Cystic fibrosis-related diabetes mellitus

INTRODUCTION — Cystic fibrosis (CF) is a life-limiting inherited single-gene disorder, and cystic fibrosis-related diabetes (CFRD) is a frequent complication for people with CF. CFRD is a distinct form of diabetes that is different from type 1 and type 2 diabetes mellitus [1]. The primary cause is relative insulin deficiency related to destruction of pancreatic islets. However, insulin resistance may also contribute to hyperglycemia, especially in association with acute respiratory exacerbations or systemic disease.

Development of CFRD is associated with worse lung function, poorer nutritional status, and more chest infections. From the 1980s onward, the diagnosis of CFRD has been associated with early mortality [2-5], particularly in females [6]. Encouragingly, more recent data show a decline in the risk of death associated with CFRD [7], which may be due to early diagnosis and insulin treatment [2,3]. Insulin is a powerful anabolic agent and insulin therapy improves nutritional status in people with CFRD [8-10]. Insulin also reduces hyperglycemia and thereby may reduce lung infections and improve lung function. However, the addition of insulin treatment necessitates glucose monitoring and may add substantially to the burden of treatment for people with CF.

The pathophysiology, diagnosis, and treatment of CFRD are discussed in this topic review. CF-associated lung disease is discussed in the following topic reviews:

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Cystic fibrosis: Treatment of acute pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Treatment with CFTR modulators".)

●(See "Cystic fibrosis: Management of advanced lung disease".)

Other aspects of CF care are also discussed separately:

●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●(See "Cystic fibrosis: Genetics and pathogenesis".)

●(See "Cystic fibrosis: Overview of gastrointestinal disease".)

●(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

●(See "Cystic fibrosis: Nutritional issues".)

●(See "Cystic fibrosis: Hepatobiliary disease".)

EPIDEMIOLOGY AND NATURAL HISTORY — CFRD is a common complication of CF encountered among individuals school-aged and older [11]. Significant hyperglycemia also has been reported in infants and young children [12]; over time, this hyperglycemia may worsen and meet the diagnostic threshold for CFRD. (See 'Diagnosis' below.)

Prevalence — The prevalence of CFRD increases with age, affecting approximately 20 percent of 20-year-olds, 30 percent of 30-year-olds, and 40 percent of 40-year-olds [13,14]. Data from the European CF Patient Registry (2008 to 2015) show that rates rise from 0.8 percent in children <10 years to 9.7 percent in those 10 to 19 years [14]. The incidence is estimated to be between 4 to 9 percent per year in the Danish population [15] and 2.7 cases per 100 individual-years [7].

Risk factors — CFRD is caused by progressive damage to the pancreas. As a result, the strongest risk factors are markers for CF-related pancreatic disease. The risk factors include:

●Severe CFTR genotype/pancreatic insufficiency – CFRD is more common in individuals with severe CF genotypes, including delta-F508 (pF508.del) homozygotes, which are associated with pancreatic insufficiency. However, CFRD has been reported in 6 percent of patients with relatively normal pancreatic exocrine function (pancreatic-sufficient) [16].

●Age – Risk for CFRD increases dramatically with age, as outlined above. (See 'Epidemiology and natural history' above.)

●Female sex – The prevalence of CFRD is higher among females, at least after 30 years of age [7]. Moreover, among patients with CFRD, women have reduced pulmonary function and survival compared with men, and this may contribute toward the overall reduced lifespan observed for women with CF [2]. (See 'Mortality' below.)

●Family history of type 2 diabetes – A family history of type 2 diabetes increases the risk of CFRD [17]. One mechanism for the observed genetic predisposition is variants in the TCF7L2 gene, which is thought to be involved in beta cell proliferation [18] and insulin secretion [19] and is known to confer susceptibility to type 2 diabetes in the general population. Gene variants in TCF7L2 among people with CF have been shown to increase their risk of diabetes approximately threefold [17].

●Cystic fibrosis-related liver disease (CFLD) – CFLD may also be associated with the development of CFRD, possibly due to reduced insulin sensitivity and secretion, or reflecting underlying systemic disease [20]. (See "Cystic fibrosis: Hepatobiliary disease".)

PATHOGENESIS

Mechanisms of impaired glucose tolerance — CF is caused by haploinsufficiency of the CFTR gene, which encodes the CFTR anion channel. This typically leads to multisystem disease including recurrent pulmonary infections, lung function decline, often with exocrine and endocrine pancreatic insufficiency resulting in CFRD. (See "Cystic fibrosis: Genetics and pathogenesis".)

CFRD is characterized by slowly progressive insulin deficiency due to destruction of pancreatic tissue. The proposed mechanism is that abnormal chloride channel function results in thick, viscous secretions, causing obstructive damage to the exocrine pancreas with progressive fibrosis and fatty infiltration [21]. This mechanism is supported by ultrasound studies demonstrating pancreatic structural abnormalities in 75 percent of children with CF under five years of age, rising to 95 percent in those older than five years and 100 percent in those over five years of age with exocrine insufficiency [22-24]. Similarly, autopsy findings in older CF subjects demonstrate disruption and destruction of islet architecture, amyloid plaques and fibrosis, and loss of islets and beta cells that are reduced more than alpha cells [25].

Other studies suggest that a developmental abnormality also contributes to the pathogenesis of CFRD. As an example, histopathology studies in very young children with CF (younger than four years of age) found no fibrosis or amyloidosis and normal islet number and mass, but low beta cell mass and reduced markers of beta cell proliferation, suggesting reduced capacity for beta cell formation [26]. Furthermore, data from a murine model suggest that beta cell loss and intra-islet inflammation rather than intrinsic islet dysfunction are important mechanisms [27]. Islet interleukin-1 beta immunoreactivity may be an early contributing factor to this process [28].

