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. 2016 Sep-Oct;113(5):384–389.

Cystic Fibrosis Related Diabetes: a Unique Challenge in Diabetes Care

Marina Litvin 1,✉, Schola Nwachukwu 2
PMCID: PMC6139848  PMID: 30228505

Abstract

Cystic Fibrosis (CF) is a common autosomal recessive disease that affects multiple organs due to a defect in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This transporter is present in various organs and tissues, including the airway epithelium, sinuses, pancreas, intestine, biliary tree, the vas deferens, and the sweat ducts, making CF a multi-system disease1. As CF patients are living longer, pancreatic function declines and diabetes emerges, further complicating the nutritional status and care of these patients.

Introduction

Cystic fibrosis is the most common autosomal recessive disease among Caucasians, affecting up to 1 person per every 2,000–3,000 live births2. Cystic fibrosis also affects Hispanic (1:9,200) and African American (1:10,900) patients, with the lowest prevalence in the Asian Population (1:30,000)1,2. CF is becoming more widely diagnosed, and is being diagnosed earlier, due to the advent of newborn screening in the U.S. and other developed countries3,4. Similarly, the number of newly recognized cases of CF continues to increase with the appreciation of its variable phenotype, which can be mild at presentation, or even limited to a single organ system5.

The pathophysiology of CF rests with the CFTR, which functions to regulate pH and ionic balance of secretions. In the lungs, the CFTR is involved in bicarbonate secretion, leading to alkalization of fluid, producing a more bactericidal environment6; proper CFTR function also allows to prevent airway mucus from being to thick, to promote proper mucociliary clearance.56 When the CFTR channel does not function properly, such as in the case of CF, the patient is predisposed to bronchiectasis and frequent infections, and may progress to respiratory failure. In addition, CFTR malfunction can lead to exocrine and endocrine pancreatic insufficiency, malabsorption, intestinal obstruction, sinus diseases, hearing loss, liver diseases and male infertility. Due to the effect on chloride secretion by the defective CFTR in sweat glands, chloride content of sweat is elevated, forming the basis for the diagnostic sweat test.1

As therapies for organ dysfunction in CF continue to evolve, patients with CF are living longer. The predicted age of median survival has increased from 32.2 years (95% CI 30.3–34.9) in 1998 to 40.7 years (CI 37.7–44.1) in 20137,2. As patients with CF age, the prevalence of CF related diabetes (CFRD) increases. According to the annual report from the Cystic Fibrosis Foundation Patient Registry, the prevalence of CFRD in patients < 18 years of age is only about 6.5%, but than 18 years old, with some series reporting up to 50% prevalence of CFRD in adults2,8,9. As CFRD is encountered more frequently in the clinical care of the CF patient, understanding the pathophysiology of CFRD, and the effect of glycemic control on outcomes for patients with CF is paramount. Impaired glycemic tolerance and poor glycemic control in patients with CFRD have been associated with CF exacerbations, worse lung function, lower BMI, and higher mortality10,11,12,13,14.

Cystic Fibrosis Related Diabetes

Cystic Fibrosis Related Diabetes (CRFD) is a unique disease process, which combines the pathophysiology of type 1 and type 2 diabetes, exhibiting both decreased insulin secretion and increased insulin resistance15. The challenges in the treatment of CFRD include dealing with increased caloric requirements for people with CF, resulting in high carbohydrate intake and frequent snacking, which exacerbates the hyperglycemia, as well as increased insulin resistance during times of illness, and the episodic need for glucocorticoid therapy16,17. Coexisting glucagon deficiency, increased energy expenditure, altered GI tact motility and absorption further complicate the management of CFRD18. Additionally, novel drug therapies correcting and/or potentiating the function of the affected CFTR channel, may influence weight, nutritional status, and insulin sensitivity and secretion15,19. Patients with cystic fibrosis may also not view CFRD as a priority, focusing more on other health-related effects of CF, which they may view as more life-limiting20,21.

CFRD does not occur in all patients with CF. It is more prevalent among CF patients with more severe defects of the CFTR22,23,24 channel, and is more likely to occur in patients with exocrine pancreatic insufficiency25,26. Specifically, patients with CFTR Class I and Class II mutations24, which lead to defective CFTR synthesis at the endoplasmic reticulum, and defective CFTR trafficking, respectively,15 are more likely to develop CFRD than patients with more mild genotypes. Additional risk factors for developing CFRD include: female sex, worse pulmonary function, liver dysfunction, glucocorticoid use, and family history of diabetes.24 Supplemental nutrition/tube feeds and infection can further exacerbate glycemic control27.

