Development Of CF-related Diabetes Research Articles

Association of race and ethnicity with the development of cystic fibrosis-related diabetes

BackgroundCF-related diabetes (CFRD) is a common, life-expectancy limiting complication of CF. While Black race and Hispanic ethnicity in youth-onset type 1 and type 2 diabetes are well-recognized risk factors for worse diabetes complications, the potential for racial/ethnic disparities in CFRD has received limited attention. MethodsWe conducted a retrospective cohort study utilizing the CF Foundation Patient Registry from 2010 to 2019 to determine the prevalence and incidence of CFRD by race/ethnicity. Three age cohorts were identified at baseline in 2010 (11–20y, 21–30y, and 31–40y). Logistic regression and Cox regression stratified by age group were used to determine the prevalence and incidence, respectively, among Hispanic, non-Hispanic Blacks (NHB), and non-Hispanic whites (NHW) after adjustment for relevant confounders, including demographics, socioeconomic status, clinical factors, and chronic medication use. ResultsAmong 14,660 registry participants, 510 were NHB and 890 Hispanic. NHB associated with higher odds of CFRD baseline prevalence in all age cohorts (11–20y: OR 2.53 (95 % CI: 1.88–3.41, P < 0.05), 21–30y: OR 1.80 (1.25–2.59, P < 0.05), and 31–40y: OR 1.93 (1.00–3.73, P < 0.05)) relative to NHW. In the 11–20y cohort, the hazard of new-onset CFRD was 40 % higher in NHB (HR 1.40 (1.09–1.8, P < 0.05)) and 19 % higher in Hispanics (HR 1.19 (1.01–1.41, P < 0.05)). ConclusionNHB had a higher prevalence of CFRD across all age groups, with NHB and Hispanics showing higher incidence of CFRD in the youngest group. Multicenter studies performed in diverse CF populations are warranted to identify modifiable factors influencing earlier CFRD development in minoritized groups and their potential contribution to diabetes complication disparities.

1753-P: Islet GLP-1R Protein Expression Is Reduced in Humans with Cystic Fibrosis–Related Diabetes

Impaired insulin secretion underlies the development of cystic fibrosis-related diabetes (CFRD). Glucagon like peptide-1 (GLP-1) is produced in islet α cells, and potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. In CFRD, α-cell mass is increased. Despite this, we hypothesized that levels of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to deficits in insulin secretion. To address our hypothesis, paraffin-embedded pancreas sections from humans with CFRD and age-matched nondiabetic controls (from nPOD) underwent immunohistochemistry to quantify protein levels of active GLP-1 and GLP-1R (n=5-6/group). Spatial transcriptomics (NanoString) was also performed to assess differentially expressed α- and/or β-cell genes between CFRD and control pancreas (n=3/group; 15 CFRD + 9 control islets). GLP-1 immunoreactivity was unchanged between CFRD and control pancreas (0.33±0.15 vs 0.51±0.15, % GLP-1 area/pancreas area; p=0.4), however islet GLP-1R immunoreactivity was significantly reduced (4.35±1.21 vs 18.70±0.50, % GLP-1R area/islet area; p=0.004). Surprisingly, few α- or β-cell genes were differentially expressed between CFRD and control islets. However, a gene set test (ROAST) to assess transcripts involved in GLP-1 production/signaling revealed that those in α cells (GCG, PCSK1, PCSK2, DPP-4) significantly changed in mixed directions (up- or down-regulated; p=0.001). No such perturbation was seen in the β-cell gene set (INS, GLP1R, DPP-4, PLCG1, PIP4P2, ITPR3, ADCY1, ADCY6, PRKACA, RAPGEF4; p=0.4). In sum, our data suggest CFRD is not associated with altered intra-islet GLP-1 levels, however α-cell genes that modulate GLP-1 levels are dysregulated. Also, islet GLP-1R protein levels are reduced, though expression of genes downstream of GLP-1R is unchanged. Thus, interventions to restore protein levels of islet GLP-1R and/or promote intracellular signaling beyond GLP-1R may improve β-cell function in CFRD. Disclosure R. Vemireddy: None. J.J. Castillo: None. B.S. Fountaine: None. T.K. Bammler: None. J. MacDonald: None. R.L. Hull-Meichle: Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health. Employee; Veterans Administration. Research Support; Veterans Administration. S. Gharib: None. S. Zraika: None. Funding National Institutes of Health (P30DK089507, P30DK017047)

Vitamin D Status and Risk of Cystic Fibrosis-Related Diabetes: A Retrospective Single Center Cohort Study.