Abnormal CFTR function within the islet is not thought to be a major factor in the pathogenesis of CFRD. Although CFTR ribonucleic acid (RNA) may be expressed in a small subpopulation of human beta cells, immunocytochemistry does not identify CFTR protein co-expression with insulin/glucagon/somatostatin positive cells and CFTR modulators do not increase insulin secretion in vitro human islets [26].

Secondary mechanisms that contribute to diabetes in some individuals include liver dysfunction, and therapies such as glucocorticoids (typically used for treatment of allergic bronchopulmonary aspergillosis) and immunosuppressant therapy following lung transplantation (eg, tacrolimus).

Clinical stages — Laboratory abnormalities in CFRD depend on the stage of disease:

●Postprandial hyperglycemia – In the initial stages of CFRD, the primary laboratory abnormality is postprandial hyperglycemia (ie, hyperglycemia in response to a glycemic load), which can be detected by sensitive measures such as continuous glucose monitoring (CGM) or by performing oral glucose tolerance tests (OGTT) with sampling every 30-minutes to detect transient postprandial glycemic excursions. These abnormalities reflect impaired first-phase insulin secretion [29-31], with a small component of insulin resistance [32]. The insulin resistance becomes more prominent during acute pulmonary exacerbations, likely mediated by increases in growth hormone and cortisol, and increased catecholamines and inflammatory cytokines.

●Fasting hyperglycemia – Later stages of CFRD are characterized by fasting hyperglycemia. At this stage, hemoglobin A1c (HbA1c) may remain normal or may rise above the normal range; some individuals may develop classical symptoms of diabetes (polyuria and polydipsia) [33]. These signs and symptoms reflect worsening insulin deficiency, which is often compounded by worsening insulin resistance, particularly during acute pulmonary exacerbations or in older individuals with CF [34]. Chronic hyperglycemia may also impair insulin sensitivity by downregulation of GLUT4 transporter expression [35,36], thus creating a vicious cycle of hyperglycemia resulting in insulin resistance and worsening hyperglycemia.

Thus, postprandial hyperglycemia is the earliest and most sensitive marker of CFRD, and fasting hyperglycemia is a late phenomenon. HbA1c has relatively low sensitivity to detect CFRD but may become elevated in the later phases of the disease and is useful to monitor during treatment. (See 'Diagnosis' below and 'Treatment' below.)

Differences from other forms of diabetes mellitus — There are a number of important differences between CFRD and type 1 and type 2 diabetes, which are summarized in the table (table 1) [37]. Importantly, CFRD is only rarely associated with islet autoantibodies or human leukocyte antigen (HLA) class II types that are seen in type 1 diabetes mellitus [38,39], although coexistent classic type 1 diabetes mellitus has been described in CF patients [39,40]. Thus, the beta-cell dysfunction seen in CFRD does not appear to have an autoimmune mechanism. Ketoacidosis rarely occurs in CFRD. Some overlap with type 2 diabetes mellitus is suggested by increased risk of CFRD in those with a family history of type 2 diabetes mellitus [17].

Several unique aspects of CF influence glucose metabolism and are not commonly encountered in other forms of diabetes. These include malnutrition, acute and chronic infection, glucagon deficiency, malabsorption, abnormal intestinal transit time, liver dysfunction, increased work of breathing and elevated energy expenditure, and exposure to some CF treatments that can precipitate glucose intolerance, such as glucocorticoids and immunosuppressants following lung/liver transplantation (eg, tacrolimus).

CLINICAL CONSEQUENCES OF CFRD — There is a well-established body of evidence showing that hyperglycemia and insulin insufficiency have detrimental impacts on clinical outcomes in patients with CF. Deterioration in pulmonary function and nutrition status are often seen two to four years before formal diagnostic criteria for CFRD are met [41].

Pulmonary function — Several studies suggest detrimental effects of CFRD on both lung function and nutrition. A longitudinal study followed 152 individuals with CF and varying degrees of glucose intolerance or CFRD but without fasting hyperglycemia over four years [16]. The highest rates of decline for forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) were among the group with CFRD without fasting hyperglycemia. Participants in the lowest quartile for insulin production at baseline experienced the highest rates of pulmonary function decline over time, suggesting a relationship between insulin deficiency and clinical deterioration. Similarly, data from the Swedish registry of individuals with CF over the age of seven years described a greater rate of lung function decline in those with CFRD compared with those without CFRD [42]. An association between early abnormalities in lung function (ventilation inhomogeneity, or unevenness of gas mixing, as measured by multiple-breath washout) and insulin secretory defects (as measured by oral glucose tolerance test [OGTT]) has been reported [43].

Laboratory studies suggest that elevated glucose levels on the airway surface promote bacterial growth and cause an exaggerated but less effective inflammatory response, providing a mechanistic explanation for the observed association between CFRD and pulmonary function. One study demonstrated that individuals with CFRD had elevated airway glucose levels, as measured by nasal glucose monitoring, compared with those without CFRD [44]. Moreover, in vitro studies demonstrated that increased glucose exposure enhanced bacterial growth of Staphylococcus aureus and Pseudomonas aeruginosa, with significant changes occurring at far lower glucose levels than those documented in individuals with CF. A separate study in a mouse model of CF showed that airway hyperglycemia was associated with impaired ability to clear bacteria from the lung, despite enhanced recruitment of neutrophils to the airways [45]. Several other effects of hyperglycemia have been reported: increased lactate generation and efflux, which acidify the airway surface liquid [46]; a deleterious effect on transepithelial ion transport and epithelial repair functions [47]; and proinflammatory changes with associated impairment of airway epithelial cell potassium channel function, which is important in mucus clearance [48]. The airway glucose barrier is regulated by insulin and is dysfunctional in CF [49].

