1 2 3 Cystic fibrosisrelated diabetes (CFRD) is a distinct - - PDF document

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• Cystic fibrosis–related diabetes (CFRD) is a distinct clinical entity from type

1 or type 2 diabetes, affecting approximately 35% of the cystic fibrosis (CF) population, with a peak age of onset in the 20-to 24-year range

• Unlike type 2 diabetes, CFRD is characterized by a severe but incomplete

insulin deficiency, and insulin resistance is modest, fluctuating with infection. Notably, A1C is not a reliable indicator of blood glucose in CFRD, and metabolic syndrome, macrovascular complications, and cardiovascular disease are not dominant causes of death as in type 2 diabetes. Neither type 2 diabetes nor CFRD have an autoimmune etiology as does type 1 diabetes Reference Moran A, Becker D, Casella SJ, et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care. 2010;33(12):2677-2683. 4

Key Points

• Oral glucose tolerance test (OGTT) results are used to diagnose glucose

metabolism disorders, including CFRD

• For healthy outpatients, OGTT is the assessment of choice for CFRD,

although assessments such as fasting plasma glucose (FPG) may be indicated during hospitalizations or acute illnesses. Diagnostic criteria for CFRD based on OGTT results are shown in the table Reference Kelly A, Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros. 2013;12(4):318-331 5

• In one study of 527 patients with CF at a single center, 33% of patients had

diabetes, and prevalence increased steadily with age peaking at 45% to 50% by age 40. Incidence was roughly 15% among adolescents and 50% among adults with CF in this study, with comparable incidences in both sexes in most of the age groups1,2

• Cases of diabetes have occurred in children as young as infants with CF,

whereas overt diabetes is comparatively rare in non-CF pediatric populations, occurring at a rate of approximately 1.5% among individuals younger than 10 years of age, and typically being associated with type 1 autoimmune diabetes2

• Other studies have shown CFRD to occur in as many as 1 of 5 younger

patients with CF, and incidences of CFRD as high as 45% have been reported by age 20 years2 References

• 1. Moran A, Dunitz J, Nathan B, et al. Cystic fibrosis-related diabetes: current

trends in prevalence, incidence, and mortality. Diabetes Care. 2009;32(9):1626-1631.

• 2. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in
• children. Lancet Diabetes Endocrinol. 2013;1(1):52-58.

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Key Point

• Glucose abnormalities may precede the onset of CFRD in children under 10 years of age1

Additional Information

• In one study of 152 patients with CF at a single center, a high prevalence of glucose

metabolism derangements (GMDs) was observed in patients with CF with pancreatic insufficiency (PI) between the ages of 6 and 10 years

• The results suggest that, despite current recommendations of the Cystic Fibrosis

Foundation, the American Diabetes Association, and the Pediatric Endocrine Society, screening for GMDs may be indicated in patients younger than 10 years of age, particularly in those with PI2

• In a prospective multicenter study in children ages 3 months to 5 years with and without

CF, at their first visit, 9 of the 23 subjects with CF with full data available met criteria for abnormal glucose tolerance (AGT) (P=0.03 vs control). One had indeterminate glucose tolerance (INDET), 6 had impaired glucose tolerance (IGT), and 2 met criteria for CFRD. None of the controls had AGT. In subjects who had multiple visits, 3 additional subjects with CF subsequently developed IGT (P=0.01 for having exhibited AGT at any visit CF vs control)3

• These findings emphasize the need for early monitoring for CFRD in patients with CF

References 1. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol. 2013;1(1):52-58. 2. Mozzillo E, Raia V, Fattorusso V, et al. Glucose derangements in very young children with cystic fibrosis and pancreatic insufficiency. Diabetes Care. 2012;35(11):e78. 3. Yi Y, et al. abnormal glucose tolerance in infants and young children with cystic fibrosis. Am J Respir Crit Care Med. 2016 Jul 22. doi: 10.1164/rccm.201512-2518OC. [Epub ahead

• f print].

