be as effective as twice-daily NPH insulin with less associated risk of hypoglycemia. As a basal insulin, glargine can be used in conjunction with regular insulin or a rapid-acting insulin analog such as Humalog (lispro) or the new Novolog (aspart), scheduled for release this year. Glargine is generally injected at bedtime while lispro or aspart insulins are given prior to mealtime.

Three standard premixed insulins are also available: 70/30, which contains 70% NPH and 30% regular insulin; 50/50, containing NPH and regular in equal amounts, and Humulin mix, with a ratio of 75% NPL to 25% lispro insulin. The NPL component uses protamine to delay the absorption of lispro, thereby combining a rapid-acting insulin with a compatible, slowly absorbed lispro. NPL and NPH have similar pharmacologic features, but NPH mixed with lispro is an unstable mixture and cannot be stored in the same syringe for a prolonged period of time. Humulin mix can be given to patients before breakfast and at dinner to improve control of postprandial glycemic excursions.

The premixed insulins may be useful in treating children or older patients who have difficulty mixing insulins on their own, or in cases where ideal glycemic control may not be practical. Patients needing intensive insulin management should be placed on four injections daily or on an insulin pump rather than on premixed insulins.

Newer technology for insulin management. An insulin pump is shown on the left and the continuous glucose sensor on the right.

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Estimating the Daily Dose

Before designing an individual regimen, the physician should estimate the total daily dose (TDD) of insulin that the patient will require. This estimate is based on several factors, including the patient's sensitivity to insulin, degree of glycemic control, insulin resistance, weight, and age (teens usually require more insulin than adults). The TDD can be calculated by multiplying the patient's weight (in kg) by 0.5 to 0.7 units. Thus, a 70-kg person would require approximately 70 3 0.7 units or 49 units in 24 hours.

The total insulin dose is then divided into basal and bolus components. Half of the TDD should be provided as basal (NPH, lente, glargine, ultralente) and half as bolus (regular, lispro, aspart). For example, if a patient's TDD is 50 units, 25 units should be given as basal and 25 units as bolus insulin. Calculating the TDD is an excellent starting point for beginning insulin therapy. Fine-tuning the total daily insulin dose can be accomplished based on carbohydrate counting, pre- and postprandial glycemic patterns, exercise timing, and nocturnal blood glucose elevations if any.

Meal planning. Diabetes is a disorder of carbohydrate metabolism. The more carbohydrates one consumes, the higher the rise in postprandial blood glucose levels. It is not necessary, however, to prescribe the American Diabetes Association's rigid 1800-calorie diet. People with diabetes can be taught to adjust their insulin dosage based on carbohydrate consumption from day to day. Patients appreciate having the flexibility to eat when and what they choose rather than being forced to eat exactly three meals per day and follow strict specifications for the weight and nutritional content of foods.

The average patient who receives 50% of the TDD as bolus insulin should receive pre-meal boluses as follows: 20% of the TDD before breakfast, 10% before lunch, and 20% before dinner. This allotment is based on the typical American diet, in which most of the daily carbohydrate intake occurs at breakfast and dinner. Another reason for it is that insulin resistance is higher in the morning, lower at midday, and higher again at dinnertime. Generally, 1 gram of consumed carbohydrates will raise blood glucose by 4 mg/dL points, so that if one eats a bag of potato chips containing 30 grams of carbohydrates, the blood glucose level will rise 120 mg/dl within 2 hours.

The intensively managed patient must consider the following factors before using a preprandial insulin dose: current blood glucose level, the type of food that will be consumed (more carbohydrates require a higher insulin dose), how much insulin is necessary to cover the meal, response to insulin doses previously given for a similar meal, and the likelihood of exercise within 2 to 4 hours of eating the meal.

In general, 1 unit of regular, lispro, or aspart insulin will cover 5 to 10 grams of carbohydrates. Thin patients have greater insulin sensitivity than obese patients. For that 30-gram bag of chips, a non-obese patient would use 3 units of insulin.