People with CF who undergo lung transplantation have more complications and a higher mortality rate if they have preceding CFRD as compared with those without CFRD [50,51]. It is hoped that with earlier and more effective treatment of diabetes, these differences in outcomes will diminish.

Nutritional status — CFRD is associated with poor nutritional status and, particularly, with a decline in nutritional status prior to its diagnosis. The nutritional impact of CFRD can be explained by the fact that insulin is a potent anabolic hormone that plays an important role in maintaining body weight and lean body mass. Insulin deficiency promotes a catabolic state with detrimental effects on nutritional outcomes. As an example, patients with CFRD (without fasting hyperglycemia) experienced a decline in body mass index (BMI) of 0.3±0.21 units over one year, and this was reversed after the initiation of insulin therapy [52]. Detrimental effects of CFRD also have been shown in milder CFRD categories. In a cohort of patients with CF and normal glucose tolerance (as defined by the OGTT), subclinical deficiencies of insulin secretion were detected by measuring the area under the curve for insulin secretion over the 120 minutes of the OGTT, and greater impairment in insulin secretion was associated with the lowest BMI [53]. Similarly, another study demonstrated that abnormalities in glucose homeostasis prior to the development of overt CFRD were associated with preceding declines in weight Z-score [54].

Vascular complications — CFRD is associated with significant microvascular complications, including retinopathy [55], neuropathy, and nephropathy. Historically, these complications have not been an important contributor to mortality for people with CFRD (unlike other forms of diabetes), but this may change with advances in treatment for pulmonary disease and related increases in longevity. Microvascular complications can develop after short diabetes duration [56], and regular surveillance for to identify these complications is recommended. (See 'Monitoring for complications' below.)

The prevalence of microvascular complications is illustrated by a large cohort of patients with CFRD, peripheral neuropathy and symptoms consistent with diabetic gastroenteropathy were each seen in 52 percent of patients [57]. This frequency of neuropathy and diabetic gastroenteropathy was similar to that in patients with longstanding type 1 or type 2 diabetes. Among those with fasting hyperglycemia, 16 percent had retinopathy and 14 percent had nephropathy (indicated by moderately elevated albuminuria). These frequencies were somewhat lower than for type 1 diabetes, but the complications tended to appear at lower levels of HbA1c [57,58]. Separate case reports have described severe retinopathy in individuals with CFRD and poor glycemic control, with proliferative retinopathy complicated by blindness despite laser therapy to the retina [59]. Other reports from CF clinics have also described peripheral neuropathy, retinopathy, and nephropathy, which were generally associated with poor glycemic control and arose after 10 years of diabetes duration [4,60,61]. Diabetic gastroenteropathy including gastroparesis also occurs in CFRD and may contribute to gastrointestinal symptoms. Antibiotic use also may contribute to the risk of peripheral neuropathy.

Macrovascular disease may occur in CFRD but is uncommon. Myocardial disease has been found at postmortem examinations [62], and symptomatic myocardial infarction has been described in a few case reports [63,64]. Noninvasive measures of arterial stiffness, as a marker of large vessel disease, are higher in patients with CF and CFRD as compared with non-CF controls, without increases in blood pressure [65], supporting the notion that CFRD increases the risk for cardiovascular disease. Of note, the advent of CFTR modulator therapies has been associated with increased longevity and weight gain, sometimes leading to obesity and adverse cardiovascular risk factors; it is possible that these factors will increase the frequency of macrovascular disease among people with CF [66,67].

Mortality — CFRD has been associated with increased mortality, especially in females, and this detrimental effect is greatly attenuated by early diagnosis and treatment. One report described the clinical course of 872 CF patients treated at a single center in Minnesota during three consecutive intervals: 1992 to 1997, 1998 to 2002, and 2003 to 2008 [7]. Mortality in patients with and without CFRD significantly decreased over time. In females, the mortality rate halved from 6.9 to 3.2 deaths per 100 patient-years between the first and last study periods; in males, the mortality rate dropped from 6.5 to 3.8 deaths per 100 patient-years. Thus, early diagnosis and effective treatment of CFRD eliminated the sex gap in mortality and also narrowed the gap in mortality between those with and without CFRD. An analysis of patient data from 2008 to 2012 found that the mortality rate of individuals with CFRD was still 3.5 times greater than those without CFRD, suggesting that CFRD still contributes to mortality in older age groups despite aggressive CFRD surveillance and management [68].

SURVEILLANCE — As outlined above, CFRD is often clinically silent but increases morbidity and mortality, and these effects can be attenuated by early diagnosis and treatment. Therefore, rigorous surveillance for the disorder is warranted.

When to test — All people with CF should undergo annual testing for CFRD beginning by 10 years of age, as outlined in multiple guidelines [69-72]. Testing is particularly important for individuals with deteriorating nutritional or pulmonary status, which could signal the onset of CFRD. Routine surveillance testing should be performed during a period of baseline health (ie, not during a pulmonary exacerbation), using an oral glucose tolerance test (OGTT), as discussed below. (See 'Diagnosis' below.)

It is possible that routine surveillance testing will be extended to younger children in the future; some centers begin surveillance as early as six years of age because abnormal glucose tolerance at this age predicts early progression to CFRD [73]. Abnormal glucose tolerance may develop even earlier and was detected in almost 40 percent of children with CF between three months and five years of age at one CF center [74].

In addition to annual testing for all patients, testing is suggested in the following situations [72]:

●Acute pulmonary exacerbations – During a significant acute exacerbation (eg, one that requires intravenous antibiotics or systemic glucocorticoids), screen by measuring fasting and postprandial blood glucose concentrations for the first 48 hours of treatment [69]. Patients with abnormal results should have follow up diagnostic testing with an OGTT after recovery from the exacerbation.

