**3. Pathophysiology**

The pathophysiology of CFRD is still poorly understood. CFTR may have a role in the cell signalling that contributes to both the timely release of and response to insulin and restora‐ tion of abnormal CFTR function.

However, although Ivacaftor (which corrects the underlying gene product defect in patients with a gating mutation) has reportedly led to normalisation of sugar handling in a single individual [15], it seems likely that the pathways directly involving CFTR are of only minor significance to overall glucose homeostasis.

CFRD involves a complex interplay between a state of relative insulin deficiency, particularly during the first phase response, and variable insulin resistance during infective exacerbations. Some level of dysglycaemia is detectable in most pancreatic-insufficient patients and the hallmark of CFRD is the presence of post-prandial glucose excursions that may be followed by spontaneous hypoglycaemic episodes.

Below we consider mechanisms that contribute to abnormal glucose handling in CF.

**Figure 1. Factors influencing glucose handling in CF**. *Italicised* – unclear role. Purple – factors pre-disposing to reac‐ tive hypoglycaemic episodes

### **3.1. Pancreatic responses in CF**

**1. Introduction**

88 Cystic Fibrosis in the Light of New Research

CF care.

longer, affecting up to 50% of CF adults [1, 2].

to be associated with poorer outcomes [7].

**2. Epidemiology, prevalence and incidence**

tion, and corticosteroid use (5, 7, 13, 14).

**3. Pathophysiology**

tion of abnormal CFTR function.

Cystic Fibrosis Related Diabetes (CFRD) is a form of abnormal glucose handling (dysglycae‐ mia) that is quite different to other forms of diabetes. It is uncommon in childhood, rarely occurring in those under 10 years of age, but its incidence rises inexorably as patients survive

The development of CFRD is associated with a significantly higher mortality rate [2, 3, 4], and has adeleterious impact onpulmonary function[5] withthedegree of glucose intolerance being directly related to the decline in FEV1 [6]. Those with CFRD suffer more frequent infective exacerbations and have a higher burden of colonisation with pathogens such as *Pseudomonas aeruginosa* and *Burkholderia cepacia* as well as a poorer nutritional status – all of which are known

However, dysglycaemia is a progressive phenomenon in many CF patients, and the associat‐ ed increased morbidity occurs many years prior to a formal diagnosis of CFRD [8, 9, 10]. This has fuelled the debate as to how the diagnosis should be made – the current "gold standard" diagnostic test for diabetes mellitus (the oral glucose tolerance test, OGTT) [11] may not be appropriate in the CF population, since the optimal time to introduce treatment (currently limited exclusively to insulin-based therapies) may be at an earlier stage of dysglycaemia.

We will explore these issues as well as consider future developments in this emerging area of

Historically, CFRD was typically only seen in paediatric practice as a pre-terminal complica‐ tion in those with advanced respiratory failure. It remains relatively rare in children under the age of 10 (2), affects less than 5% of individuals during their early teen years, but the inci‐ dence rises exponentially with age, occurring in approximately 20% of adolescents and up to 50% of individuals in theirfourth decade. The average age of onset for CFRD is 18-21 years (12). Furthermore,itis estimatedthat 70-90%of all adultCFpatientswillhave somedegreeofglucose intolerance and therefore dysglycaemia is the commonest co-morbidity that complicates care in adult CF and its prevalence is likely to increase further as life expectancy continues to rise. In addition to age, other factors associated with an increased incidence of CFRD are severity of CFTR mutation, poor pulmonary function, low BMI, pancreatic insufficiency, liver dysfunc‐

The pathophysiology of CFRD is still poorly understood. CFTR may have a role in the cell signalling that contributes to both the timely release of and response to insulin and restora‐ The predominant mechanism underpinning dysglycaemia in CF patients is sluggish clearance of proteolytic enzymes from the pancreatic ducts causing progressive β-cell destruction that directly reduces insulin levels, as well as causing ischaemic damage and amyloid deposition [16], further impairing the ability of remaining islet cells to sense and respond to glucose levels Page No.

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4 25 Add

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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). Proof Corrections Form Author(s) Name(s): Paula Dyce, Gareth Huw Jones & Martin Walshaw

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 to stimulation [18, 19]. Chapter Title: Cystic Fibrosis Related Diabetes

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). No. Delete Replace with 3 16 Please add caption Factors influencing glucose handling in CF.

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 treatment in CF [11] (see below). Italicised – unclear role. Purple – factors predisposing to reactive hypoglycaemic episodes 4 11 [Registry data] [5] 4 16 (10, 18, 20, 21, 22, 23) [10, 18, 20, 21, 22, 23]

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

1

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

of the following)

mmol/l

CF.)

As progressive damage to the pancreas accumulates, there is an associated loss of endocrine tissue such that over time patients become relatively insulinopaenic [26]. Although pancreatic β-cell mass may be significantly reduced in patients with CFRD [27, 28], absolute insulino‐ paenia and ketoacidosis, typical features of Type 1 Diabetes (T1DM) [29], do not occur even in the minority of patients with sufficient pancreatic damage to cause fasting hyperglycaemia. Indeed, the presence of true ketoacidosis is so rare in this population that its occurrence should stimulate investigation for the development of concurrent T1DM [11, 30, 31]. It is possible that the loss of α-cells as part of the indiscriminate pancreatic damage that occurs in CF results in relatively low glucagon levels, protecting against the development of ketosis as well as adding to the propensity for symptomatic hypoglycaemia [32].