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• Studies of CFRD prevalence have shown that elevations in fasting plasma

glucose are less common among younger patients, and instead predominate in the older age groups

• In a study of 527 patients with CF at a single center, 33% of patients had

diabetes, and incidence increased steadily with age. The prevalence of CFRD with fasting hyperglycemia increased with age and predominated after the age of 40 years, whereas CFRD without fasting hyperglycemia was more prevalent in the younger age groups Reference Moran A, Dunitz J, Nathan B, et al. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care. 2009;32(9):1626-1631. 8

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• The results from a prospective, 4-year study of patients with CF without diabetes has

shown a pattern of decline in pulmonary function, as assessed by ppFEV1, that was directly proportional to the severity of glucose intolerance at baseline

• The study group comprised 152 patients (n=77 female; n=75 male) without fasting

hyperglycemia and having stable lung health status. Patients were found on OGTT to have either normal glucose tolerance (45.4%), impaired glucose tolerance (38.8%), or CFRD without fasting hyperglycemia (15.8%)

• There was a difference among the groups based on OGTT; whereas patients with

normal glucose tolerance had no decline in their percent FEV1 rates, those with impaired glucose tolerance or CFRD without fasting hyperglycemia had significant declines of -1.36 and -2.44/year, respectively

• These differences were observed after adjustment for sex and baseline body mass

index (BMI), microbiology, and FEV1

• Similar findings were observed for insulin AUC, and after adjustment for sex and

baseline BMI, microbiology, and FEV1, with those subjects in the lowest quartiles having the highest degree of decline relative to those in the higher quartiles

• The results suggest that the degree of glucose tolerance impairment and the degree of

insulin deficiency correlates with the rate of lung functional decline in patients with CF, suggesting a direct cause/effect relation Reference Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med. 2000;162(3 Pt 1):891-895.

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Key Point

• CFRD is important to recognize as a condition in patients with CF, as it has been

associated with increased mortality Additional Information

• In a retrospective cohort study of 8029 individuals with CF in the UK Cytsic

Fibrosis Registry from 1996 to 2005, a total of 5892 patients were included in an analysis of mortality rates1

• Results showed that individuals with diabetes had higher age-adjusted mortality

rates compared with those without diabetes (4.2 vs 1.5 per 100 person-years, respectively). Absolute mortality rates were also significantly higher across all age groups (P=0.009), with the greatest relative difference occurring in the <10-year age group1

• In a more recent study of 664 patients followed from 2008 through 2012, there

remained a significantly higher incidence of mortality for patients with CFRD, regardless of genotype, compared with patients with CF without CFRD2 References

• 1. Chamnan P, Shine BS, Haworth CS, Bilton D, Adler AI. Diabetes as a

determinant of mortality in cystic fibrosis. Diabetes Care. 2010;33(2):311-316.

• 2. Lewis C, Blackman SM, Nelson A, et al. Diabetes-related mortality in adults with

cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200.

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Key Point

• CFRD is important to recognize as a condition in patients with CF, as it has

been associated with increased mortality. The difference in mortality rate between patients with and without CFRD is higher in male patients compared with female patients Additional Information

• In a study of 664 patients followed from 2008 through 2012, there was a

significantly higher incidence of mortality for patients with CFRD, regardless

• f genotype, compared with patients with CF without CFRD

Reference Lewis C, Blackman SM, Nelson A, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200. 12

Key Point

• The early appearance of impaired glucose metabolism was associated with

a higher rate of lung transplantation Additional Information

• Early appearance was defined as before 15 years for IGT and before 18

years for diabetic OGTT

• In the entire cohort, rates of transplantation did not differ between boys and

girls Reference Bismuth E, Laborde K, Taupin P, et al. Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis. J Pediatr. 2008;152(4):540- 545. 13

Key Point

• OGTT and insulin levels at 1 hour have been correlated with BMI in patients

with CF Additional Information

• In a cross-sectional analysis of 240 adult patients with CF from the Montreal

Cystic Fibrosis Cohort, the average age was 25.8 years and the average BMI was 21.7 kg/m2

• OGTT plasma glucose levels at 1 hour, or G60 values (based on a median

value of 11 mmol/L), showed that higher G60 was significantly associated with lower lung function (r = -0.225, P=0.001)

• Similarly, analysis of OGTT plasma insulin levels at 1 hour, or I60 values

(based on a median value of 43.4 mU/mL), showed that lower I60 values were associated with lower BMI and pulmonary status

• By combining the G60 and I60 values, it was found that the worst case

scenario in terms of lung function occurs with a low I60 and a high G60 value, which was associated with a 13% decline in lung function in %FEV1 compared with the best case scenario (high I60 and low G60) Reference Coriati A, Ziai S, Lavoie A, Berthiaume Y, Rabasa-Lhoret R. The 1-h oral glucose tolerance test glucose and insulin values are associated with markers

• f clinical deterioration in cystic fibrosis. Acta Diabetol. 2016;53(3):359-366.

