INTRODUCTION

Diabetes is a metabolic condition where either not enough insulin is made, or the insulin that is made doesn't work well enough. Dietary nutrients are broken down into sugar (glucose), which circulates in the blood. With the help of insulin, the glucose is then absorbed by the cells of the body for energy. Insulin also helps the body maintain fat and muscle stores. In the absence of insulin, blood sugar levels are high but the cells of the body are starving, due to an inability to absorb the sugar; weight loss and illness occur unless insulin is provided. The most common forms of diabetes worldwide are type 1 (formerly called insulin dependent or juvenile onset) diabetes and type 2 (formerly called non-insulin dependent or adult type) diabetes. Cystic fibrosis related diabetes (CFRD) shares features of types 1 and 2 diabetes, but it is a unique and distinct form of diabetes that requires a special management approach.

The average age of onset of CFRD is 18-21 years. As in type 1 diabetes, these are slender individuals whose primary problem is insulin deficiency. The clinical presentation is more similar to that of type 2 diabetes, however, the onset of the disease is insidious and a patient may have the disease for years without knowing it. Microvascular complications (eye, kidney and nerve problems) have been reported in CFRD but, unlike both type 1 and type 2 diabetes, macrovascular complications (atherosclerotic heart disease, stroke) do not appear to be a serious concern in CFRD. Several factors unique to CF influence both the development of diabetes and the way it is managed:
o CF patients are chronically infected and suffer frequent acute infectious exacerbations. This influences insulin resistance (how well insulin works in the body).
o Energy needs are increased because of infection and pulmonary disease. A high calorie diet is necessary to meet these needs.
o Malnutrition may be present in CF, which can impair the ability of the pancreas to make insulin. Conversely, untreated diabetes can cause malnutrition.
o Malabsorption due to pancreatic exocrine insufficiency is common despite enzyme supplementation, contributing to malnutrition.
o Anorexia and nausea may be present and may contribute to malnutrition.
o Abnormal intestinal movement may affect food absorption and thus influence blood sugar levels.
o Liver disease is often present, which influences how the body uses nutrients.
o Food intake and activity levels vary widely from day to day, depending on the acute health status of the individual. Thus, the diabetes regimen needs to be flexible.

Providing diabetes care to patients with CFRD is challenging. It requires an understanding of their disease process, and an approach to diagnosis and treatment that is tailored to their specific needs.

DIAGNOSIS
The criteria used to diagnose CFRD are the same as for all forms of diabetes:
o fasting (first thing in the morning before eating) glucose = 7.0 mM (126 mg/dl) on 2 or more occasions
o fasting plasma glucose = 7.0 mM (126 mg/dl) plus a casual glucose level (random, anytime during the day) = 11.1 mM (200 mg/dl)
o Casual glucose level = 11.1 mM (200 mg/dl) on 2 or more occasions with symptoms
o Two hour plasma glucose = 11.0 mM (200 mg/dl) during a standard oral glucose tolerance test (OGTT)

The OGTT is a test which can be done to diagnose diabetes and other, milder forms of blood sugar abnormalities. It divides patients into 4 categories of increasing severity: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes without fasting hyperglycemia (the blood sugar is normal first thing in the morning but gets high after eating), and diabetes with fasting hyperglycemia (the blood sugar is always high, even without eating).

The North American Cystic Fibrosis Foundation, following 1998 consensus conference guidelines recommends that fasting glucose levels be measured annually, and that fasting and post-prandial (after eating) glucose levels be measured during hospitalization for acute illness. The OGTT is commonly used in Europe but has thus far not been well-accepted in the U.S., primarily because of lack of agreement on whether it is important to diagnose or treat CFRD without fasting hyperglycemia.

Like type 2 diabetes, CFRD is usually insidious in onset and may have been present for years before diagnosis. Potential symptoms of CFRD, in addition to increased thirst and increased urination, include failure to gain or maintain weight despite aggressive nutritional intervention, poor growth rate, unexplained decline in pulmonary function, and failure to progress normally through puberty. While none of these symptoms is specific for CFRD, diabetes needs to be considered in the evaluation of patients with these problems.

