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The incidence of diabetes is related to duration of CF, and with the significantly improved survival into adulthood, more are surviving long enough to develop diabetes. Dodge and colleagues (2005)4 _{reported that CF was no longer an important cause of death in children in the} UK. Better treatment means that about half are expected to survive beyond the age of 50.5 _{So a} higher proportion will develop diabetes than in the past.

The proportion that develops CFRD depends on age at which prevalence is reported, comprehensiveness of screening, genetic factors, and possibly other factors (to be determined from the systematic review). Reports of the prevalence of CFRD have risen from 3–10% in 1969,

to 14–30% in the early 1990s (see Mackie 2003 for review).6 _{Similar numbers have impaired} glucose tolerance (IGT). The average age at onset is 20. In the over-30s, about 40% have diabetes and 30% have IGT.7

The UK Cystic Fibrosis database (2004) reported that 39% of those over 10 years and who had been tested, were diabetic. For the over 30-year olds it was 59%. 47% of the over 10s had not been tested. In the 15 year olds, 9% had diabetes and another 8% were classed as glucose intolerant. CFRD is characterised by insulin deficiency,8 _{with an approximately 50% loss in β-cell mass,} which is similar to that seen in type II diabetes mellitus patients.9 _{This occurs after fibrosis and} fatty infiltration of the pancreas.8 _{Many, but not all, of the islets are destroyed.}7 _{The glucagon and} pancreatic polypeptide secretions are also reduced,7 _{because whole islets are destroyed, unlike the} β-cell specific defect seen in type 1 diabetes.10 _{Islet amyloid deposits are also within the β-cells.} However, it is not clear if the amyloid accumulates during the disease process or if it contributes to β-cell dysfunction.6

So CFRD does not fit into the definitions of either type 1 or type 2 diabetes. It is more like T2DM in that there are functioning islet cells, but with a reduced total beta cell capacity. However patients are not overweight and are not, at least initially,10 _{insulin resistant, though those with} IGT appear more likely to have insulin resistance, and others may have resistance during infective exacerbations (see Brennan 2004 for review).11 _{It also resembles T2DM in that onset can be} insidious (hence the putative need for screening). However treatment is usually with insulin because of the reduced beta cell mass, though sulphonylureas have been used. Repaglinide has also been shown to reduce postprandial glucose, though not as effectively as insulin lispro.12 As people with CF live longer, they may acquire not only diabetes but its complications such as retinopathy and nephropathy.13–15 _{However two complications are particularly important. The} first is the direct effect of diabetes on the lung. The second is increased growth of some bacteria due to elevated glucose levels in pulmonary tissue and secretions.

Lung function in diabetes mellitus

Diabetes itself can affect the lung. This was reviewed in detail in our technology assessment report on inhaled insulin (to be published in September – full version available on request). In brief:

■ diabetes is associated with loss of lung recoil, and a greater rate of decline in lung function with increasing age than in normal subjects. This makes the lungs a little stiffer to inflate/ deflate. The pulmonary function tests which measure the ability to breath out rapidly (forced expiratory volume in one second – FEV – and the volume of air expelled after a deep breath – forced vital capacity or FVC) show some reduction

■ there are changes in small blood vessels, similar to those seen in the kidney but less marked ■ the diffusion capacity, as measured by diffusion of carbon monoxide (DLco),

is slightly reduced, probably due to changes in the alveolar epithelium and the pulmonary microvasculature.

In diabetes, pulmonary effects are slight and usually subclinical. However in people with CF, in whom pulmonary function is impaired, the changes due to diabetes itself may have a greater impact. It is also worth noting that some of the microvascular changes considered characteristic of diabetes, may also be seen in IGT. In the Diabetes Prevention Programme, 10% of those with only IGT had retinopathy.16

Some of the lung changes appear to be related to control, so if treatment improves control, it might have beneficial effects on lung function. Insulin treatment has been reported to improve lung function.17

Bacterial growth

Brennan and colleagues18 _{reported that elevated blood glucose levels led to elevated glucose in} the airways, and that growth of S. aureus and P. aeruginosa was increased when airway glucose was elevated.

2.3. Terminology

In this proposal, the following categories of glucose status will be used.

1. Normal glucose tolerance. Normal glucose tolerance (NGT) requires both fasting PG of under 5.6 mmol/l, and 2-hour under 7.8 mmol/l 2 hours after a 75g glucose load.

2. Diabetes is defined as fasting plasma glucose over 7.0mmol/l and/or 2-hour OGTT level of over 11.1 mmol/l, except that the diagnosis must be confirmed – a single glucose level is not enough.

3. Impaired glucose tolerance (IGT) is based on a 2-hours OGTT level of 7.8 to 11.1 mmol/l. 4. Impaired fasting glucose (IFG) means a fasting PG between 6.1 and 6.9 mmol/l, as used by

WHO (Alberti 1998). The American Diabetes Association defines it at a lower threshold of 5.6 mmol/l. The WHO system does not give any name to those with FPGs of 5.6 to 6.0mmol/l, who are above normal but under the IFG threshold.

5. Postprandial hyperglycaemia (PPG). There are patients in whom PG after a meal is abnormally high for the first hour or so, but returns to normal by 2 hours. The term ‘lag storage’ has been used in the past. Unpublished data from the Royal Hospital for Sick Children in Glasgow (Craigie and colleagues, submitted for publication) show that many patients have high PG levels at 30, 60 and 90 minutes but normal fasting and 2-hour levels. Some of these results are into the range for random blood glucose at which diabetes would be diagnosed.

The WHO criteria for diabetes are based on the risk of harms such as retinopathy. It may be that the threshold for harm in cystic fibrosis, such as bacterial growth, may have a different threshold, and one by-product of this review, or of subsequent primary research, may be to produce a definition of CFRD.

We also need to take into account the occurrence of temporary disturbances of glucose regulation in CF, for example during infectious episodes or steroid treatment.