Objective: Cystic fibrosis-related diabetes (CFRD) affects up to half of the people with cystic fibrosis (CF) by adulthood. CFRD is primarily caused by pancreatic dysfunction that leads to insufficient insulin release and/or insulin resistance. Exocrine pancreatic insufficiency in people with CF is associated with fat-soluble vitamin malabsorption, including vitamins A, D, E, and K. This study examined the relationship between vitamin D status, assessed by serum 25-hydroxyvitamin D (25(OH)D), and the development of CF-related diabetes (CFRD) in adults with CF. Methods: This was a retrospective cohort study of adults seen at a single CF center. The data were extracted from the electronic medical records and the Emory Clinical Data Warehouse, a data repository of health information from patients seen at Emory Healthcare. We collected age, race, the first recorded serum 25-hydroxyvitamin D (25(OH)D) concentration, body mass index (BMI), and onset of diabetes diagnosis. Log-rank (Mantel–Cox) tests were used to compare the relative risk of CFRD onset in the subjects with stratified vitamin D status and weight status. A sub-group analysis using chi-square tests assessed the independence between vitamin D deficiency and CFRD risk factors, including gender and CF mutation types (homozygous or heterozygous for F508del, or others). Unpaired t-tests were also used to compare the BMI values and serum 25(OH)D between the CF adults based on the CFRD development. Results: This study included 253 subjects with a mean age of 27.1 years (±9.0), a mean follow-up time period of 1917.1 (±1394.5) days, and a mean serum 25(OH)D concentration of 31.8 ng/mL (±14.0). The majority (52.6%) of the subjects developed CFRD during the study period. Vitamin D deficiency (defined as 25(OH)D < 20 ng/mL) was present in 25.3% of the subjects. Close to two thirds (64.1%) of the subjects with vitamin D deficiency developed CFRD during the study. Vitamin D deficiency increased the risk of developing CFRD (chi-square, p = 0.03) during the course of the study. The time to the onset of CFRD stratified by vitamin D status was also significant (25(OH)D < 20 ng/mL vs. 25(OH)D ≥ 20 ng/mL) (95% CI: 1.2, 2.7, p < 0.0078). Conclusion: Our findings support the hypothesis that adults with CF and vitamin D deficiency are at a higher risk of developing CFRD and are at risk for earlier CFRD onset. The maintenance of a serum 25(OH)D concentration above 20 ng/mL may decrease the risk of progression to CFRD.

Cystic fibrosis-related diabetes and lung disease: an update

The development of cystic fibrosis-related diabetes (CFRD) often leads to poorer outcomes in patients with cystic fibrosis including increases in pulmonary exacerbations, poorer lung function and early mortality. This review highlights the many factors contributing to the clinical decline seen in patients diagnosed with CFRD, highlighting the important role of nutrition, the direct effect of hyperglycaemia on the lungs, the immunomodulatory effects of high glucose levels and the potential role of genetic modifiers in CFRD.

Trajectories of oral glucose tolerance testing in cystic fibrosis.

Annual oral glucose tolerance testing (OGTT) is the recommended screening modality for cystic fibrosis-related diabetes (CFRD) in patients with cystic fibrosis (CF). This study aimed to determine if there were patterns of progression of worsening glucose homeostasis in pediatric CF patients and to explore any relationship to lung function. We conducted a retrospective cohort study of CF patients, ages 10-18 years, without CFRD and with ≥3 OGTT from 2013 to 2016. Latent class mixture models were used to determine unique trajectories of 2-hOGTT glucose values (2hrGlu) over time. Multivariable linear models were used to adjust for clinical covariates. For 63 subjects, three unique 2hrGlu trajectories were identified: high (impaired glucose tolerance) to higher (n = 8), low (normal glucose tolerance [NGT]) and increasing (n = 47), and low (NGT) and flat (n = 8). There was high variability of 2hrGlu, but most patients belonged to a trajectory that increased over time. After controlling for age, pancreatic insufficiency, modulator use, and mutation type, there was a significant difference in the study baseline forced expiratory volume in 1 s percent predicted (ppFEV1) in the high to higher group compared to the low and increasing and low and flat groups (p < .005). Among pediatric CF patients without diabetes, three 2hrGlu trajectories were identified with 87% of patients exhibiting a trajectory where glucose homeostasis worsened over time. Starting ppFEV1 was lower in those with a high to higher trajectory, supporting that lower lung function is present early in the development of CFRD.

Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet.

Cystic fibrosis (CF) is due to mutations in the CF-transmembrane conductance regulator (CFTR) and CF-related diabetes (CFRD) is its most common co-morbidity, affecting ~50% of all CF patients, significantly influencing pulmonary function and longevity. Yet, the complex pathogenesis of CFRD remains unclear. Two non-mutually exclusive underlying mechanisms have been proposed in CFRD: i) damage of the endocrine cells secondary to the severe exocrine pancreatic pathology and ii) intrinsic β-cell impairment of the secretory response in combination with other factors. The later has proven difficult to determine due to low expression of CFTR in β-cells, which results in the general perception that this Cl−channel does not participate in the modulation of insulin secretion or the development of CFRD. The objective of the present work is to demonstrate CFTR expression at the molecular and functional levels in insulin-secreting β-cells in normal human islets, where it seems to play a role. Towards this end, we have used immunofluorescence confocal and immunofluorescence microscopy, immunohistochemistry, RT-qPCR, Western blotting, pharmacology, electrophysiology and insulin secretory studies in normal human, rat and mouse islets. Our results demonstrate heterogeneous CFTR expression in human, mouse and rat β-cells and provide evidence that pharmacological inhibition of CFTR influences basal and stimulated insulin secretion in normal mouse islets but not in islets lacking this channel, despite being detected by electrophysiological means in ~30% of β-cells. Therefore, our results demonstrate a potential role for CFTR in the pancreatic β-cell secretory response suggesting that intrinsic β-cell dysfunction may also participate in the pathogenesis of CFRD.

Dyslipidemia is not associated with the development of glucose intolerance or diabetes in cystic fibrosis

BackgroundA high-fat, high-calorie diet is recommended in patients with cystic fibrosis (CF) as it improves nutritional status, respiratory health and longevity. In the general population, this diet is associated with the risk of diabetes. It is unknown whether dyslipidemic changes might contribute to the development of CF-related diabetes (CFRD). ObjectiveThis study aimed to (i) characterize dyslipidemia and (ii) examine the association between dyslipidemia and development of glucose intolerance. MethodsProspective observational study with serial assessments of pulmonary function, glucose tolerance, and lipid profile. Due to intrinsically low total, HDL and LDL cholesterol in patients with CF, subjects were characterized as having dyslipidemia if they had i) HDL in the lowest quartile and/or ii) hypertriglyceridemia (≥1.7 mmol/L). ResultsA total of 256 patients with CF were included (age: 25.5 ± 7.7 years; BMI: 21.7 ± 3.0 kg/m2; FEV1%: 73.2 ± 22.1%; pancreatic insufficiency: 87%). Amongst these patients, 22.7% had low HDL, 9.0% had hypertriglyceridemia and 3.9% had mixed dyslipidemia. There were no differences in HbA1c (p = 0.583) or estimated insulin resistance [HOMA-IR (p = 0.206) or Stumvoll index (p = 0.397)]. Patients with hypertriglyceridemia had higher fat mass (p = 0.038) and fewer had pancreatic insufficiency. Lipid profiles were similar between subjects with CF and subjects with de novo CFRD. There was no effect of low HDL or hypertriglyceridemia on the development of CFRD over 10 years (p = 0.683). ConclusionIn adult patients with CF, dyslipidemia is not associated with the risk of developing hyperglycemia or CFRD.

Association between HbA1c and the development of cystic fibrosis-related diabetes.