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Key Point

• In patients with CF and a normal 2-hour OGTT, abnormal glucose levels as

detected by continuous glucose monitoring (CGM) have been associated with declines in lung function Additional Information

• In this study of 38 patients with normal OGTT, 2 groups were defined, those

either having (Group 1) or not having (Group 2) interstitial glucose levels greater than 11 mmol/L during CGM

• FEV1 and FVC levels were significantly lower in Group 2 vs Group 1

patients

• P. aeruginosa colonization was also more frequently observed in Group 2

patients compared with Group 1 (83.3% vs 44.0%)

• These results were independent of age, age at diagnosis, sex, genotype,

exocrine pancreatic insufficiency, and BMI standard deviation score

• The findings suggest that early glucose abnormalities, as detected by CGM

but not via 2-hour OGTT, are associated with declines in lung function and a greater rate of pathogenic microbial colonization Reference Leclercq A, Gauthier B, Rosner V, et al. Early assessment of glucose abnormalities during continuous glucose monitoring associated with lung function impairment in cystic fibrosis patients. J Cyst Fibros. 2014;13(4):478- 484. 15

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• Glucose abnormalities may be diagnosed in patients with CF and healthy individuals

by a variety of means, including fasting plasma glucose, OGTT, and glycated hemoglobin, but all methods are appropriate for use in the diagnosis of CFRD1,2

• Beginning in 2010, the US Cystic Fibrosis Foundation and the International Society of

Pediatric and Adolescent Diabetes have recommended screening for CFRD in patients with CF starting at 10 years of age2

• For healthy outpatients, OGTT is the assessment of choice for CFRD, although

assessments such as fasting plasma glucose may be indicated during hospitalizations

• r acute illnesses2
• Hemoglobin A1c is not recommended to be used as a screening tool, as it is believed

to underestimate overall glycemic control in patients with CF; however, levels of 6.5%

• r greater are indicative of CFRD2
• Screening during overnight enteral feeding is also recommended3

References 1. National Institute of Diabetes and Digestive and Kidney Diseases. Comparing Diabetes Blood Tests. http://www.niddk.nih.gov/health-information/health- topics/diagnostic-tests/comparing-tests-diabetes- prediabetes/Documents/Comparing_Tests_for_DM_Chart_Only_508.pdf. Accessed February 17, 2016. 2. Kelly A, Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros. 2013;12(4):318-331. 3. Moran A, Pillay K, Becker DJ, Acerini CL; International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr

• Diabetes. 2014;15(Suppl 20):65-76.

• There is evidence that 1-hour OGTT may be a more sensitive indicator of

abnormal glucose tolerance in patients with CF1

• In one study of 101 children with CF who underwent OGTT, there were 14 (14%)

with plasma glucose levels of ≥200 mg/dL at 1 hour. Among this group, there were 9 (64%) who had a normal plasma glucose of <140 mg/dL as assessed at 2 hours and would have previously been labeled as normal glucose tolerance. Two of these 14 patients had CFRD as defined by a plasma glucose at 2 hours of 200 mg/dL or greater, and an additional 3 of the 14 had impaired glucose tolerance1

• Another small study (N=16) of stable patients with CF compared CGM, 1-hour

OGTT, and 2-hour OGTT. CGM was the most sensitive method of detecting and excluding dysglycemia (100% sensitivity and negative predictive value [NPV]) and therefore was used as the comparator for OGTT2

• The results suggest that among children undergoing screening for CFRD, the 1-

hour plasma glucose is frequently elevated despite normal 2-hour or fasting glucose concentrations. Thus, plasma glucose excursions that are clinically relevant may be missed using only 2-hour OGTT assessments1 References

• 1. Brodsky J, Dougherty S, Makani R, Rubenstein RC, Kelly A. Elevation of 1-hour

plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis. Diabetes Care. 2011;34(2):292-295.

• 2. Dyce P et al. NACFC 2014. Abstract 574.

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• Patients with fasting glycemia <6.9 mmol/L who were at least 10 years of age (range:

12.4 to 57.3 years) were followed at the CF center of Strasbourg University Hospital (France) and enrolled in a prospective monocentric cross-sectional cohort study between March 2009 and September 20121 – Among 38 patients in the study who had normal OGTT and also underwent CGM, 12 (31.6%) had glucose abnormalities on CGM, defined as glucose values of 11 mmol/L or greater1 – The results of a representative CGM for a patient with CF with normal OGTT are shown in the figure. The results show pathological CGM recordings over the course of 3 days (Saturday, in green; Sunday, in purple; and Monday in light blue) in a patient with normal OGTT results. There were several interstitial glucose peaks higher than 140 mg/dL (7.8 mmol/L) present after each meal. A single peak higher than 200 mg/dL (11 mmol/L) was observed on Sunday evening1 – The findings suggest that abnormalities in glucose tolerance among patients with CF can be detected by CGM but not conventional OGTT results1