●Patients with enteral tube feedings – Screen by measuring blood glucose concentrations midway through and immediately after a feed, at the time of enteral tube feeding initiation and monthly thereafter.

●Pregnancy – Screen with OGTT prior to conception (if possible), at the end of both the first and second trimesters, and again 6 to 12 weeks after delivery [72]. The diagnostic criteria for gestational diabetes are the same as for pregnant people without CF [69,75]. Women with CF are at increased risk for gestational diabetes, but positive results of testing during pregnancy are considered to be gestational diabetes rather than CFRD. CFRD is diagnosed if the diabetes persists after delivery. Rigorous screening is important because CFRD can be detrimental to both the mother and the fetus.

Interpretation of the results is discussed below. (See 'Other diagnostic tests' below.)

Selection of tests

Oral glucose tolerance test — The best test for diagnosis of CFRD is the OGTT. Interpretation of the results is outlined in the table (table 2) and discussed below. (See 'Interpretation of the oral glucose tolerance test' below.)

Other tests

●Not recommended – Tests not recommended for surveillance purposes (due to low sensitivity) include:

•Hemoglobin A1c (HbA1c) – If HbA1c is measured, a value ≥6.5 percent is consistent with a diagnosis of CFRD, as for other types of diabetes. This threshold has low sensitivity for detecting CFRD, with only 16 percent of CF patients having elevated HbA1c values at the time of CFRD diagnosis [15]. The possibility of surveillance using HbA1c using a lower threshold of 5.8 percent has been proposed [76], but this test still performs poorly for diagnosis in comparison with OGTT [77]. Even lower thresholds (5.5 percent) may be appropriate, with sensitivity of 91 to 95 percent compared with the OGTT [78,79].

•Clinical symptoms – Symptoms are not a good method for surveillance for CFRD. In a population of pediatric CF patients in Toronto, only 2.7 percent were clinically recognized as having CFRD, but on OGTT testing of asymptomatic adolescents (aged 10 to 18 years), 17 percent were found to have impaired glucose tolerance (IGT) and 13 percent had CFRD (without fasting hyperglycemia) [80]. In this cohort, an abnormal glucose tolerance was almost exclusively found in those with pancreatic insufficiency and severe (class 1 to 3) variants in the CFTR gene.

●Possibly useful

•Continuous glucose monitoring (CGM) – CGM is highly sensitive for identifying early stages of abnormal glucose tolerance, but its clinical utility as a diagnostic test has not been established [69]. CGM is able to detect early abnormalities in glucose tolerance that may be missed by OGTT [78,81-83], but diagnostic thresholds and clinical significance of mild abnormalities have not been established for the CF population. Glucose thresholds identifying risk of CFRD have been proposed but require further validation [84]. In addition, the utility of treating CGM-detected abnormalities remains unclear, although one retrospective study suggested a beneficial effect of insulin on lung function and weight outcomes in adult patients with CGM evidence of hyperglycemia [85].

Possible utility of CGM as a diagnostic tool is suggested by numerous studies showing an association between elevated CGM glucose values and adverse clinical outcomes such as weight and lung function decline. Among patients with CF and normal OGTT results, those with higher maximum glucose values during CGM monitoring (≥11 mmol/L [200 mg/dL]) have worse pulmonary function and more P. aeruginosa colonization compared with those with lower maximum glucose values (<11 mmol/L) [53]. In participants aged 10 to 18 years, positive correlations between CGM abnormalities and the rate of lung function decline have been reported [86]. In children under six years of age, transient glucose excursions are associated with P. aeruginosa infection and pulmonary inflammation compared with no glucose excursions [12]. Furthermore, elevated CGM values can predict worsening glycemia. In adults, CGM glucose levels >200 mg/dL predicted the development of later CFRD [84].

If CGM is used, the optimal CGM metrics to monitor also remain unclear. Some examples of metrics explored are minimum daytime glucose; interquartile range; peak glucose; excursions >140 mg/dL/day (>7.8 mmol/L); percent of time within an acceptable range or, alternatively, time >140 mg/dL (>7.8 mmol/L); and standard deviation and mean amplitude of glycemic excursions [86-88].

Although CGM has not been validated as a diagnostic tool for CFRD, its utility for monitoring glucose during insulin therapy for those with established CFRD is well established [78]. (See 'Continuous glucose monitoring' below.)

DIAGNOSIS — The oral glucose tolerance test (OGTT) is the test of choice for diagnosis of CFRD and prediabetic stages of the disease. It is performed using a glucose load of 1.75 g/kg body weight (up to a maximum of 75 grams). At a minimum, plasma glucose concentrations should be measured in the fasting state and both one and two hours after the glucose load. If possible, more frequent sampling is preferred (ie, taking samples at 0, 30, 60, 90 and 120 minutes) because this defines the rise in glucose levels in a more detailed way and captures the peak glucose that may otherwise be missed [54].

In addition, testing for islet autoantibodies should be performed for selected people with CFRD and [69]:

●Initial diagnosis of CFRD at age <10 years

●Presentation with diabetic ketoacidosis

●Type 1 diabetes or other autoimmune disease in a first-degree relative

●Personal history of other autoimmune disease

Interpretation of the oral glucose tolerance test — CFRD represents one end of a spectrum of abnormalities of glucose tolerance in cystic fibrosis (CF). This spectrum is reflected in the diagnostic categories used for interpretation of the OGTT (table 2):

●Normal glucose tolerance (NGT) – Fasting plasma glucose <100 mg/dL (5.6 mmol/L) and two-hour plasma glucose <140 mg/dL (7.8 mmol/L).

