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Subjects with diabetes mellitus have been shown to have higher morbidity and mortality from pulmonary infection than those with normal BG.108–111 _{A review by Ardigo et al.}112 _{concluded that} although the effect on lung function might be quite small (a reduction of 8%, related to vessel wall thickness, leading to stiffness and impaired gas exchange), this would be enough to cause problems when lung function was threatened by other comorbidities. They also noted the poorer outcomes in pneumonia in people with diabetes.

Niranjan et al.113 _{found that patients with T1DM demonstrated significant impairments in lung} volume and maximal O₂ uptake, compared with control subjects without diabetes, but that these could be reduced by improved glycaemic control [in this case, using continuous subcutaneous insulin infusion (CSII)].113

Chance et al.114 _{found that gas exchange was impaired in T2DM, and that the reduction was} associated with microvascular disease and with elevated levels of HbA_1c. They assumed that the lung damage was probably due to microvascular disease affecting the very extensive pulmonary capillary bed, but wondered if abnormal connective tissue metabolism could also lead to stiffness. Weynand et al.,115 _{in a small series of six deceased diabetics and six non-diabetic control subjects,} found that diabetes causes thickening of the pulmonary basal lamina. In a subset of the Fremantle Diabetes Study patients with T2DM, Davis et al.116 _{found that FVC fell over time, by about 1% a} year, lung function started to decline before diabetes was diagnosed, and there was an association between impaired lung function and mortality, with a 12% increase in all-cause mortality for every 10% reduction in FEV₁.

Black et al.53 _{reviewed evidence on the effects of diabetes on the lung for a Health Technology} Assessment (HTA) review of inhaled insulin and noted:

TABLE 4 Classification of glucose tolerance in patients with CF

Abbreviation FPG Two-hour post 75 g glucose load

CF patients with NGT NGT < 7.0 mmol/l < 7.8 mmol/l

CF patients with IGT IGT < 7.0 mmol/l 7.8–11.0 mmol/l

CFRD without FH CFRD – FH < 7.0 mmol/l ≥ 11.1 mmol/l

■ There is a loss of lung elasticity and recoil in diabetes and a greater rate of decline in lung function with age compared with non-diabetic subjects. As a result, the lungs become stiffer and harder to inflate and deflate. This is reflected in reductions in FEV₁ and FVC.

■ The diffusion capacity is slightly reduced. This is measured by the diffusion of carbon monoxide from the alveoli, across the epithelium and into the blood. The diffusion capacity is probably reduced owing to thickening in the alveolar epithelium and the pulmonary capillary basal lamina. Changes have been seen in arterioles and capillaries of the lung, which are similar to those in the diabetic kidney, although less marked.

There are several mechanisms by which elevation in airways secretion glucose concentration might be related to increased frequency and severity of pulmonary infection.117 _{The air spaces are} lined with a thin layer of fluid which normally contains little or no glucose,118 _{but the level can be} increased by both hyperglycaemia and inflammation, both of which occur in CF. The presence of glucose encourages the proliferation of colonising and infective microorganisms. It may also foster virulence.117 _{Increased glycosylation of both immune proteins and epithelial cells might} further impair local defences.118 _{Optimising glycaemic control, and so maintenance of normal} or near-normal concentration of glucose in airways secretions, could be a significant factor protecting patients with CF from intercurrent and chronic microbial infection.

Deterioration in pulmonary function is now well reported in those with CFRD.15,119,120 _{Adler et} al.121 _{noted reductions in FEV}

1 and FVC in both CFRD and CFIGT. It is concerning that this decline is seen from at least 2–4 years before diabetes is diagnosed using the standard OGTT.32,122 In non-diabetic adults, lower FVC and FEV₁ were associated with higher fasting glucose,123,124 _and with hyperinsulinaemia and estimated insulin resistance.125–127

McKeever et al.86 _{used data from the National Health and Nutrition Examination Survey} (NHANES) to examine the effect of hyperglycaemia below diabetes levels. They found a correlation between 2-hour OGTT glucose in the IGT range and reduced FEV₁ and FVC. This association was seen also if the HbA_1c level was raised, but there was no clear link with FPG. Decline in pulmonary function, even before the classical definition of diabetes mellitus has been achieved, was reported by Schaedel et al.128 _{from Sweden. They followed up 343 patients with} CF (out of a prevalent total of 475 for all of Sweden), who all had at least two sets of pulmonary function tests (PFTs), and examined the effects on lung function of genotype, gender, pancreatic exocrine sufficiency, Pseudomonas colonisation, diabetes and liver disease. There was a faster decline in PFTs in those with diabetes, but this was seen only in the over-15-year-olds. One problem with interpretation was the close link between diabetes and pancreatic insufficiency – all of those with diabetes had pancreatic insufficiency. This raises the possibility that the mechanism is via undernutrition, leading to poor lung function.