Pancreatic exocrine insufficiency, which is more likely to occur with severe CF genotypes, is a risk factor for development of CFRD and often predates the diagnosis of CFRD28. When pancreatic CFTR function is deficient, the altered, bicarbonate-poor, acidic secretions cause pro-enzyme precipitation, obstructing the pancreatic ducts, leading to inflammation, amyloid deposition, fatty infiltration, necrosis and eventual fibrosis and atrophy of the pancreas15,18,29. This process eventually leads to insulin deficiency due to decreased β-cell mass. In addition to fibrosis, increased ER stress from misfolding of the CFTR protein, and deficiency of anti-oxidants due to chronic malabsorption, may contribute to the development of CFRD30.

Immune-mediated destruction of the endocrine pancreas may exacerbate β-cell dysfunction15. Clinically, weight loss and worsening lung function are seen before the development of overt CFRD. This process may reflect the imbalance of pro-inflammatory cytokines (IL-17 secreted by T-helper 17 lymphocytes) that leads to both β-cell dysfunction and decreased lung function31. Underlying vitamin D deficiency from chronic malabsorption may contribute to the immune dysfunction adversely affecting the pancreatic β-cell32.

It is unlikely that fibrosis of the pancreas is the only pathogenic mechanism in CFRD. In a well-characterized ferret model of CFRD, the absence of functional CFTR channels causes abnormalities in glucose tolerance and first phase insulin secretion before these animals develop overt pathology (fibrosis) of the pancreas33. This suggests that intrinsic abnormalities in insulin secretion occur early in CF, likely due to altered insulin secretion caused by defective CFTR channel activity. The concept of an intrinsic defect in insulin secretion by the CF pancreas is further supported by Wooldridge et al. who examined insulin secretion in CF patients without CFRD during an OGTT, and found that the insulinogenic index (a measure of the capacity for insulin secretion) in pancreatic sufficient patients with CF was significantly lower than in control patients without CF34.

Due to the underlying intrinsic defect in insulin secretion secondary to the aberrant CFTR channel, patients have delayed and blunted first-phase insulin response18, as the glucose peak occurs early during the two-hour oral glucose tolerance test13. Initially, patients may develop hyperglycemia only at times of illness, or when treated with glucocorticoids. Upon screening of stable patients, postprandial hyperglycemia is the earliest detectable abnormality in glucose homeostasis, and is a sensitive indicator of defective insulin secretion. As the disease progresses, fasting hyperglycemia occurs.

As β-cells are destroyed, the simultaneous destruction of glucagon producing β-cells may make treatment of CFRD especially challenging, rendering patients susceptible to severe and prolonged hypoglycemia if they are being treated with insulin. However, severe hypoglycemia appears to be more common in people with type 1 diabetes as compared to matched patients with CFRD21.

Decreased incretin (GLP-1, GIP) production due to changes in the entero-pancreatic axis and increased insulin clearance may also contribute to the development of CFRD15,35. Additionally, insulin resistance associated with inflammation, as well as increased growth hormone, cortisol, and catecholamines, induced by acute pulmonary exacerbations, can further contribute to hyperglycemia. Poorly controlled CFRD is associated with reduced BMI and worsening pulmonary function (as measured by FEV1). Both of these findings can be present before the diagnosis of CFRD is made36,37. CFRD is associated with higher mortality, with up to six fold greater mortality reported in female patients with CFRD as compared to those without CFRD38, 39. This discrepancy in mortality may disappear with improved glycemic control8. CFRD can also increase the risk of graft failure and mortality in patients with CF undergoing lung transplant40.

In addition to the adverse effects of CFRD on the clinical outcomes described above, patients with CFRD are also at risk for microvascular complications. The risk parallels that seen in patients with type 1 diabetes (T1D), as assessed by HbA1c41. Van den Berg et al. compared microvascular complications in patients with CFRD versus patients with T1D41. They found that overall, patients with CFRD and T1D had the same number of microvascular complications. However, retinopathy was more common in T1D (24% vs 10%, p=0.044), while prevalence of peripheral neuropathy was comparable between the two groups. Patients with CFRD had significantly lower BMI, and significantly lower cholesterol. Nonetheless, patients with CFRD had significantly more microalbuminuria (21% vs. 4.1%, p=0.003) than patients with T1D. The authors speculate that the higher rate of microalbuminuria in patients with CFRD is likely multifactorial, and may be related to factors unique to CFRD, such as chronic inflammation, insulin resistance, exposure to nephrotoxic drugs such as aminoglycoside antibiotics, and deficiency of renal cystic fibrosis transmembrane regulator protein function41.

Macrovascular complications are rare in patients with CFRD and have not been reported to date. Unlike patients with type 1 and type 2 Diabetes, who are more likely to die from cardiovascular disease, patients with CFRD, despite their increasing survival into adulthood, most frequently succumb to their pulmonary disease, and are more likely to die from cardiorespiratory failure42,2.