To examine HbA1c as a predictor of risk for future development of cystic fibrosis-related diabetes and to assess the association with the development of retinopathy in people with cystic fibrosis-related diabetes. A 7-year retrospective longitudinal study was conducted in 50 adults with cystic fibrosis, comparing oral glucose tolerance test results with HbA1c values in predicting the development of cystic fibrosis-related diabetes. Retinal screening data were also compared with HbA1c measurements to assess microvascular outcome. An HbA1c value ≥37 mmol/mol (5.5%; hazard ratio 3.49, CI 1.5-8.1) was significantly associated with the development of dysglycaemia, as defined by the oral glucose tolerance test over a 7-year period. Severity of diabetic retinopathy was associated with a higher HbA1c and longer duration of cystic fibrosis-related diabetes. There is a link between HbA1c level and the future development of dysglycaemia in cystic fibrosis based on oral glucose tolerance test, as well as microvascular outcomes. Although current guidance does not advocate the use of HbA1c as a diagnostic tool in cystic fibrosis-related diabetes, it may be of clinical use in determining individuals at risk of future development of cystic fibrosis-related diabetes.

Effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients

ObjectiveTo investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis (CF) (Phe508del/Phe508del). MethodsA standard oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed to investigate glucose metabolism and insulin secretion before and after 6–8weeks of treatment with Lumacaftor/Ivacaftor in 5 Phe508del-homozygous CF patients. The area under the curve (AUC) for glucose and insulin levels was calculated using the trapezoidal approximation. Results5 participants were investigated. Treatment with Lumacaftor/Ivacaftor was followed by an improvement of the 2h glucose levels in 3 patients and worsening in 2 patients. Analysis of the time course of blood glucose levels during OGTT revealed an increase of the AUC in 3 of 5 patients. In response to IVGTT, acute insulin secretion improved in 2 patients and worsened in 3. ConclusionThe investigation could not demonstrate that treatment with Lumacaftor/Ivacaftor had a consistent impact on glucose tolerance and insulin secretion. Further adequately-powered studies examining glucose metabolism are needed to properly evaluate drug response in the endocrine pancreas and to test whether this treatment could eventually prevent the development of cystic fibrosis-related diabetes (CFRD).

Islet-intrinsic effects of CFTR mutation.

Cystic fibrosis-related diabetes (CFRD) is the most significant extra-pulmonary comorbidity in cystic fibrosis (CF) patients, and accelerates lung decline. In addition to the traditional view that CFRD is a consequence of fibrotic destruction of the pancreas as a whole, emerging evidence may implicate a role for cystic fibrosis transmembrane-conductance regulator (CFTR) in the regulation of insulin secretion from the pancreatic islet. Impaired first-phase insulin responses and glucose homeostasis have also been reported in CF patients. CFTR expression in both human and mouse beta cells has been confirmed, and recent studies have shown differences in endocrine pancreatic morphology from birth in CF. Recent experimental evidence suggests that functional CFTR channels are required for insulin exocytosis and the regulation of membrane potential in the pancreatic beta cell, which may account for the impairments in insulin secretion observed in many CF patients. These novel insights suggest that the pathogenesis of CFRD is more complicated than originally thought, with implications for diabetes treatment and screening in the CF population. This review summarises recent emerging evidence in support of a primary role for endocrine pancreatic dysfunction in the development of CFRD.Summary• CF is an autosomal recessive disorder caused by mutations in the CFTR gene• The vast majority of morbidity and mortality in CF results from lung disease. However CFRD is the largest extra-pulmonary co-morbidity and rapidly accelerates lung decline• Recent experimental evidence shows that functional CFTR channels are required for normal patterns of first phase insulin secretion from the pancreatic beta cell• Current clinical recommendations suggest that insulin is more effective than oral glucose-lowering drugs for the treatment of CFRD. However, the emergence of CFTR corrector and potentiator drugs may offer a personalised approach to treating diabetes in the CF population

