OBJECTIVE: Cystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database. RESEARCH DESIGN AND METHODS: Data were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992–1997, 1998–2002, and 2003–2008. RESULTS: CFRD is currently present in 2% of children, 19% of adolescents, and 40–50% of adults. Incidence and prevalence are higher in female subjects aged 30–39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992–1997 to 2003–2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003–2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia. CONCLUSIONS: Previously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed. We believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients.

Teplizumab treatment of nondiabetic relatives at high risk for T1D induces partially exhausted CD8 ⁺ T cells and improves beta cell function.

Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity in subjects with cystic fibrosis (CF). A consensus conference on CFRD was cosponsored by the Cystic Fibrosis Foundation (CFF), the American Diabetes Association (ADA), and the Pediatric Endocrine Society (PES) in September 2009. The committee's evidence-based recommendations for clinical management of CFRD are published in this issue of Diabetes Care . This review article describes the epidemiology, pathogenesis, and prognostic implications of CFRD. ### Epidemiology CFRD is part of a continuum of glucose tolerance abnormalities, ranging from normal glucose tolerance (NGT), to impaired glucose tolerance (IGT), to CFRD without fasting hyperglycemia (CFRD FH−), to CFRD with fasting hyperglycemia (CFRD FH+) (Fig. 1). Unlike patients with type 1 diabetes, those with CFRD do not develop complete absence of insulin secretion. At the other end of the spectrum, few CF patients have truly normal glucose metabolism. Approximately 20% of children who are categorized as having NGT based on their fasting and 2-h oral glucose tolerance test (OGTT) glucose levels have glucose elevation >200 mg/dl (11.1 mmol/l) mid-OGTT, which is termed indeterminate glycemia (INDET) (1). As in the general population where INDET is a risk factor for progression to diabetes (2), INDET in children with CF is associated with early development of CFRD (1). Home continuous glucose monitoring (CGM) has shown that intermittent, asymptomatic hyperglycemia is common even in CF patients whose OGTT is normal, but the prognostic significance of these early impairments in glucose metabolism is unknown (3,4). Impaired fasting glucose has also been described in CF (5,6). Figure 1 The spectrum of glucose tolerance in CF. Unlike patients with type 1 diabetes, insulin secretion is never completely absent in CFRD. Clinical deterioration (pulmonary function, underweight) is associated with worse glucose tolerance status. Abnl CGM = abnormal home continuous glucose monitoring, T1D …

OBJECTIVE: Cystic fibrosis–related diabetes (CFRD) without fasting hyperglycemia (CFRD FH−) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients. RESEARCH DESIGN AND METHODS: A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin aspart, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. RESULTS: One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH− and 20 with severly impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Among the group with CFRD FH−, insulin-treated patients lost 0.30 ± 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 ± 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 ± 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group. CONCLUSIONS: Insulin therapy safely reversed chronic weight loss in patients with CFRD FH−.

Rationale: Diabetes is associated with increased mortality in cystic fibrosis. Aggressive screening and early institution of insulin treatment significantly reduced this risk over the period of 1992–2008. Objectives: To determine if progressive improvement in cystic fibrosis–related diabetes (CFRD) mortality has continued since 2008, and examine associations with CFTR genotypes linked to pancreatic insufficiency and to sex. Methods: Chart review was performed on 664 patients followed from 2008 to 2012. Measurements and Main Results: Overall mortality for patients with CFRD was 1.8 per 100 person-years, compared with 0.5 in patients with CF without diabetes (P = 0.0002); neither rate changed significantly from mortality reported for 2003–2008. Genotype impacted both mortality and diabetes risk: adults with severe CFTR genotypes experienced greater mortality at every age older than 32 years than those with mild genotypes (P = 0.002), and the risk of developing CFRD was also greatly increased in those with severe genotypes (prevalence 60% in adult patients with severe vs. 14% in adults with mild mutations). CFRD had a direct influence on mortality because it was associated with increased risk of death within each genotype category (20 vs. 2%, P = 0.007 for mild; 12 vs. 4%, P = 0.012 for severe). There was also a sex difference in adults with severe CFTR genotypes; both mortality and CFRD prevalence were higher at every age in females than males. Conclusions: Despite substantial improvement over time, mortality for CFRD patients greater than 30 years remains higher than for patients with CF without diabetes.