Patients should be advised to check postprandial blood glucose levels to make certain that the dose of insulin they took for a given meal was correct. The postprandial blood glucose levels measured 90 minutes to 2 hours after eating should be between 80 and 180 mg/dl. If the level is higher, the patient should remember to use a higher dose of bolus insulin the next time a similar meal is consumed. Keeping a food diary aids the patient in planning the preprandial doses of insulin required when eating out at different restaurants. The table below, lists the target blood glucose levels for patients with diabetes.

Target Blood Glucose Levels (mg/dl) Time Ideal level Acceptable level Preprandial 70-110 70-130 1 hour postprandial 80-120 80-180 2 hours postprandial 80-120 100-140 2 AM - 3 AM 80-120 100-140

Fine-tuning preprandial insulin doses can be practiced by checking blood glucose levels prior to eating and making the insulin dose adjustments shown in the table below.

Fine-Tuning Preprandial Insulin Doses Blood glucose (mg/dl) Dose adjustment (regular/lispro/aspart) Meal timing <50 Decrease 2 U Inject and eat 51-70 Decrease 1 U Inject and eat 71-130 Routine dose Delay 30 minutes 131-150 Increase 1 U Delay 30 minutes 151-200 Increase 2 U Delay 30 minutes 201-250 Increase 3 U Delay 45 minutes 251-300 Increase 4 U Delay 1 hour 301-350 Increase 6 U Delay 90 minutes 351-400 Increase 8 U Delay 90 minutes *If lispro or aspart is used, insulin can be administered at the beginning of the meal. Regular insulin should be given 30 to 60 minutes before eating to allow for the absorption and metabolic activation of that insulin.

The rule of 1500. Another way to adjust the preprandial insulin dose is to use the rule of 1500. This is a formula reflecting insulin sensitivity that makes it possible to determine how much 1 unit of bolus insulin will lower an individual's blood glucose. To calculate that, you would divide 1500 by the patient's TDD of insulin. For example, a patient with a TDD of 50 units of insulin would expect a glucose reduction of 30 mg/dl per unit of regular, lispro, or aspart insulin used. If the target blood glucose level is 100 to 120 mg/dl and the current level is 200 mg/dl, a supplemental dose of 3 units would be needed to bring the blood glucose into the target range. This supplemental insulin can be added to the normal preprandial injection or used correctively as a separate injection when blood glucose is found to be elevated. Patients using an insulin pump can easily give a compensatory bolus if the postprandial blood glucose level measured 2 to 3 hours after a meal is outside the target range.

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Exercise and Type 1 Diabetes

Every diabetes treatment program should incorporate exercise, dietary instruction, and drug therapy. The American Diabetes Association concludes its position statement on exercise by stating that "all patients with diabetes should have the opportunity to benefit from the many valuable effects of exercise." Activities such as walking, biking, cardiovascular conditioning, resistance training, and swimming not only improve patient well-being, but can also limit the weight gain that commonly occurs in patients with type 1 diabetes after insulin therapy is initiated. Walking for 20 minutes four times weekly is sufficient exercise for many people with diabetes.

In type 2 diabetes, exercise helps the patient to use endogenous insulin more effectively. The long-term disease-modifying benefits of exercise in patients with type 1 diabetes are less prominent-for example, no improvement in hemoglobin A1c (glycosylated hemoglobin) levels is seen-but physical training nevertheless often leads to an increase in insulin sensitivity and a decrease in insulin requirements. Patients who have well-controlled diabetes can participate in most exercise activities without fear of worsening their blood glucose levels. However, a patient whose glycemic control is erratic is at high risk for exercise-related hyperglycemia and ketoacidosis, and those with disease complications such as neuropathy, retinopathy, nephropathy, autonomic dysfunction, or coronary artery disease should undergo a comprehensive medical evaluation before embarking on a strenuous exercise program.

The sidebar below lists the exercise guidelines suggested for patients with type 1 diabetes.

