**3.2. Insulin sensitivity in CF**

appropriately [17]. It seems likely that the same mechanism might also prevent incretin hormones (e.g. GLP-1 and GIP) from evoking their physiological insulinogenic effect during the post-prandial period, although this is an area still under investigation (see below).

Loss of pancreatic endocrine function is a continuum in patients with CF with impaired release of both insulin and glucagon [18]. Those with significant pancreatic insufficiency (almost 90% of patients with CF use pancreatic enzyme supplements [5]) have deranged glucose handling even if not formally diabetic [17], typically displaying a slow and prolonged insulin response

The initial abnormality seen in CF patients is a delayed first-phase insulin response combined with preserved total insulin secretion that occurs in response to various stimuli even in CF subjects with normal glucose tolerance [10, 18, 20, 21, 22, 23]. Even at this early stage, patient outcomes can be affected and the loss of pulmonary function is directly related to the degree of dysglycaemia [6]: this has implications for CFRD screening and diagnosis (see below).

The CFTR mutation also causes rapid absorption of glucose from the small intestine compared to the non-CF gut [23]. This combination of rapid glucose absorption and slow prolonged insulin response helps to explain both the typical high post-prandial glucose excursions seen in this group (Fig. 2) (an independent marker of worsening clinical status prior to a formal CFRD diagnosis [10]), as well as the symptomatic hypoglycaemia (often termed reactive or rebound) that may develop several hours later, as insulin continues to be secreted despite falling glucose levels (see Fig. 2) [24, 25]. A tendency to spontaneous hypoglycaemia may be further exacerbated by intense periods of exercise, something that forms a cornerstone of

Italicised – unclear role. Purple – factors predisposing to reactive hypoglycaemic episodes

Fig 2. Continuous glucose monitoring

**Figure 2.** Continuous glucose monitoring showing a typical glucose profile seen in CFRD

showing a typical glucose profile seen in

Table 2. Diagnostic criteria for CFRD (any

• 2-hr 75g OGTT plasma glucose

• Fasting plasma glucose ≥7.0

• HBA1C ≥6.5% (A1C <6.5% does

• Classical symptoms of diabetes

presence of a casual glucose

level ≥11.1 mmol/l

not rule out CFRD because this

value is often spuriously low in

(polyuria and polydipsia) in the

result ≥11.1 mmol/l

of the following)

mmol/l

CF.)

to stimulation [18, 19].

No. Delete Replace with

3 16 Please add caption Factors influencing glucose handling in CF.

Proof Corrections Form

90 Cystic Fibrosis in the Light of New Research

Author(s) Name(s): Paula Dyce, Gareth Huw Jones & Martin Walshaw

4 16 (10, 18, 20, 21, 22, 23) [10, 18, 20, 21, 22, 23]

Chapter Title: Cystic Fibrosis Related Diabetes

4 11 [Registry data] [5]

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6 26 Add

treatment in CF [11] (see below).

The role of insulin sensitivity in the development of CFRD is unclear: CFTR may have a theoretical role in cell signalling to increase glucose uptake by peripheral tissues but such responses are predominantly mediated through GLUT receptors. Insulin resistance increases during periods of acute illness [33] including pulmonary exacerbations which may frequently occur in those with an underlying suppurative lung condition. Hardin et al. [34] suggested that insulin sensitivity may be abnormal even in clinically stable CF patients, where on-going indolent infection may up-regulate inflammatory pathways, thereby inducing a degree of chronic insulin resistance.

However, despite these mechanisms, it is relatively rare for pancreatic-sufficient CF individ‐ uals, even when colonised with pathogens and suffering regular exacerbations, to develop significant dysglycaemia [35] and overall it has been shown that insulin resistance is not a major determinant of the development of diabetes in CF [36].

It is recognised that at times of high inflammatory stresses or concurrent glucocorticoid use – such as during a pulmonary exacerbation – insulin resistance may contribute to or unmask clinically relevant dysglycaemia in predisposed individuals [17, 30, 34] and extra glucose monitoring is therefore recommended during such periods [37] since initiation or escalation of treatment may be required [30]. As the nutritional aspects of CF care are increasingly well addressed particularly by the early institution of highly effective pancreatic enzyme supple‐ mentation, it is becoming increasingly common for patients with CF to have a raised BMI indeed almost a quarter of patients in one recent series were reported to be overweight or obese [38]. It may be that in future, insulin resistance will play a larger role in the development of dysglycaemia in this population.

### **3.3. Other factors**

1

Not all CF individuals with pancreatic insufficiency develop CFRD, raising the possibility that other genetic factors might play a part [39].

However, with few exceptions, antibodies associated with the development of T1DM have not been found in CFRD [40-42]. Genetic variation in the CAPN10 gene, which encodes Calpain-10, may be a common risk factor for the development of both CFRD and T2DM [43], explaining

in part why CF individuals with a familial history of T2DM are at increased risk of developing CFRD themselves [35] despite a lack of insulin resistance.

It seems likely that genetic modifiers have a significant role in determining to what extent dysglycaemia complicates the clinical course of an individual with cystic fibrosis. [35].

Glucose handling may also be disturbed in individuals with CF-related liver disease, partic‐ ularly in severe cases where the hepatic uptake and storage of glucose is diminished, poten‐ tially rendering treatment for hypoglycaemia with exogenous glucagon ineffective. Chronic kidney disease, which may develop in CF because of recurrent uroliathiasis/nephrocalcinosis, repeated exposure to nephrotoxic medications or indeed as a complication of CFRD itself, may also effect glucose regulation.

Although it is unclear how important this is for overall blood sugar control, severe renal failure may lead to an accumulation of exogenous insulin therapy causing an apparent improvement in diabetic control (if judged by insulin requirements) as well as predisposing to hypoglycae‐ mic episodes.

Incretin hormones released from the bowel are a major determinant of pancreatic responses in the post-prandial period, causing significantly more insulin to be secreted compared to the presence of glucose alone – this so-called incretin effect is lost in T2DM and a range of treatments that target components of the diffuse endocrine system have revolutionised the treatment of this condition. Whilst it has been shown that enteroendocrine cells are present in the expected amounts in the bowels of both animal models and direct intestinal biopsies from children with CF [44, 45], the incretin effect itself has not been definitively investigated in a CF setting, with various small-scale studies showing conflicting results. Whether or not the incretin system is attenuated in CF, it is unclear whether augmenting its function pharmaco‐ logically would in any way improve the responses of a pathologically damaged pancreas.

Considering the mechanisms above, it is clear to see that although CFRD has a number of features in common with both T1DM and T2DM it is clearly significantly different to both – a comparison of CFRD with the more common forms of diabetes is shown in Table 1.


**Table 1.** Comparison of CFRD with other forms of diabetes