●Impaired fasting glucose (IFG) – Fasting plasma glucose 100 to 125 mg/dL (5.6 to 7 mmol/L).

Because the clinical significance of IFG in people with CF is unclear, it is not generally used as a diagnostic category in the CFRD spectrum [89,90]. However, it is a common finding; in a registry study from Germany and Austria, IFG was present in 25 percent of individuals with CF at 14 years of age and was more common than IGT at all ages [89].

●Prediabetic categories

•Indeterminate glycemia (INDET) – One-hour plasma glucose peak ≥200 mg/dL (11.1 mmol/L), but normal two-hour plasma glucose and fasting plasma glucose.

This category is unique to CF. It is included in the CFRD classification system because blood glucose levels in people with CF are often elevated at the 30, 60, or 90 minute time points, then return to normal by the two-hour timepoint [54,91,92].

•Impaired glucose tolerance (IGT) – Two-hour plasma glucose 140 to 200 mg/dL (7.8 to 11.1 mmol/L).

Both INDET and IGT are important risk factors for progression to overt diabetes [33]. In one study, participants classified as INDET on OGTT were 10 times more likely to develop CFRD over the five-year study period compared with those classified as having IFG or NGT [93]. The clinical significance of these categories will become more apparent as comprehensive data become available, describing the natural history of CFRD and its pulmonary, nutritional, and microvascular complications. (See 'Clinical consequences of CFRD' above.)

●CFRD – Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L). If this result is found on the initial OGTT, repeat testing is recommended to confirm the diagnosis, unless there are symptoms of polyuria and polydipsia [69,72].

Historically, CFRD was subcategorized by the absence or presence of fasting hyperglycemia (fasting plasma glucose ≥126 mg/dL [7.0 mmol/L]). Fasting hyperglycemia usually represents a more advanced stage of disease and is associated with microvascular complications [72]. However, because treatment is beneficial for patients with and without fasting hyperglycemia, this distinction is no longer made routinely [52,69,72].

While there is a general trend from INDET to frank CFRD with fasting hyperglycemia, fluctuation between severity stages may occur. As an example, in a four-year study, glucose tolerance deteriorated in 22 percent of participants and improved in 18 percent [16]. In another prospective study, 58 percent of those with IGT subsequently had normal OGTT results [15]. These changes in diagnostic categories may be due to acute changes in clinical status (eg, pulmonary exacerbations), which affect insulin sensitivity [94].

●Gestational diabetes – For individuals who are pregnant, the diagnostic criteria for gestational diabetes are the same as for pregnant people without CF [69,75]. CFRD is diagnosed if the diabetes persists after delivery. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention", section on '75 gram oral glucose tolerance test'.)

Other diagnostic tests — As an alternative to diagnosing CFRD based on results of an OGTT, other tests may qualify for the diagnosis under certain circumstances [72]:

●CFRD may be diagnosed during a period of stable baseline health if a patient meets other standard criteria for diagnosis of diabetes on two occasions (hemoglobin A1c [HbA1c] ≥6.5 percent, fasting plasma glucose ≥126 mg/dL [7 mmol/L]) or classical symptoms of diabetes in the presence of a random plasma glucose concentration ≥200 mg/dL (11.1 mmol/L). However, it should be noted that HbA1c and fasting plasma glucose have low sensitivity for detecting CFRD, so normal values do not exclude the diagnosis.

●In patients on enteral tube feedings, CFRD may be diagnosed if mid- or post-feeding plasma glucose levels are ≥200 mg/dL (11.1 mmol/L) on two separate days.

●In CF patients with acute illness (eg, those hospitalized with a pulmonary exacerbation), the diagnosis of CFRD can be made if fasting plasma glucose is ≥126 mg/dL (7 mmol/L) or postprandial plasma glucose is ≥200 mg/dL persist for more than 48 hours. (See 'Selection of tests' above.)

TREATMENT

Diet and drinks — Most patients with CF, including those with CFRD, require a high-calorie diet. Hence, caloric restriction is not recommended, except possibly for people with significant obesity.

Nutritional management alone, without insulin treatment, is not recommended for CFRD [69]. Insulin doses can be distributed to reflect carbohydrate consumption, and carbohydrate counting can be useful in determining the premeal dose.

Other than these considerations for glycemic load, dietary goals are identical to those for all people with CF, including [37,72,95]:

●Liberal intake of total energy (calories) – Recommended intakes are generally 120 to 150 percent or more of the estimated energy requirement for age and sex, with a goal of maintaining BMI ≥50^th percentile for age and sex. For comparison, recommended intakes of energy and key nutrients for children without CF are summarized in the table (table 3). (See "Dietary history and recommended dietary intake in children", section on 'Energy needs'.)

●Liberal intake of fat – eg, 40 percent of total energy.

●Moderate proportion of carbohydrates – eg, 45 to 50 percent of total energy (ideally with low glycemic load for patients with CFRD or abnormal glucose tolerance).

●High intake of protein – eg, 1.5 to 2 times the dietary reference intake for age, including in patients with nephropathy.

●High intake of salt – Sodium intake is unrestricted, because people with CF have increased requirements.

These dietary goals differ from those for patients with type 1 or type 2 diabetes mellitus, for whom dietary recommendations restrict total energy, fat, protein, and sodium intakes. Nutritional management of patients with CF is discussed in detail in a separate topic review. (See "Cystic fibrosis: Nutritional issues".)

Insulin therapy — We recommend treatment with insulin therapy for all patients with CFRD. The insulin dose, regimen, and glycemic targets differ from those used for type 1 and type 2 diabetes, as outlined below.