PATHOPHYSIOLOGY
In the CF pancreas, fibrosis causes scarring and destruction. Many, but not all, of the insulin-producing pancreatic islets are destroyed. This leads to abnormally low levels of insulin secretion. Insulin resistance may also play a role in the development of CFRD, especially during acute infection.

The majority of non-diabetic CF patients, in their usual state of health, appear to be insulin sensitive. During bouts of infection, however, they may become insulin resistant. Treatment with glucocorticoid drugs (like prednisone) or pregnancy are other reasons why some CF patients without diabetes become insulin resistant. Because insulin doesn't work well in the body when one is insulin resistant, more insulin is required to achieve the same effect. If the pancreas is unable to make the extra insulin, blood sugar levels become elevated.

There is a continuum of glucose tolerance in CF ranging from normal glucose tolerance, to increasingly severe abnormal glucose intolerance, to diabetes (figure 1).

figure 1

In their baseline state of health, CF patients are generally insulin sensitive, and their place on this spectrum is determined by how much insulin they are able to make. During the stress of acute infection, pregnancy, or glucocorticoid therapy (prednisone, for example), patients become more insulin resistant and move towards the diabetes end of the spectrum because insulin does not work as well in their body.

When the stress resolves, the insulin resistance usually goes away and they move back to their baseline. Thus, it is common for CF patients to have temporarily higher blood glucose levels during physical stress.

Patients who are close to, but not quite at, the diabetes end of the spectrum may move into the diabetes range during stress and require insulin therapy to prevent high blood glucose levels until the stress resolves. These patients are said to have 'intermittent' diabetes. For patients on insulin therapy at baseline, insulin needs to be increased tremendously during periods of acute illness. Thus, the acute infectious status of the patient always needs to be considered when evaluating CFRD.

PREVALENCE
The North American Cystic Fibrosis Foundation, which maintains a registry of approximately 21,000 patients, reported a diabetes prevalence of about 6% in 1998. Because most US CF centers were not screening for diabetes at the time these data were collected and CFRD is often clinically silent, this figure underestimates the true prevalence of diabetes in CF. In Denmark, OGTT screening of the entire CF population demonstrated no diabetes in patients less than 10 years of age, 12% diabetes in individuals age 10-19, and 48% diabetes in adults age 20 and older.

At the University of Minnesota, where annual oral glucose tolerance testing of CF patients is routine, only about half of children and one quarter of adults with CF have normal glucose tolerance (figure 2).

Glucose tolerance prevalence at the University of Minnesota. Taken from Moran A, Doherty L, Wang X, Thomas W: Abnormal glucose metabolism in cystic fibrosis. J. Pediatr. 133:10-16, 1998.

Diabetes is seen in 9% of CF children, 26% of adolescents, 35% of adults age 20-29, and 43% of adults age 30 and older. Of those with diabetes, approximately 1/3 have fasting hyperglycemia (high blood glucose levels when they wake up in the morning before they have eaten) and two-thirds have diabetes without fasting hyperglycemia. Everyone agrees that diabetes with fasting hyperglycemia is dangerous in CF and must be aggressively treated, but there is a lot of disagreement about whether diabetes without fasting hyperglycemia is dangerous. That is because there is so little scientific information about this form of CFRD.

OUTPATIENT MANAGEMENT OF CFRD WITH FASTING HYPERGLYCEMIA
Team approach
CFRD patients are best treated in the diabetes team setting, where they can receive coordinated care from physicians, diabetes nurse educators, dietitians and mental health professionals. Ideally, their pulmonary team is located in the same clinic to facilitate communication and to coordinate diabetes and pulmonary care. Whatever the circumstances, it is important that those caring for CFRD patients are familiar with their special needs. The patient and his or her family are the most important members of the treatment team.

Our goal is to empower patients to become self-sufficient in diabetes management, and to help them work diabetes into their lifestyle rather than have them significantly change their lifestyles to fit the diabetes.