Screening and Diagnosis of Cystic Fibrosis Related Diabetes (CFRD)

Given the adverse effects of CFRD on nutritional status, pulmonary function, and mortality, annual screening for CFRD starting at 10 years of age is recommended42. Screening also applies to specific subpopulations of patients with cystic fibrosis, such as pregnant women, post-partum women with a history of gestational diabetes, and patients being evaluated for lung transplantation. Screening for CFRD using hemoglobin HbA1c is not recommended, since a normal HbA1c result lacks the sensitivity to diagnose CFRD. Although data have been conflicting, the majority of the studies did not find a reliable correlation between hemoglobin HbA1c and glucose tolerance in the CF population42. Similarly, fructosamine, urine glucose, and random glucose levels have a low sensitivity for detecting CFRD in patients with cystic fibrosis42.

Patients can be screened using current American Diabetes Association (ADA) guidelines for oral glucose tolerance testing while their health is stable. As noted above, hemoglobin HbA1c should not be used for diagnosis. The 75-gram oral glucose tolerance test (OGTT) should be used to screen for CFRD. The test should be performed when a patient is in stable health, at least six weeks after a CF exacerbation. Patients not meeting criteria for CFRD may exhibit isolated impaired fasting glucose (IFG), or impaired glucose intolerance (IGT), and may potentially benefit from treatment. Abnormal OGTT results should be confirmed with another testing modality, or the OGTT should be repeated on another day. Table 1 lists the diagnostic criteria based on OGTT results. Patients who develop hyperglycemia with classic symptoms, during illness or while on tube feeds, may be diagnosed with CFRD without screening, as summarized in Table 2. Since CFRD rarely occurs before the age of 10, a diagnosis of type 1 diabetes must be considered in patients younger than 10 years of age who develop diabetes.

Table 1.

Diagnostic criteria for Cystic Fibrosis Related Diabetes (CFRD) during stable health..

Time Normal Glucose Tolerance (glucose in mg/dL) Impaired Fasting Glucose (glucose in mg/dL) Impaired Glucose Tolerance (glucose in mg/dL) CFRD (glucose in mg/dL)
0 min (fasting) < 100 ≥ 100 AND <126 < 100 ≥ 126
1 hour ----- ----- ----- ------
2 hour < 140 < 140 ≥ 140 AND ≥ 200 ≥ 200
Confirmatory Testing May predict increased risk of CFRD; repeat test in 6 weeks55. Monitor blood glucose during illness May predict increased risk of CFRD; repeat test in 6 weeks55. Monitor blood glucose during illness Confirm result by any modality recommended by ADA (HbA1c, repeat OGTT, fasting plasma glucose)
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Table 2.

Diagnostic criteria for CFRD during illness.

CFRD Diagnosis Symptomatic Hyperglycemia CFRD Diagnosis During acute illness CFRD Diagnosis On Tube Feeds
Classic symptoms of DM (polyuria, polydipsia) AND Fasting glucose ≥ 126 OR Random glucose ≥ 200 Random blood glucose ≥ 200
Random blood glucose ≥ 200 mg/dL Hyperglycemia must persist beyond the first 48 hours of treatment (IV antibiotics, etc) Document two occasions within 48 hours
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Treatment of CFRD

The prevalence of microvascular complications in patients with CFRD is low, and macrovascular complications are uncommon. Thus, the goals of treatment of CFRD are to prevent the catabolic effects of hyperglycemia, improve nutritional status and BMI, and reduce the frequency of pulmonary exacerbations while minimizing hypoglycemia. According to ADA guidelines, the hemoglobin HbA1c goal in CFRD is < 7%42.

Oral Agents

Given the complexities of CF therapies and the multi-organ involvement of most patients, many oral medications cannot be used safely and effectively in the treatment of CFRD. Metformin, for instance, is contraindicated in patients with cystic fibrosis. Treatment with metformin may be unsafe due to the increased risk of lactic acidosis in patients with frequent hypoxia and underlying liver and chronic kidney disease43.

Thiazolidinediones are not recommended due to concern for hepatic toxicity in CF patients. Drugs limiting carbohydrate absorption are not recommended since CF patients exhibit significant malabsorption43.

The use of sulfonylureas is not recommended due to concern for hypoglycemia. By affecting intracellular chloride transport, these medications may interact with new therapeutic agents that potentiate or correct the CFTR channel activity directly43. Unlike insulin, which has been shown to preserve beta cell mass, sulfonylureas may decrease beta cell mass44.