182 Impact of ivacaftor on glycaemic health in patients carrying the G551D mutation

Objectives Ivacaftor has led to significant benefits for patients with CF carrying the G551D mutation. The multisystem effects of CFTR modulation is increasingly recognised but often in the form of case reports. CF related diabetes has a significant impact on pulmonary function and mortality. We aimed to prospectively assess the effects of ivacaftor on glycaemic health. Methods We conducted a prospective observational study of patients with the G551D mutation. Baseline measures were recorded including spirometric measures, weight and sweat chloride. Glycaemic control was assessed using HbA1c and repeated measures were recorded at 1, 3, 6 and 12 months. Results Of 24 subjects included, 16 had normal glucose handling as defined by oral glucose tolerance test, 5 subjects had a diagnosis of CF-related diabetes and 3 subjects had impaired glucose tolerance prior to ivacaftor. FEV 1 , BMI and sweat chloride significantly improved at all timepoints compared to baseline. For the whole population, there was a significant decrease in HbA1c from baseline to 6 months: median 42.5 mmol/L vs 39.5 mmol/L, p=0.004. In patients with normal glucose tolerance there was a significant reduction in HbA1c at 3 (–2.1 mmol/L, p=0.027), 6 (–2.4 mmol/L, p=0.002) and 12 months (–1.9 mmol/L, p=0.03) compared to baseline. There were no significant changes in HbA1c or insulin requirements in the other subgroups. Conclusion Effective CFTR modulation may have an impact on the glycaemic health of patients with residual pancreatic endocrine function. These findings need to be followed longitudinally to see whether intervention with modulation therapy may protect against the development of CF related diabetes.

172 Does the 60-minute OGTT value have clinical significance in CF adults?

Objectives The 120 minute Oral Glucose Tolerance Test (OGTT) is the recommended diagnostic test for CF related diabetes (CFRD). In children, higher glucose levels 60 minutes after glucose challenge correlate with worse lung function and predict future development of CFRD. We examined whether a 60 minute glucose value could be used to identify patients at risk of clinical decline in adults with CF, who may benefit from early insulin treatment. Methods Correlation was sought between OGTT values at 0, 60 and 120 minutes and FEV1, Body Mass Index (BMI), number of days of IV antibiotics and glycosylated haemoglobin (HbA 1c ) in 83 adults attending the Bristol Adult CF Centre. In 14 cases in which 60 minute glucose was ±T1.1 mmol/L, repeated measures ANOVA/Friedman test were used to test for change in FEV1, BMI and number of IV days 1 year before, at the time of, and 1 year after the OGTT. Results There was no correlation between 0, 60 or 120 minute glucose and FEV 1 , BMI or IV days. There was a weak positive correlation between HBA 1C and 0, 60 and 120 minute glucose. In the patients with 60 minute glucose 11.1 mmol/L there were no changes in FEV 1 , BMI or number of IV days over two years (see table). Year −1Year 0Year +1Significant change over time?%predicted FEV 1 , mean±SD83±2183±1983±19No, p=0.57BMI, mean±SD24±4.424±4.124±3.9No, p=0.64IV Days, sum (median)219 (14)183 (0)186 (0)No, p=0.85 Conclusion The 60 minute glucose value does not correlate with FEV 1 , BMI or IV days in our adult population and does not identify patients who will clinically decline over the next year. Its use as a routine test is therefore questionable and newer tests such as CGMS may be of more value.

Cystic fibrosis-related diabetes: A distinct condition

Cystic fibrosis is the most common fatal inherited autosomal recessive disease in Caucasians, affecting approximately one out of every 2,000 births. Survival of patients with cystic fibrosis has significantly improved due to advances in respiratory and nutritional care, and their current average life expectancy is 30-40 years. Development of cystic fibrosis-related diabetes is a comorbidity that increases with age and may reach a prevalence up to 50% in adults. Its development is associated to impaired lung function and nutritional status, and early diagnosis and treatment are therefore essential to improve quality of life and performance status. Insulin therapy for diabetes and other early carbohydrate metabolism disorders may improve lung function and nutritional status of patients with cystic fibrosis.

Diabetes en la fibrosis quística: una entidad diferente

Cystic fibrosis is the most common fatal inherited autosomal recessive disease in Caucasians, affecting approximately one out of every 2,000 births. Survival of patients with cystic fibrosis has significantly improved due to advances in respiratory and nutritional care, and their current average life expectancy is 30-40 years. Development of cystic fibrosis-related diabetes is a comorbidity that increases with age and may reach a prevalence up to 50% in adults. Its development is associated to impaired lung function and nutritional status, and early diagnosis and treatment are therefore essential to improve quality of life and performance status. Insulin therapy for diabetes and other early carbohydrate metabolism disorders may improve lung function and nutritional status of patients with cystic fibrosis.