Medical Therapy
At present, insulin is the only medical therapy officially recommended for CFRD with fasting hyperglycemia. Initially, many patients are overwhelmed by the idea of adding insulin injections to their already complex medical routine. Eventually, most patients become convinced that it is worthwhile because they gain weight (often much more than they have been able to gain for years), and they feel better and have more energy. Many different insulin regimens are possible, depending on the needs of the patient. Very little basal (background) insulin is necessary in CFRD, and the most effective regimens are those that focus on meal coverage.

Once they get used to the insulin injections, most adult CF patients are more concerned about flexibility in dietary intake than about the inconvenience of injections. At the University of Minnesota, the most common insulin regimen chosen by patients who have been on insulin therapy for at least 6 months is rapid-acting insulin (insulin lispro or aspart) 3-6 times per day with meals plus a small dose of NPH insulin (longer acting insulin) at bedtime. This allows the patient to eat whatever they want, whenever they want, as long as they cover it with insulin.

The insulin dose is based on carbohydrate (sugar and starch) intake. In other words, a high carbohydrate meal such as pasta or rice or ice cream will require more insulin than a low carbohydrate meal such as meat or eggs. Most patients use pen devices for insulin delivery. We have occasionally used insulin pumps, but because so little basal insulin is needed in CF, they do not offer any particular advantage for CF diabetes control.

Patients who are ill or who suffer from nausea sometimes do not know how much food they will be able to tolerate. In this situation, patients are advised to take the rapid-acting insulin after eating. We have found that this places the patient at risk, however, for hypoglycemia (low blood sugars) 3-4 hours later. Therefore, we suggest that patients who take their insulin after a meal should eat or drink additional carbohydrates 2-3 hours after the injection.

Many CF patients receive nighttime continuous drip feedings. In this situation, the combination of NPH and regular insulin (short-acting) just before the feeding works well. The regular insulin covers the first half of the feeding and the NPH the second half. The glucose level two hours into the drip can be used to adjust the regular insulin and the glucose level at the end of the drip to adjust the NPH. The goal at these times is to achieve a glucose level less than 180 mg/dl.

Oral diabetes agents are not recommended in CFRD except in the context of research studies. There are theoretical reasons to avoid each of the presently available agents, and the few data available on their use in CF have not been promising. Anecdotal clinical experience suggests that they are not helpful in the patient with fasting hyperglycemia. Their role in CF patients without fasting hyperglycemia is more controversial. Studies are underway to determine whether oral diabetes agents in these patients improve insulin secretion and nutritional status.

Dietary Management
The dietary management of CFRD is critical for the health and survival of these patients, and is very different from that of type 1 and type 2 diabetes. Calorie restriction is never appropriate in CF. Being underweight is associated with significant mortality, and these patients work very hard to consume an adequate number of calories to maintain weight and normal growth.

For the patient on insulin therapy, the method called 'carbohydrate counting' offers the greatest degree of flexibility while allowing achievement of excellent blood glucose control. Patients 'count' how many grams of carbohydrate are in a given meal, and dose their insulin accordingly. Patients may eat as much or as little as they choose, at any time, provided they cover it with the appropriate amount of insulin.

Patients with diabetes without fasting hyperglycemia or impaired glucose tolerance are also taught the method of carbohydrate counting. While total caloric intake is not restricted, they are asked to evenly distribute the carbohydrate calories throughout the day and to avoid concentrated carbohydrate loads.

Monitoring
All patients on insulin therapy are asked to monitor blood glucose levels at least 4 times per day. Many CF patients have sensitive fingertips. Lancet devices which have adjustable depths and glucose monitoring devices that use minimal blood volumes are preferred. The glucose goal is 80-120 mg/dl (4.4-6.7 mM) fasting and less than 180 mg/dl (10 mM) 2 hours after eating.

Patients with CFRD need to be monitored and treated for the same microvascular complications (eye, kidney, nerve disease) as patients with type 1 and type 2 diabetes. If these problems are caught early, they can be treated. Regular blood pressure measurements and foot examinations should be performed. Annually, the patient should have a dilated eye examination and assessment of urine albumin (protein) concentration.