Repaglinide is an oral anti-diabetic medication that lowers blood glucose by binding to the sulfonylurea receptor, stimulating insulin release. It is less likely to cause hypoglycemia than a sulfonylurea, since its action on insulin release occurs in a glucose-dependent fashion, and tends to be of shorter duration45. Moran et al have shown that repaglinide may have some limited benefit in patients with CFRD with regard to post-prandial hyperglycemia and improvement in BMI and chronic weight loss, although the beneficial effect on weight was not sustained beyond 6 months of therapy, and the effect on post-prandial glucose was less than that of insulin. 43,50

No studies are available addressing the use of GLP-1, DPP-IV or SGLT-2 therapies for CFRD. GLP-1 levels are reduced in patients with CFRD, and it is possible that therapy with this agent may be of benefit in patients with CFRD35. Currently, due to lack of proven efficacy, oral or non-insulin therapy is not recommended for treatment if CFRD outside of a clinical trial42. An open randomized prospective multi-center trial examining the effect of oral therapy vs. insulin therapy in patients with CDRD without fasting hyperglycemia is ongoing 46.

Insulin Therapy

Insulin is currently the only recommended medical therapy for CFRD. Patients with CFRD without fasting hyperglycemia can initially be started on prandial insulin, which can reverse chronic weight loss47. It is reasonable to start therapy with prandial insulin at 0.5–1 unit of insulin for 15 grams of carbohydrates in patients requiring meal coverage. For patients with fasting hyperglycemia, basal insulin at 0.25 u/kg daily can be used48.

Recommendations regarding insulin use in patients with isolated fasting hyperglycemia remain unclear. Limited studies show that insulin therapy in these patients may improve BMI and lung function47. This effect of insulin therapy may be due to the anabolic benefits of insulin, possibly increasing respiratory muscle strength, rather than a direct effect of glucose lowering therapy49. Insulin therapy carries with it the burden of multiple daily injections, risk of hypoglycemia, and titration needed during times of acute inflammatory states, such as CF exacerbation, when insulin requirements can increase up to four fold48. In addition to fluctuating insulin requirements during illness, other challenges of diabetic management include gestational diabetes, and deteriorating control of CFRD after lung transplant, although incidence of diabetes after lung transplant is not increased in CF patients42,50. Enzyme supplementation and fat content of meals can also affect gastric emptying, making glycemic excursions more variable49.

Pancreatic transplantation

Although pancreatic transplantation can improve both endocrine and exocrine pancreatic deficiencies, it is not commonly performed. Usatin et al report under-utilization of pancreatic transplants in patients with CF, despite up to 100% survival two years after a combined pancreas-kidney transplant51.

CFTR correctors and potentiators

Current development of medications to specifically target CFTR dysfunction makes this an a hopeful time for the treatment of CF and CFRD. Lumacaftor (VC-809) is an oral agent used for CFTR correction. The molecule facilitates proper maturation and delivery of the CFTR protein to the plasma membrane by directly interacting with the protein to facilitate proper folding. This medication is used in patients who are delta 508 homozygotes, targeting a Class II mutation. CFTR potentiators, such as ivacaftor, increase the flow of ions through the activated CFTR channel, and can be used in people with class III mutations of the CFTR cannel (such as those with the G551D mutation), who have normal amounts of protein at the cell surface but exhibit defects in channel gating52. These medications have shown to improve lung function and BMI in patients with CF. Additionally, these agents may improve insulin secretion, since the CFTR channel is present in the pancreas. A small pilot study involving five patients with CF taking ivacaftor for the G551D mutation demonstrated an improved insulin response to an oral glucose load within 1 month after starting therapy, suggesting that these agents can favorably affect insulin secretion53. Hayes et al. reported that a 25-year-old man with the deltaF508 G551D mutation, previously taking 20 units of glargine daily for CFRD, was weaned off insulin therapy within one year of starting irvacaftor54. The combination of lumacaftor/ivacaftor provides greater benefit for many CF patients. More targeted therapies affecting the CFTR channel and gene therapy are potential future treatments for CF and its associated comorbidities, including CFRD.

Future Directions

The emergence of CFTR targeted therapies, improved nutrition, and advances in treatment of underlying organ dysfunctions in CF have increased survival of patients with cystic fibrosis, and thus, also increased the prevalence of CFRD. As patients with cystic fibrosis live longer, they may develop microvascular complications of CFRD. Patients with CFRD pose a unique challenge to the management of diabetes and should receive care by multidisciplinary teams that can address the complexity of CF and the related comorbidities, including CFRD, to help patients achieve desired targets and optimal outcomes in the control of their disease.

Acknowledgment

We thank Dr. Janet McGill for help with the manuscript. We also thank Dr. Rosenbluth for his mentorship and support.

Biography

Marina Litvin, MD, (left), is an Assistant Professor, and Schola Nwachukwu, MD, (right), is a Clinical Fellow, Division of Endocrinology, Metabolism, and Lipid Research, department of Medicine, Washington University School of Medicine, St. Louis.

Contact: litvinm@wustl.edu

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Footnotes

Disclosure

ML: Receives funding from the Cystic Fibrosis Foumdation CF EnVision Grant. 2016–2019.

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