© Borgis - New Medicine 1/2003, s. 8-11
Agnieszka Szypowska, Ewa Pańkowska
Cystic fibrosis-related diabetes
Department of Paediatric Diabetology and Birth Defects, Medical University of Warsaw
Head of the Department: Lech Korniszewski, MD, PhD
Summary
Cystic fibrosis-related diabetes has become increasingly common with the increased longevity of patients with cystic fibrosis. Identification of patients with abnormal glucose tolerance is important, because they are at greater risk of deterioration of lung function. Accelerated weight loss and deterioration of pulmonary function have been reported to occur up to 4 years before diabetes develops. They are also at risk for the development of microvascular complications. Diabetes might adversely affect cystic fibrosis morbidity and mortality rates and pulmonary function. The pathophysiology, clinical manifestation, diagnosis, and management of cystic fibrosis-related diabetes are reviewed.
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).
Common forms of diabetes mellitus
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 |
Epidemiology
Incidence in population at risk
Presentation
Peak at age (yrs)
Genetic markers HLA
Immunology
Islet cell autoantibodies
Hormonal status
C-peptide levels
Fasting insulin levels
Early phase insulin secretion
Overall insulin production
Glucagon levels
Clinical features
Nutritional status
Acute complications
Long term complications
Insulin responsiveness
Response to sulfonylureas |
1%
Abrupt
10-19
HLA types DR3, DR4
Present at onset
Absent or very low
Absent or very low
Absent
Very low
Elevated
Thin or normal
Common
Common
Normal
Unresponsive |
10%
Gradual
> 40
No specific HLA types
Absent
Normal
Normal or increased
Delayed
Normal or increased
Elevated
Obese
Uncommon
Common
Impaired
Responsive |
8-15%
Gradual
20-25
No specific HLA types
May be present secondarily
Decreased
Decreased
Reduced and delayed
Decreased
Normal or low
Thin
Uncommon
Possible
Normal or increased |
HLA – human leukocyte antigen (3).
Pathophysiology
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).
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Piśmiennictwo
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