Department of Paediatric Diabetology and Birth Defects, Medical University of Warsaw
Head of the Department: Lech Korniszewski, MD, PhD
Cystic fibrosis is an autosomal recessive systemic disease that affects about one out of every 2500 children. In recent years, as respiratory and nutritional therapies have improved for patients with cystic fibrosis, their life expectancy has increased dramatically. The current median life expectancy is about 30 years. Many patients with cystic fibrosis live to their third, fourth, or fifth decade (1).
Cystic fibrosis-related diabetes is becoming an increasing problem as more individuals with cystic fibrosis survive into adulthood. Impaired glucose tole-rance occurs in 40% of patients with cystic fibrosis (2). The incidence of diabetes increases with age. Diabetes mellitus affects 5% to 15% of patients with cystic fibrosis overall, but as many as 30% of adult patients (3). The prevalence of diabetes mellitus in patients with cystic fibrosis varies among populations. In North America it ranges between 2.5% and 7.6%, whereas in Denmark it is 14.7% (4,5). Because patients with cystic fibrosis rarely have ketosis, diabetes may frequently be undiagnosed or undetected. The prevalence of diabetes may therefore be higher (6).
A recent study found that diabetes mellitus is more likely to affect DF508 homozygous patients. The results suggest that the high frequency of diabetes mellitus in the Danish cystic fibrosis population could be in part related to the high frequency of the DF508 mutation in their population (7, 8).
As patients with cystic fibrosis survive longer because of new treatments that target the control of pulmonary complications and infection, diabetes is expected to become one of the major causes of morbiolity and death. Sixty percent cystic fibrosis patients without diabetes survive to age 30, whereas fewer than 25% with diabetes mellitus survive to this age (9, 10).
Cystic fibrosis-related diabetes is different from either type 1 or type 2 diabetes. All forms of diabetes mellitus are characterised by inability to maintain normal levels of blood glucose and an absolute or relative deficiency of insulin.
Type 1 diabetes, caused by autoimmune destruction of pancreatic beta cells, leading to complete dysfunction of insulin secretion, is associated with specific HLA-genotypes and the presence of islet cell autoantibodies. Type 1 diabetes probably occurs in cystic fibrosis with the same frequency as in the general population. Patients may develope microvascular complications, including retinopathy, nephropathy, and neuropathy.
Type 2 diabetes is a disease whose pathogenesis may show from peripheral insulin resistance, and abnormal beta cell function. Typically, type 2 diabetes occurs after the age of 40 years. The patients do not commonly have ketoacidosis. They are at risk of having microvascular and macrovascular complications (11).
Cystic fibrosis-related diabetes is different from either type 1 or type 2 diabetes. It usually occurs in patients with an age at onset of 18 to 21 years. Why some patients with cystic fibrosis develop diabetes and why others do not is uncertain, but some researchers suggest that particular patients may have a genetic predisposition to beta cell dysfunction (12). Diabetes may be more likely to affect individuals who are homozygous for the most common mutation, DF508 (8). Some of the differences between the common forms of diabetes mellitus are summarized in table 1.
Table 1. Comparison between common forms of type 1 diabetes mellitus (type 1 DM), type 2 diabetes mellitus (type 2 DM), and cystic fibrosis-related diabetes mellitus (CF-DM).
| ||type 1 DM||type 2 DM||CF-DM|
Incidence in population at risk
Peak at age (yrs)
Genetic markers HLA
Islet cell autoantibodies
Fasting insulin levels
Early phase insulin secretion
Overall insulin production
Long term complications
Response to sulfonylureas
HLA types DR3, DR4
Present at onset
Absent or very low
Absent or very low
Thin or normal
No specific HLA types
Normal or increased
Normal or increased
No specific HLA types
May be present secondarily
Reduced and delayed
Normal or low
Normal or increased
HLA – human leukocyte antigen (3).
Diabetes and impaired glucose tolerance in cystic fibrosis result from insulin deficiency. Obstruction of the pancreatic ducts by thick viscous exocrine secretions leads to progressive damage to both the exocrine and endocrine pancreas, and fibro-adipose replacement of the pancreatic tissue (13).
Fibrosis and fatty infiltration of the exocrine pancreas disrupt the islet architecture and destroy many, but not all, of the islets. Pancreatic tissue from patients with cystic fibrosis, both with and without diabetes, shows an overall loss of islet cells and alteration of the proportion of cells. Patients with cystic fibrosis-related diabetes mellitus have a more severe loss of insulin-secreting beta cells, a relative increase of somatostatin-producting delta cells, decrease in pancreatic polypeptide-secreting (PP) cells, and diminished or unchanged glucagon-secreting alpha cells (3).
Somatostatin inhibits the secretion of both insulin and glucagon. It may play a physiological role as a paracrine regulator of insulin secretion. Increased somatostatin could worsen the deficient insulin response by inhibiting beta cell function locally.
Islet tissue from patients with cystic fibrosis-related diabetes mellitus frequently contains amyloid deposits similar to those seen in patients with type 2 diabetes mellitus. Amyloid accumulation may simply be a consequence of the diabetic process, or it may be a contributor to beta-cell dysfunction. Whether such amyloid plays an essential role in the dysfunction or loss of beta cells is unknown, but its presence suggests that the pathogenesis of cystic fibrosis-related diabetes may have features in common with the pathogenesis of type 2 diabetes mellitus (3, 14, 20).