Exercise Guidelines for Type 1 Diabetes Check blood glucose levels before exercise; target range for exercise is 100-240 mg/dl. Exercising with a blood glucose level of <100 mg/dl can precipitate hypoglycemia. Conversely, exercising vigorously with a blood glucose level >240 mg/dl can lead to ketoacidosis. Check blood glucose levels every 30-60 minutes, especially in the unconditioned athlete. If the level is <70 mg/dl, consume a 35-gram carbohydate snack. Never swim alone. Do no inject insulin into the leg 60-90 minutes before exercising. The preferred site of injection before exercise is the abdomen. Reduce by 50% the insulin dose administered before the meal that precedes exercise. Do not exercise at the expected time of peak insulin activity (e.g., 1-2 hours for regular, lispro, and aspart insulin and 6-8 hours for NPH and lente insulin). Exercise times should be as consistent as possible. The best time to exercise is 2 hours after breakfast. The less trained the patient is for a particular exercise, the more likely it is that their blood glucose level will drop in response to that activity. Always carry a rapid-acting carbohydrate such as glucose tablets or raisins to counteract a sudden hypoglycemic episode. In an unconditioned athlete, hypoglycemia may occur up to 16 hours post-exercise. Frequent blood glucose testing is required, especially to identify nocturnal hypoglycemia. Recognize that the physical effects of exercise (palpitations, sweating, fatigue) may mask symptoms of hypoglycemia, which also include vigorous sweating, rapid fatigue, loss of muscle tone, and visual changes. Patients experiencing such symptoms should immediately check their blood glucose level. Patients concerned about the effect of a single type of exercise on blood glucose control should consider undergoing continuous glucose sensor monitoring while participating in that exercise.

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Preventing Hypoglycemia

Managing diabetes would be very simple if patients never developed low blood glucose levels. However, patients undergoing intensive insulin management are at increased risk for developing hypoglycemia (defined as blood glucose below 70 mg/dl). In the DCCT, severe hypoglycemia (defined as episodes requiring outside assistance) was increased threefold in the intensively managed patients versus conventionally treated individuals on one or two daily injections. Among severe hypoglycemic episodes, 54% occurred during sleep and 35% produced none of the classic symptoms (sweating, palpitations, hunger, nausea, blurred vision, headache, weakness, irritability, confusion, altered personality). Hypoglycemia can impair cognitive function and thereby may compromise the concentration and good judgment necessary for safe work and driving. Unusual symptoms, such as violent behavior and falling out of bed, have also been reported.

Patients should always be instructed to perform home blood glucose monitoring frequently, especially before driving a car. Continuous glucose sensor monitoring is helpful in identifying patients who develop nocturnal or asymptomatic hypoglycemia (often referred to as hypoglycemic unawareness). Treatments for hypoglycemia include using commercially available glucose tablets, each of which raises blood glucose by 20 mg/dl. A small (snack-size) box of raisins should also be carried by all patients receiving insulin therapy, since this quantity of raisins will raise blood glucose levels rapidly by about 40 mg/dl. For individuals with severe hypoglycemia and altered level of consciousness, glucagon 1 mg IM can be injected at home or by the health care provider.

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Principles of Continuous Insulin Infusion

Continuous subcutaneous insulin infusion (insulin pump therapy) can be used to simulate normal pancreatic function in a patient with type 1 diabetes. The device used to accomplish this is a pump about the size of a beeper that weighs 4 ounces and has a 3-ml insulin reservoir in the rear. The reservoir is connected to a 42-inch long infusion set catheter that is painlessly inserted into the subcutaneous tissue of the abdomen, buttock, or arm by the patient. The reservoir and infusion set should be changed every 3 days.

Each pump comes with alarms that prevent inadvertent insulin delivery and warn the patient if the infusion set becomes clogged or malfunctions, which would stop the flow of insulin into the subcutaneous tissue. The pump's operating parameters are programmed into its memory by the physician. Rapid-acting insulin (regular, lispro, aspart, or velosulin, a form of regular insulin approved for use in insulin pumps) is used in the pump, which eliminates the need for mixing different types of insulin.