Indications

●Established CFRD – We recommend insulin therapy for CFRD, with or without fasting hyperglycemia, consistent with multiple guidelines [69,72].

For people with established CFRD, insulin therapy clearly has beneficial effects on nutrition and probably improves pulmonary function and survival. In a randomized trial, adult patients with CFRD without fasting hyperglycemia gained 0.39±0.21 body mass index (BMI) units during one year of insulin therapy, which reversed the BMI decline that they had experienced during the year prior to treatment [52] (see 'Nutritional status' above). Among the insulin-treated participants, there was a trend toward slower rate of decline in pulmonary function compared with the rate of decline prior to treatment; insulin-treated participants also tended to have a slower overall decline in pulmonary function compared with those treated with placebo, but neither of these findings reached statistical significance [52]. Multiple small observational studies with one to three years follow-up confirm improvements in BMI after initiation of insulin therapy and also document improvements in pulmonary function, as measured by forced expiratory volume in one second (FEV₁), or reductions in acute pulmonary infections [9,96-99]. As an example, among 42 young adults with CFRD, insulin therapy slowed the annual rate of decline for FEV₁, delaying the decline by an average of 34 months [9]. CFRD-associated mortality was described in an observational study from a single center and documented progressively lower mortality rates over a 20-year period, which narrowed the gap in mortality between CF patients with and without diabetes and eliminated the sex gap in mortality [7]. Because the center progressively improved protocols for early identification and treatment of CFRD, this study provides indirect evidence that insulin therapy reduces CFRD-associated mortality. (See 'Mortality' above.)

●INDET or IGT – For people with OGTT results in these prediabetic categories (see 'Interpretation of the oral glucose tolerance test' above), there is insufficient evidence to support the use of insulin treatment as standard care.

However, a clinical trial (CF-IDEA) is in progress to determine the utility of insulin treatment prior to the onset of CFRD (NCT01100892). This is a multicenter randomized controlled trial of once-daily insulin detemir in people with CF who have a peak OGTT glucose value ≥8.2 mmol/L (148 mg/dL), but not CFRD, and is powered to detect a difference in weight and lung function decline. Similarly, protein turnover changes are being studied following insulin treatment in a similar patient group (NCT02496780).

General approach — General principles for CFRD management are:

●Give as much insulin as can be safely tolerated to eliminate the catabolic effects of CFRD

●Maintain hemoglobin A1c (HbA1c) as low as possible

•HbA1c target is <7 percent and ideally in the lower part of the normal range (<5.5 percent)

•An increase in HbA1c above the baseline level (prior to insulin therapy) suggests that insufficient insulin is being given

●Test blood glucose preprandially (fasting) and postprandially (approximately one hour after eating)

•If preprandial hypoglycemia is detected, reduce basal insulin dose

•If postprandial hyperglycemia is detected, increase basal insulin dose or add prandial insulin to maximize benefits for the lung

Insulin dose and administration — During periods of clinical stability, patients with CFRD typically require insulin doses of 0.5 to 0.8 units/kg/day [69]. The dose should be adjusted up to the maximum that can be safely tolerated to eliminate the catabolic effects of CFRD without causing frequent or severe hypoglycemia. Considerably higher insulin doses may be required during acute pulmonary exacerbations or other conditions of systemic illness.

Several approaches to insulin dosing may be used, depending on the patient's characteristics and response (table 4A-B):

●Basal insulin – Early in the course of disease, a single daily basal insulin injection usually can achieve desired outcomes and has lower treatment burden than regimens that include multiple daily insulin injections. In our practice, we initiate insulin therapy with a long-acting insulin analog (such as insulin detemir in the morning) at 0.1 units/kg. We then increase the dose by increments of 0.1 unit/kg, aiming for postprandial blood glucose <140 mg/dL (7.8 mmol/L) without hypoglycemia.

If hypoglycemia (blood glucose <70 mg/dL [<3.9 mmol/L]) occurs prior to the midday meal, then we split the dose of detemir to two-thirds in the morning and one-third in the evening. The respective doses can then be titrated to keep daytime and nighttime glucose levels in the normal range.

For those on overnight feeds, insulin is given in the evening, using a long-acting insulin (eg, detemir) in combination with a rapid-acting or regular insulin. Blood glucose should be checked at four to five hours after commencement and at the end of feeds to titrate the dose.

●Prandial insulin – If fasting hyperglycemia develops and postprandial hyperglycemia persists, then we add a prandial bolus prior to meals while reducing the dose of basal insulin. The prandial bolus is a rapid-acting insulin, with a starting dose of 0.5 to 1 unit per 15 grams carbohydrate.

Alternatively, basal insulin can be started at a dose of 0.1 to 0.2 units/kg together with prandial insulin 0.5 to 1 unit per 15 grams carbohydrate.

In addition to prandial insulin, we correct for ambient hyperglycemia with rapid-acting insulin using a starting dose (also referred to as a correction factor) of 1 unit to lower blood glucose by 3 to 6 mmol/L (54 to 108 mg/dL) to a target of 5 mmol/L (90 mg/dL).

●Insulin pump – Insulin pumps are increasingly used for management of CFRD, as they are for other forms of diabetes [97,100]. The approach to determining basal and prandial insulin doses is similar to that described above, although the total daily insulin dose may be somewhat lower for pump users.

Insulin pump therapy has evolved to "advanced hybrid closed-loop" therapy. These systems automatically adjust insulin delivery according to algorithms to prevent hypoglycemia and correct hyperglycemia based on sensor glucose values from a continuous glucose monitor (CGM). It is not known if these systems will work in people with CF in the same manner as for those with type 1 diabetes, but preliminary results are encouraging [101,102]. (See "Continuous subcutaneous insulin infusion (insulin pump)".)