Clinical manifestation and diagnosis
Because of the reduced number of beta cells, patients with cystic fibrosis-related diabetes are insulinopenic. In these patients, first-phase insulin secretion is impaired. Patients with cystic fibrosis without diabetes also have a reduced first-phase insulin response (3).
Glucose intolerance and diabetes can occur as a result of increased resistance to the effects of insulin, associated with acute infection or glucocorticoid therapy.
Postprandial hyperglycaemia could occur because of hyperalimentation. Glucose metabolism is further influenced by clinical factors distinctive of cystic fibrosis, including undernutrition, malabsorbtion, abnormal intestinal transit time, liver dysfunction, and increased work in breathing (3, 13).
Potential symptoms of cystic fibrosis-related diabetes include polyuria, polydipsia, failure to gain or maintain weight despite appropriate calory intake, accelerated or delayed puberty, unexplained decline in pulmonary function or increased frequency of complications. In this group ketonuria and ketosis are uncommon (15).
The diagnosis of cystic fibrosis-related diabetes is important. The majority of adult patients with cystic fibrosis have normal fasting blood glucose and glycosylated haemoglobin levels, despite abnormal glucose tolerance and impaired insulin secretion. Various methods when used alone-including random blood glucose, fasting blood glucose, glycosylated haemoglobin, and symptoms of hyperglycaemia – have not been found to be sufficiently sensitive or specific in the diagnosis of this diseases. A two-hour glucose tolerance test (OGTT) is generally regarded as the "gold standard” in the diagnosis of diabetes. It has been suggested for all patients aged 10 or above with cystic fibrosis (16, 17, 18) (Sea Table 2).
Table 2. Classification of glucose tolerance.
mmol/l (mg%)|| ||OGTT 2-hr glucose
|CF-DM with fasting hyperglycaemia||> 7.0
(126)|| ||OGTT not necessary|
|CF-DM without fasting hyperglycaemia||< 7.0
FBG – overnight fasting blood glucose level
OGTT – oral glucose tolerance test
From reference 14, modifications by the CF diabetes consensus conference of the American Diabetes Assotiation (1997) criteria for the diagnosis and classification of diabetes mellitus.
Diabetes management in cystic fibrosis
Optimal nutrition is the principle goal in case of patients with cystic fibrosis. The dietary plan is quite different from that recommended for diabetics. The energy intake for a patient with cystic fibrosis-related diabetes may be 100-200% of the recommended daily allowance, whereas for patients with diabetes alone, it may be 100% or less (3). To achieve the high calory intake, all patients should follow a diet in which 40% of the calories come from fat. Although fat intake is limited in the diets of patients with type 1 and 2 diabetes because of their high risk of cardiovascular disease, patients with cystic fibrosis-related diabetes do not appear to have the risk. The intake of mono- and disaccharides, normally restricted in diabetics, is less restricted in this group of patients to increase overall energy intake. Salt restriction is almost never indicated (19, 20).
Cystic fibrosis patients with diabetes are usually treated with anti-diabetic drugs. Insulin is recommended for children with diabetes and for adults when hypoglycaemic agents are ineffective (HbA1c1c greater than 8%, or fasting blood glucose levels averaging more than 150mg/d) (3). Insulin should be implemented for severely malnourished patients, with ketosis, or actually infected. Those patients often require more insulin to achieve glycaemia homeostasis, than age- or puberty-matched patients with type 1 diabetes. Daily management routines for patients on insulin therapy should include blood glucose monitoring at least 3-4 times a day, and a 7-point profile once a week.
Intensive insulin therapy is the chosen method for children and adolescent patients with diabetes and CF. This method imitates the natural supply of insulin. It is based on multiple injection of short-acting insulin before a meal, usually 3-4 times a day, and long or intermediate-acting insulin injected once or twice times a day as a basal insulin. Meal insulin is calculated using the insulin-carbohydrate ratio, which is individually established. This method gives the possibility of achieving near-normal postprandial glycaemia and positive calory intake. Intensive and effectively implemented insulin therapy is strongly related to the growing process, weight gain, and could reduce loss of calories.
Patients with cystic fibrosis and diabetes are at risk of the development of microvascular complications. Retinopathy, nephropathy, and neuropathy have been reported at a prevalence of 5-16%, 3-16%, and 5-21%, respectively. These patients should undergo routine screening for complications. Regular measurements of blood pressure, examination of the feet, urine albumin measurement, and annual ocular examination, are necessary to detect early signs of diabetic nephropathy, retinopathy, and neuropathy. Macrovascular compli-cations have not been described (21).
The Toronto adolescent study clearly presented the relationship between pulmonary function and hyper-glycaemia, expressed as the average level of HbA1c. Hyperglycaemia was negatively correlated with pulmonary function. Other studies carried out in ado-lescents with cystic fibrosis suggest early identification of patients with abnormal glucose tolerance. This group are at greater risk of deterioration of lung function (22). There is evidence that diabetes and even glucose intolerance might adversely affect cystic fibrosis morbiolity and mortality rates. Accelerated weight loss and deterioration of pulmonary function have been reported to occur up to 4 years before diabetes develops. Progressive clinical deterioration has also been reported. Early diagnosis of cystic fibrosis related-diabetes is important to establish adequate preventative measures (23, 24).
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