Effects of the microbial secondary metabolites pyrrolnitrin, phenazine and patulin on INS-1 rat pancreatic β-cells

The effects on pancreatic β-cell viability and function of three microbial secondary metabolites pyrrolnitrin, phenazine and patulin were investigated, using the rat clonal pancreatic β-cell line, INS-1. Cells were exposed to 10-fold serial dilutions (range 0-10 μg mL(-1)) of the purified compounds for 2, 24 and 72 h. After 2 h exposure, only patulin (10 μg mL(-1)) was cytotoxic. All compounds showed significant cytotoxicity after 24 h. None of the compounds altered insulin secretion with 2 and 20 mM glucose after 2 h. However, after 24 h treatment, phenazine and pyrrolnitrin (10 and 100 ng mL(-1)) potentiated insulin production and glucose-stimulated insulin secretion, whereas patulin had no effect. Exposure (24 h) to either phenazine (100 ng mL(-1)) or pyrrolnitrin (10 ng mL(-1)) caused similar increases in the Ca(2+) content of INS-1 cells. The outward membrane current was inhibited after 24 h exposure to either phenazine (100 ng mL(-1)) or pyrrolnitrin (10 or 100 ng mL(-1)). This study presents novel data suggesting that high concentrations of pyrrolnitrin and phenazine are cytotoxic to pancreatic β-cells and thus possibly diabetogenic, whereas at lower concentrations these agents are nontoxic and may be insulinotropic. The possible role of such agents in the development of cystic fibrosis-related diabetes is discussed.

Validation of insulin secretion indices in cystic fibrosis patients

Background and aims Impaired insulin secretion plays a key role in the development of cystic fibrosis-related diabetes (CFDR). Numerous indices to evaluate insulin secretion have been proposed, but their validity has not been explored in cystic fibrosis (CF). The aim of the present study was to validate surrogate indices of insulin secretion in CF patients against the gold standard, the intravenous glucose tolerance test (IVGTT). Methods 32 subjects were enrolled: 16 controls, 10 cystic fibrosis-normal glucose tolerant (CF-NGT) and 6 CFRD patients. All subjects underwent a 2-h oral glucose tolerance test (OGTT) and an IVGTT. Insulin secretion was estimated using three indices: the HOMA-β cell, the Stumvoll's early insulin secretion, and the insulin secretion rate (ISR). Results In control subjects, all insulin secretion indices correlated significantly with the IVGTT. In CF-NGT patients, the HOMA-β cell correlated significantly with the IVGTT at shorter time points but not over longer time-period. On the other hand, both OGTT-derived indices (Stumvoll and IRS) correlated significantly with the IVGTT for the CF-NGT and CFRD groups. Conclusion Since the OGTT is required on a regular basis in CF patients to screen for CFRD, OGTT-derived indices appear to be suitable for evaluating insulin secretion.

Calpain 10 and development of diabetes mellitus in cystic fibrosis

Diabetes mellitus (DM) and abnormal glucose tolerance (IGT) are common in cystic fibrosis (CF). The loss of pancreatic β-cells due to pancreatic fibrosis is thought to be one of the principal causes of diabetes in CF, but the aetiology of DM remains somewhat puzzling. Genetic factors may contribute to the development of CF related diabetes (CFRD). The purpose of this study was to investigate the role of polymorphisms in six genes on IGT or DM incidence. PCR and dHPLC were used to screen DNA samples for polymorphisms. Using 2-h oral glucose tolerance tests, 163 adult pancreatic insufficient CF patients have been subdivided in 3 groups: 54 NGT (normal glucose tolerance), 33 IGT and 76 CFRD. We found the first evidence for the association between CFRD and UCSNP-19 polymorphism in the CAPN10 gene. The UCSNP-19 genotype distribution differed significantly between NGT, IGT and CFRD groups. The difference reflected an increase in the 22 genotype (3 copies of 32-bp sequence) in IGT and CFRD patients ( p = 0.05). Odds ratio for the homozygote 22 versus homozygote 11 was 3.4 ( p = 0.02). All allele and genotype distributions for the other polymorphisms were similar in the three groups. In conclusion, our observations suggest that UCSNP-19 of CAPN10 may be involved in the pathogenesis of diabetes in CF.