●Special situations – During hospitalizations, the starting dose for basal insulin is generally 0.2 units/kg. During treatment with glucocorticoids, the insulin requirement typically increases considerably. Most patients also require prandial insulin during intercurrent infections.

For surgical procedures such as port insertions, insulin usually can be withheld without risk of significant hyperglycemia. CFRD is rarely associated with ketoacidosis, so there is a low risk of developing ketosis during short periods without insulin.

Glycemic targets and adjustment of insulin

Self-monitoring of blood glucose — People with CFRD on insulin therapy should either use a CGM device (see 'Continuous glucose monitoring' below) or perform self-monitoring of blood glucose (SMBG; via "fingerstick") at least three times a day, as is recommended for all individuals with diabetes [69,72]. In selected patients unwilling or unable to perform this frequent SMBG, less frequent but staggered SMBG monitoring to provide an overall picture of glucose control may be suitable.

●Preprandial blood glucose – SMBG should be performed prior to meals (fasting), especially during periods of illness or changes in insulin dosing, and routinely during periods of baseline health. Target fasting blood glucose is 70 to 90 mg/dL (3.9 to 5 mmol/L) when on basal insulin. If preprandial hypoglycemia is detected, the basal insulin dose should be decreased. Preprandial testing is important because spontaneous hypoglycemia is common among individuals with CF, even in the absence of insulin therapy [103,104].

CF patients are prone to hypoglycemia in the fasting state because of malnutrition and/or increased energy needs, and also to postprandial hypoglycemia (reactive hypoglycemia), due to delayed and disordered insulin secretion [69]. They tend to have reduced glucagon response to hypoglycemia but normal catecholamine response [72]. Patients on insulin therapy should be educated about the risks and of hypoglycemia and its management, including the use of glucagon.

●Postprandial blood glucose – SMBG also should be performed one to two hours after meals. If hyperglycemia is detected, the basal insulin dose should be increased or a prandial dose of rapid-acting insulin should be added; the goal is to maintain postprandial blood glucose in the normal range (<140 mg/dL [7.8 mmol/L]). More frequent SMBG may be needed after changes in insulin dose or during acute illness. Postprandial testing is important to maximize the benefit of insulin therapy on pulmonary function, and the optimal time point for testing may be one hour after meals. This was suggested by a study of young adolescents with CF in good baseline health, in which the one-hour glucose excursion on OGTT was negatively associated with lung function; this was not the case for the two-hour stimulated value, which is typically used to make the diagnosis of diabetes [105].

Hemoglobin A1c — Although HbA1c is not recommended as a diagnostic test for CFRD, it is helpful in monitoring treatment and should be measured every three months in patients on insulin treatment [69,72].

The goals and glycemic targets for CFRD differ from those used for type 1 diabetes:

●For patients with CFRD, we suggest trying to maintain HbA1c as low as possible, ideally in the lower part of the normal range (eg, HbA1c <5.5 percent). This target is selected to optimize lung function and reduce pulmonary exacerbations. At diagnosis, patients with CFRD often have HbA1c in the nondiabetic range (<6 percent) or in the borderline dysglycemic range (6 to 6.5 percent). This has been postulated to be because HbA1c is affected by the shorter lifespan of red blood cells in chronic disease. More recent data suggest that HbA1c is correlated with average glucose in CFRD [106]. If the HbA1c increases above the baseline level (measured prior to insulin therapy), the insulin dose usually should be increased. In one study, good CFRD control (defined in this study as HbA1c <7 percent) was not associated with fewer pulmonary infections, but it is possible that a benefit would have been found if a more stringent HbA1c threshold had been used [107].

●By contrast, in type 1 diabetes, treatment goals are to achieve HbA1c <7 percent for most adolescents and adults [108,109]. This is because the primary goals of treatment for type 1 diabetes are to reduce risks for microvascular complications and to avoid acute episodes of hyper- and hypoglycemia.

Continuous glucose monitoring — CGM provides frequent measurements of glycemia and insight about insulin needs and responsiveness. Many people with diabetes prefer CGM over fingersticks, and CGM is particularly useful for those whose CFRD is difficult to manage through standard approaches, such as those with poor growth despite insulin therapy. CGM has been validated in people with CF and its utility is comparable to individuals with diabetes who do not have CF [110-112].

Changes in interstitial glucose levels lag behind changes in plasma glucose, often by several minutes [113]. For this reason, fingerstick levels should be checked if there are symptoms of hypoglycemia or other clinical reasons to suspect the CGM result may not reflect the blood glucose value.

Monitoring for complications — Patients with CFRD should undergo routine monitoring for complications, as outlined in the table (table 5) and detailed below.

●Microvascular complications – CFRD leads to chronic microvascular complications, including retinopathy, nephropathy, and neuropathy. The frequency of these complications depends on disease duration and glycemic control and appears to be similar to that for type 1 diabetes, although in CFRD, they tend to appear at lower levels of HbA1c. (See 'Vascular complications' above.)

Annual monitoring for microvascular complications is recommended, beginning five years after the diagnosis of CFRD or at the time that CFRD with fasting hyperglycemia is first diagnosed (whichever is earlier) [69,72]. Monitoring procedures are the same as for patients with type 1 diabetes and consist of dilated eye examination for retinopathy, urine albumin:creatinine ratio (spot specimen), and sensory examination of the feet for peripheral neuropathy. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Vascular complications'.)

●Hypertension – Measurement of blood pressure is recommended at all routine visits [72]. Hypertension is a concern in CFRD primarily because it may contribute to nephropathy. If hypertension is present, it should be treated as recommended for other people with diabetes, usually with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB). (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Hypertension'.)

