Evolving Mechanistic Views and Emerging Therapeutic Strategies for Cystic Fibrosis–Related Diabetes

John C. Yoon


J Endo Soc. 2017;1(11):1386-1400. 

In This Article

Risk Factors and Natural History of Diabetes Associated With Cystic Fibrosis

Pancreatic involvement in cystic fibrosis includes exocrine insufficiency with malabsorption, pancreatitis, and insulin sufficiency with abnormal glucose tolerance and cystic fibrosis–related diabetes (CFRD). Diabetes is the most common endocrine complication of cystic fibrosis and affects about 20% of adolescents and 40% to 50% of adults.[11] Certain CFTR genotypes that cause complete lack of protein function, such as ΔF508 (also referred to as F508del, p.Phe508del, or c.1521_1523delCTT), carry a much higher risk of CFRD than do genotypes that partially spare protein function.[12] Nearly all patients with these severe genotypes develop exocrine pancreatic insufficiency by the end of the first year, and about 80% develop CFRD by middle age.[13,14] Other risk factors include older age, female sex, hepatobiliary disease, and corticosteroid use.[12,13,15] The diagnosis of CFRD is associated with worse clinical outcomes in patients with cystic fibrosis, reflected in more frequent pulmonary exacerbations, greater reduction in lung function (as measured by forced expiratory volume in 1 second), poorer nutritional status, and decreased survival, particularly in female patients.[11,13,16,17] Even impaired glucose tolerance occurring well before the diagnosis of overt diabetes has been linked to major clinical deterioration.[16,18–20] Insulin therapy in CFRD has been shown to improve pulmonary function, increase body weight, and reduce the frequency of lung exacerbations.[21–26]

As the average life span of people with cystic fibrosis continues to grow, CFRD is expected to become more common. To enhance early diagnosis and intervention, annual screening of all patients with cystic fibrosis using a 75-g oral glucose tolerance test (OGTT) starting at age 10 years is currently recommended by the Cystic Fibrosis Foundation and the European Cystic Fibrosis Society.[22,27] Although hemoglobin A1c, fasting plasma glucose, or random plasma glucose level can also establish the diagnosis of diabetes, the OGTT is currently the test of choice for diagnosing CFRD because of its higher sensitivity.[22,28,29] The OGTT still has a number of disadvantages, and alternative diagnostic methods that are less time-consuming and more sensitive are being sought.[29] Clinical hyperglycemia may initially manifest only during periods of acute pulmonary infections or corticosteroid therapy. With disease progression, postprandial hyperglycemia develops, followed by CFRD without fasting hyperglycemia, and eventually CFRD with fasting hyperglycemia. The β-cell dysfunction is evident many years before the onset of frank diabetes in the form of impaired first-phase insulin secretion in response to intravenous glucose.[30,31]

A. Comparisons to Type 1 and Type 2 Diabetes

CFRD is classified separately from type 1 diabetes and type 2 diabetes.[32] It is distinguished from type 1 diabetes because of its insidious onset over years to decades, rather than weeks to months, and the persistence of some insulin production long after diagnosis. Accordingly, ketoacidosis is uncommon. Autoantibodies are not detected in most patients with CFRD. CFRD differs from type 2 diabetes because insulin resistance is not the defining feature of the disorder, although substantial insulin resistance may be induced in the context of chronic inflammation and active infections.[33] Similar to both type 1 and type 2 diabetes, CFRD is associated with microvascular complications such as retinopathy and nephropathy, and the risk is dependent on disease duration and glycemic control.[34] Macrovascular disease in CFRD is rare and is not a major source of mortality. However, as an increasing number of CFRD patients reach middle age and beyond, it is conceivable that macrovascular complications may become more recognized in CFRD.

Because of the uniqueness and growing importance of CFRD, a better understanding of how it develops is needed to improve rational therapeutic options. The relative inaccessibility of the pancreatic tissue and the lack of appropriate genetic model systems have hampered mechanistic investigations in the past. With the availability of new animal models and increased focus on human studies examining early phases of CFRD development, there is reason to be optimistic that major conceptual advances are forthcoming. This review addresses new mechanistic insights acquired from cell, animal, and patient studies and the recent and emerging strategies for treatment of CFRD.