The pump will deliver insulin automatically using the programmed basal rate. As in an intermittent injection regimen, the basal rate delivery is based on half the TDD of insulin. If the TDD is 70 units, 35 units are given as basal insulin over the course of the day and 35 units are infused as pre-meal boluses. The basal insulin delivery rate is calculated by dividing 35 units by 24 hours or 1.5 units per hour. Multiple basal rates can be programmed into the pump's memory to be activated in predictable situations, such as nocturnal hyperglycemia or hypoglycemia, or prior to exercise. Because women occasionally have to vary their basal rates while menstruating, some insulin pumps are designed to store a separate set of basal rates for the onset of menstruation in order to fine-tune glycemic control.

Prior to eating a meal, the patient determines his preprandial blood glucose level, estimates the grams of carbohydrate that will be consumed, and gives himself a specified insulin bolus via the pump. A feature of the newer insulin pumps allows patients to use a dual-wave bolus, in which half of the total calculated bolus is given immediately and the remainder is given over 2 to 3 hours following the meal's consumption. This allows patients to better control postprandial hypoglycemia because the delivery of insulin will more completely match the speed of carbohydrate absorption and metabolism into glucose from the meal.

The box below lists the patients who should be considered insulin pump candidates. In general, any patient who is highly motivated and closely following his or her insulin regimen is eligible. The majority of insulin pump patients are extremely adept at managing their diabetes and are very appreciative of the flexibility that the pump brings to their busy lives.

Candidates for Insulin Pump Therapy Pregnant patients who have type 1 diabetes Patients with hypoglycemic unawareness. Patients who have poorly controlled diabetes such as those with daily wide glycemic variations of more than 150 mg/dl. Patients with significant early morning hyperglycemia (dawn phenomenon) Patients who need flexibility in their insulin regimen, such as those who work irregular shifts, travel frequently, or have erratic schedules Patients with diabetic complications such as retinopathy, neuropathy, or nephropathy. The severity of these complications can improve with pump therapy. Adolescents with frequent ketoacidosis requiring hospitalization can improve their diabetes control with the use of an insulin pump

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Sick Day Regimen for Type 1 Diabetes

Stress associated with infection, inflammatory disease, injury, surgery, or emotional disturbances can alter the metabolic stability of patients with type 1 diabetes, resulting in the development of diabetic ketoacidosis (DKA). Insulin resistance is very common during illness due to increased hepatic glucose production and decreased glucose utilization by the adipose tissue and muscles. Therefore, blood glucose levels will rise without an increase in food intake.

In order to prevent the onset of DKA, insulin injections must never be omitted. A high fluid intake-8 to 12 ounces of fluids hourly-is important to prevent dehydration. Fluids should include fruit juices, popsicles, jello, milk shakes, and regular (not diet) sodas. These fluids contain carbohydrates that are metabolized into bicarbonate, thus improving acidosis. The goal for sick days is to keep blood glucose levels below 240 mg/dl and preferably in the range of 120 to 180 mg/dl. Patients should be instructed to check blood glucose and urine ketone levels every 4 hours while ill. Only regular insulin should be used on sick days. The correct dose of regular insulin can be determined by dividing the patient's current total daily dose of insulin (NPH and regular or lispro) by 6 and injecting that amount of regular insulin every 4 hours. For example, if the total daily insulin dose is 60 units, the ailing patient would inject 10 units of regular insulin every 4 hours if the urine is free of ketones. If ketones are present, additional insulin should be provided as shown in the table below.

Additional Insulin for Sick Days with Ketonuria Blood Glucose Level (mg/dl) Extra Dose of Regular if Ketones Present 120-150 +2 units 151-200 +4 units 201-250 +6 units 251-300 +8 units 301-350 +10 units 351-400 +14 units

Patients on insulin pumps should temporarily increase their basal rate by half so that more insulin is delivered every hour while they are ill. In addition, patients on a pump can use compensatory boluses based on the rule of 1500 to lower their blood glucose levels into the target range. The patient should get to a hospital if he has been vomiting for more than 2 hours, is dehydrated, has blood glucose above 240 mg/dl, or has had ketonuria for more than 24 hours.