●Dyslipidemia – Annual testing with a lipid panel is recommended for people with CFRD and pancreatic sufficiency, or for those with risk factors for cardiovascular disease (post-transplantation, obesity, or family history of early cardiovascular disease) [72]. Hyperlipidemia and macrovascular disease are rare in patients with CF except in those with pancreatic exocrine sufficiency (which is particularly uncommon among patients with CFRD). However, with improvements in nutritional status, dyslipidemia may become more common.

Oral hypoglycemic agents — Oral antidiabetic agents are not currently recommended in CFRD [69]. Only a few such agents have been evaluated in clinical trials, and were largely unsuccessful [114].

Most of the trials were of repaglinide, which is a meglitinide that promotes beta cell insulin secretion [52,115]. In a randomized trial, treatment with repaglinide yielded transient improvement in IGT during the first six months of therapy but the benefit was not sustained at 12 months, whereas insulin therapy had an ongoing positive effect on weight gain [52].

Exenatide (a glucose-like peptide-1 agonist), was evaluated in a small crossover trial in six participants with impaired glucose tolerance but not CFRD, which reported some improvement in postprandial hyperglycemia that was probably due to delayed gastric emptying rather than improvements in insulin secretion [116]. A small randomized trial of sitagliptin found no benefit on glucose tolerance or measures of beta-cell glucose sensitivity [117].

Effect of CFTR modulator treatments — A new class of drugs known as CF transmembrane conductance regulator (CFTR) modulators target the underlying defect in CFTR function [118]. Emerging evidence suggests that these drugs can have beneficial effects on a wide range of CF outcomes. Their effect on CFRD has not been fully established, but preliminary results suggest possible benefits [119,120]. In one study of adults with CF and at least one F508del mutation, initiation of elexacaftor-tezacaftor-ivacaftor (ETI) was associated with improvements in glycemic control (reduced time above CGM target range 70 to 180 mg/dL, but no change in time below range) [121]. A separate study described reduced insulin requirements with ivacaftor treatment in adult patients with ivacaftor-sensitive CFTR mutations [122]. In other studies, treatment with lumacaftor-ivacaftor (a CFTR modulator that has relatively modest effects on other CF outcomes) did not improve insulin secretion or glycemia [123-125]. Further data on glycemic outcomes following use of combination therapies are awaited.

Details of CFTR modulator therapy, including selection based on genotype and efficacy for other CF-related outcomes, are discussed in a separate topic review. (See "Cystic fibrosis: Treatment with CFTR modulators".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and natural history – Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF) among individuals school-aged and older. Its prevalence increases markedly with age, rising to more than 40 percent after 30 years of age. Risk factors for developing CFRD include severe genotype (eg, F508del homozygotes), pancreatic insufficiency, and female sex. (See 'Epidemiology and natural history' above.)

●Pathogenesis – The primary abnormality predisposing to CFRD is slowly progressive insulin deficiency due to fibrosis and atrophy of pancreatic tissue. Acute pulmonary exacerbations tend to further impair glucose tolerance and may trigger CFRD because inflammatory cytokines and catecholamines promote insulin resistance. (See 'Differences from other forms of diabetes mellitus' above.)

●Clinical consequences – CFRD is associated with clinically important declines in pulmonary function and nutritional status, and with increased mortality. These effects can be attenuated or reversed by treatment with insulin. (See 'Clinical consequences of CFRD' above.)

●Surveillance – All patients with CF should undergo annual testing for CFRD, beginning by 10 years of age. The most appropriate test is an oral glucose tolerance test (OGTT), performed during a period of baseline health. A normal hemoglobin A1c (HbA1c) should not be used to exclude CFRD. In addition to annual testing described above, monitoring of blood glucose is suggested during acute pulmonary exacerbations and for patients on enteral tube feedings. (See 'Surveillance' above.)

●Diagnosis – Interpretation of OGTT is outlined in the table (table 2). (See 'Interpretation of the oral glucose tolerance test' above.)

●Insulin treatment – We recommend treatment with insulin for all patients with CFRD rather than dietary management or no treatment (Grade 1B).

•Glycemic targets and dose adjustment – For CFRD, the insulin dose, regimen, and glycemic targets differ from those used for type 1 and type 2 diabetes. General principles for CFRD management are to give as much insulin as can be safely tolerated to eliminate the catabolic effects of CFRD, maintain HbA1c as low as possible (ideally <5.5 percent), and minimize postprandial hyperglycemia while avoiding episodes of hypoglycemia. The insulin regimen varies depending on the patient's characteristics and response (table 4A). (See 'Insulin dose and administration' above and 'Glycemic targets and adjustment of insulin' above.)

•Monitoring – Monitoring during insulin therapy includes self-monitoring of blood glucose (SMBG) via fingerstick or continuous glucose monitoring (CGM) and laboratory measurement of HbA1c every three months (table 5). In addition, patients with CFRD should undergo annual surveillance for microvascular complications, beginning five years after diagnosis of CFRD. (See 'Glycemic targets and adjustment of insulin' above and 'Monitoring for complications' above.)

●Future directions – Technologies for the management of diabetes including CGM, insulin pumps, and automated closed-loop pump systems are revolutionizing the management of other forms of diabetes and are now being introduced to manage CFRD. (See 'Insulin therapy' above.)

CF transmembrane regulator (CFTR) modulator drugs have important benefits on pulmonary outcomes and other markers of CF-related disease. They are likely to alter the emergence of glycemic abnormalities in CF, and their effects of the management of CFRD will be studied in the coming years. (See 'Effect of CFTR modulator treatments' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kim Donaghue, MB, BS, PhD, FRACP, who contributed to earlier versions of this topic review.