Milla et al.,15 _{from Minnesota, reviewing the previous studies, noted that a number of studies} suggested a cause-and-effect relationship between insulin deficiency and decline in health. However, most of these were retrospective, making it difficult to decide whether glucose intolerance accelerated the decline or whether the sickest patients were more likely to get diabetes. Therefore, they carried out a prospective study of 152 patients who did not have CFRD with FH, divided into three groups by OGTT:

■ NGT – 45% ■ IGT – 39%

Over the 4-year follow-up period, lung function declined in those with IGT and CFRD without fasting hyperglycaemia (CFRD – no FH), but not in those with baseline NGT. Interestingly, there was an association between baseline insulin production and lung function decline, with the highest decline in those with the lowest quartile of baseline insulin. However, insulin levels did not correlate with the glucose groups. This suggests a direct relationship between insulin and lung function, rather than it all being related to PG. Milla et al.15 _{speculate that this may be related to} the catabolic effect of insulin deficiency.

Lanng et al.122 _{reported that FEV}

1 and FVC were reduced (by 20% and 10%, respectively) 6 years prior to the diagnosis of CFRD. Koch et al.,14 _{from the European Epidemiologic Cystic} Fibrosis Registry, also noted that FEV₁ was reduced in those patients with CFRD compared with those with CF alone. Brown et al.129 _{found a reduction in lung function prior to diabetes only} in females.

Studies of the effect of insulin show that the decline in lung function is halted after insulin is started. Drummond et al.130 _{reported a steady decline in the 5 years before insulin was started,} and a plateau afterwards, and recommend treatment at the IGT stage.

Glucose is not usually detectable from the airways secretions of those with normal BG, but is found in such fluids in those with hyperglycaemia. Wood et al.131 _{determined the BG threshold at} which glucose became detectable in nasal secretions by raising BG concentrations in 12 healthy human volunteers (using either a 20% dextrose intravenous infusion or a 75-g oral glucose load) and then measuring nasal glucose concentrations with modified glucose oxidase strips. An airway glucose threshold of 6.7–9.7 mmol/l was identified (n = 12). Nasal glucose was never as high as BG and fell in parallel.

The presence of such a threshold, along with the concentration of BG being constantly higher than that of nasal secretions, was said to suggest that an active glucose transport system in the airway epithelium maintained low glucose concentrations in normal subjects. As BG was detected in the nasal secretions of usually normoglycaemic individuals who had BG raised with an insulin infusion or measured oral glucose load, it was postulated that people with hyperglycaemia would daily experience prolonged periods of glucose in their airways secretions. So a short peak of hyperglycaemia after meals might cause longer periods of high glucose levels in the fluid lining the airways.

Brennan et al. have carried out a number of studies examining the relationship between BG and airway glucose. Having noted that the presence of glucose in airway secretions was associated with increased infection in people intubated in intensive care, they hypothesised that a similar effect might be seen in CFRD. In a 2005 study,132 _{they studied breath condensates in groups of} healthy volunteers (n = 23), people with CF with (n = 10) and without (n = 10) CFRD, and people with diabetes but not CF (n = 17). Glucose levels in breath condensates were low in the healthy volunteers, but raised in the other groups. However, the levels were higher in those with CF than in those with just diabetes, leading Brennan et al.132 _{to conclude that the airway glucose} was raised by both hyperglycaemia and inflammation. The highest levels were seen in those with CFRD.

In a study published in 2007, Brennan et al.133 _{compared BG and airway secretion glucose (using} nasal secretions), but added studies of the growth rates of S. aureus and P. aeruginosa. They found that glucose was present in airway secretions in 85% of cases when BG levels were > 8 mmol/l, but in only 19% (but none with high airway glucose) when it was < 8 mmol/l. It was also higher (0.5–3.0 mmol/l) in the former than the latter (0.5–1.0 mmol/l). People with CFRD had PG levels of > 8 mmol/l for 45% of the day compared with 6% in people with CF but NGT, and 1% in

healthy volunteers. S. aureus growth increased once glucose concentration reached 0.5 mmol/l, and P. aeruginosa growth increased at 1–4 mmol/l.

The relationship between PG and airway glucose in bronchial secretions was similar to that seen in the intensive care unit study,118 _{in which glucose was found in 70% when PG level was} ≥ 8 mmol/l but in only 16% when it was < 8 mmol/l.