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Monitoring Glycemic Control

Long-term glycemic control can be assessed by following glycosylated hemoglobin (HbA1c), which can accurately portray an average blood glucose level over a 2- to 3-month period of time. The percentage of HbA1c multiplied by 25 is the average blood glucose level. A 9% HbA1c level, for example, translates into an average blood glucose of 225 mg/dl. The target range for patients with diabetes is an HbA1c level of 6.5%-7.2%.

Short-term glycemic control traditionally is determined using home blood glucose monitoring. Patients should check their blood glucose levels before meals, at bedtime, before driving, before and after exercising, and occasionally in the middle of the night to see if they are hypoglycemic on their prescribed insulin regimen. Frequent self-monitoring is an absolute component of intensive insulin therapy.

Newer methods of monitoring glycemic control are now available using continuous glucose sensor monitoring. A glucose sensor is inserted into the patient's subcutaneous tissue by a nurse. The sensor reads interstitial glucose levels every 10 minutes and transmits the information to a monitor that is worn by the patient for 3 days as shown in the figures below.

The sensor can be helpful in determining specific glycemic patterns such as nocturnal hypoglycemia, postprandial hypoglycemia, the effect of different foods and exercise on blood glucose levels, and the effect of different oral agents or insulins on glycemic control. The figure below shows the results of a sensor study on a poorly controlled patient using four injections of insulin a day.

Sensor shows inadequate glycemic control.This is the readout from a continous glucose sensor for a 33-year-old patient using 4 injections of insulin a day as follows: NPH 14 units/lispro 12 units before breakfast, lispro 6 units before lunch, lispro 12 units before dinner, and NPH 14 units at bedtime. Note that the interstitial glucose levels are consistently above the target of 80-120 mg/dl. Each different color line represents an individual day of glucose sensing. In this case the patient wore the sensor for 60 hours.

After he was placed on an insulin pump, the sensor study was repeated as shown in the figure below.

Pump provides a solution.The same patient has now been placed on an insulin pump with a basal rate of 1.1 units per hour and boluses of 11 units for breakfast, 6 units for lunch, and 12 units for dinner. This continous glucose sensor study demonstrates the improvement of glycemic control that can be attained by using insulin pump therapy rather than multiple daily injections of insulin.

As the DCCT demonstrated, tightening glycemic control in type 1 diabetes can produce substantial health benefits. This objective can be achieved with multiple daily injections of insulin or through the use of continuous subcutaneous insulin infusion therapy. The emergence of continuous glucose sensor monitoring should enable clinicians to fine-tune glycemic control, providing even better protection from both nocturnal hypoglycemia and dangerous long-term disease complications.

Next month: Intensive Management of Type 2 Diabetes.

Suggested Reading American Diabetes Association: Diabetes mellitus and exercise. Diabetes Care 22(suppl l):S49-53, 1992. Bode BW, et al: Continuous glucose monitoring facilitates sustainable improvements in glycemic control. Diabetes 2000 49(suppl. 1):393, 2000. Brackenridge BP: Carbohydrate gram counting: a key to accurate mealtime boluses in intensive therapy. Pract Diabetol 1992;11:22-28. Marcus A: Patient selection for insulin pump therapy. Pract Diabetol 11:12-18, 1992. Unger J: A primary care approach to continuous subcutaneous insulin infusion. Clin Diabetes 17(3):113-120, 1999. Unger J: Type 1 Diabetes: Intensive therapy in the female patient. The Female Patient 24(12):35-42, 1999. Unger J, Fredrickson L: A primer on intensive insulin management and insulin pump therapy. Primary Care Reports 1997; 3:9-17.

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