Hyperlipidemia and macrovascular disease (heart disease, stroke) do not appear to be of concern in CF, but this notion may change as CF patients live longer. A baseline lipid profile (cholesterol, triglycerides) is recommended once diabetes has been brought under control.

Hypoglycemia
Too much insulin can cause a low blood sugar (hypoglycemia). Before the relatively recent availability of insulin lispro, symptomatic hypoglycemia was quite common 3-4 hours after meals or during the night. In our experience, this was not severe (requiring outside assistance or causing a seizure or loss of consciousness), but it was uncomfortable for the patient. When insulin lispro is used instead of longer acting insulin, hypoglycemia is rare.

INPATIENT MANAGEMENT OF CFRD WITHOUT FASTING HYPERGLYCEMIA
During acute illness, CF patients are insulin resistant and this is a time when they are at high risk for developing diabetes. Screening for diabetes is important at this time. If fasting hyperglycemia is present for more than 48 hours, insulin therapy is usually recommended. Often, the insulin requirements are extremely large, and an aggressive regimen is needed to bring glucose levels under control.

CFRD patients who regularly receive insulin therapy require much more insulin during illness. It is not uncommon for insulin needs to quadruple. Sometimes, an unexpected rise in the insulin requirement is the first sign that a patient is becoming acutely ill. Insulin doses must be aggressively increased and then lowered as the physical stress waxes and wanes.

MANAGEMENT OF THE PATIENT WITH CFRD WITHOUT HYPERGLYCEMIA OR IMPAIRED GLUCOSE TOLERANCE (IGT)

There are no guidelines for management of CFRD without fasting hyperglycemia because so few data are available. The risks of this condition are not known. Currently in the US, insulin therapy is not routinely recommended unless symptoms of diabetes are present such as poor growth, inability to maintain normal weight, or an unexpected decline in pulmonary function.

Because these patients may be at risk for microvascular complications, routine screening should be performed as in other patients with diabetes. Clearly, they are at risk for progression to fasting hyperglycemia, and thus periodic monitoring of blood glucose levels is important. We ask patients to check a glucose profile (4 glucose level determinations per day) one day per month and during times of illness.

In individuals who do not have CF, there is no evidence that impaired glucose tolerance is a risk factor for microvascular disease. There are no data in CF. CF patients with IGT do have a greater risk of progression to diabetes than those with normal glucose tolerance, and should be monitored with annual oral glucose tolerance testing.

PROGNOSIS
The additional diagnosis of diabetes is associated with a poorer prognosis in CF. Patients with CFRD are more underweight and have worse pulmonary function than those without diabetes. We have found that the degree of insulin deficiency correlates with the rate of future decline in pulmonary function.

We believe that insulin deficiency in CF leads to abnormal protein breakdown, and thus negatively influences weight, pulmonary function, and ultimately, survival. Aggressive replacement of insulin may be able to reverse this process. In Denmark, Susanne Lanng and her colleagues found that insulin therapy reversed negative changes in weight and lung function that began several years before diabetes was diagnosed.

CONCLUSION
Diabetes is common in CF. Because of its insidious onset, it is important that patients are screened for this disease. Although CFRD shares many features with type 1 and type 2 diabetes, it is a distinct clinical entity that requires a unique approach.

Aggressive therapy is necessary to prevent nutritional and perhaps microvascular complications of insulin deficiency. Flexibility in the treatment regimen, attention to nutritional issues, and adjustment for frequent acute illness are critical.

ABBREVIATIONS

CF	Cystic fibrosis
CFRD	Cystic fibrosis related diabetes
FH	Fasting hyperglycemia
IGT	Impaired glucose tolerance
OGTT	Oral glucose tolerance test

Antoinette Moran, M.D.
Department of Pediatrics,
University of Minnesota,
Minneapolis,
Minnesota.

Editor's Note: Dr Moran has supplied us with a list of recommended reading for this topic. For a copy of this list, please contact us: editor@iacfa.org