• Another small study (N=16) of stable patients with CF compared CGM, 1-hour OGTT,

and 2-hour OGTT. CGM was the most sensitive method of detecting and excluding dysglycemia (100% sensitivity and NPV). Using the parameter of any abnormality on OGTT improved the detection rate further; however, 14 patients with clinically significant dysglycemia, as identified on CGM (21%), had completely normal OGTT responses2 References 1. Leclercq A, Gauthier B, Rosner V, et al. Early assessment of glucose abnormalities during continuous glucose monitoring associated with lung function impairment in cystic fibrosis patients. J Cyst Fibros. 2014;13(4):478-484. 2. Dyce P et al. NACFC 2014 Abstract 574.

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Key Point

• Glycemic status is a significant predictor of CFRD in patients with CF

Additional Information

• Schmid and coworkers used standardized OGTT to determine predictors for

future CFRD in a large prospectively followed cohort of patients (N=1093). They showed that impaired fasting glucose and impaired glucose tolerance were predictors of future CFRD Reference Schmid K, Fink K, Holl RW, Hebestreit H, Ballmann M. Predictors for future cystic fibrosis-related diabetes by oral glucose tolerance test. J Cyst Fibros. 2014;13(1):80-85. 20

Key Points

• Microvascular complications are common in individuals with type 1 and type

2 diabetes and represent a significant source of morbidity and mortality

• A significant percentage of patients with CFRD with fasting hyperglycemia

showed signs of microvascular complications compared with those without fasting hyperglycemia Additional Information

• From 1990 to 2005, 775 patients aged ≥6 years were followed
• CFRD was diagnosed by an oral glucose tolerance test or fasting

hyperglycemia in 285 subjects (52% female), 64% of whom had fasting hyperglycemia

• Most patients with CFRD without fasting hyperglycemia progressed to

CFRD with fasting hyperglycemia over time

• No subject with CFRD without fasting hyperglycemia had retinopathy or

abnormal Ualb:Cr

• In subjects with CFRD with fasting hyperglycemia and diabetes for >10

years, 14% had microalbuminuria and 16% had retinopathy Reference Schwarzenberg SJ, Thomas W, Olsen TW, et al. Microvascular complications in cystic fibrosis-related diabetes. Diabetes Care. 2007;30(5):1056-1061. 21

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Key Points

• In healthy individuals, insulin plays a key role in the storage of glucose, amino acids, and
• fat. In the fed state, insulin secretion is upregulated and glucose is stored via glycogen

synthesis and uptake by fat and muscle. Insulin also acts to inhibit glycogenolysis and gluconeogenesis by the liver, and suppresses lipolysis and ketogenesis in the fed state1

• Insulin action is carefully regulated in response to circulating glucose concentrations. Insulin

is not secreted if the blood glucose concentration is ≤3.3 mmol/L, but is secreted in increasing amounts as glucose concentrations increase beyond this threshold2

• Postprandially, the secretion of insulin occurs in 2 phases: An initial rapid release of

preformed insulin, followed by increased insulin synthesis and release in response to blood

• glucose. Long-term release of insulin occurs if glucose concentrations remain high2
• The incretins, gastric inhibitory peptide (GIP) and glucagon-like peptide (GLP-1) secreted in

the gastrointestinal tract,2 are responsible for approximately 70% of the insulin response to an oral glucose load, and thus the insulin response to intravenously administered glucose is markedly diminished relative to an oral glucose load3

• Incretins also play a role in suppressing glucagon secretion, delaying gastric emptying, and

promoting lipogenesis2 References 1. Nussey S, Whitehead S. Chapter 2. The endocrine pancreas. In: Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. 2. Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and regulation: beyond insulin and glucagon. Diabetes Spectrum. 2004;17(3):183-190. 3. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non- insulin-dependent diabetes. Diabetologia. 1986;29(1):46-52.

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Key Point

• Few patients with CF have normal glucose tolerance, and patients with CF

have been shown to have a varying degree of postprandial hyperglycemia, as evidenced by 30, 60, and 90 plasma glucose levels during an OGTT Additional Information

• The population shown is from a cross-sectional analysis of baseline data

from the Montreal Cystic Fibrosis Cohort (MCFC)

• Non-diabetic adult patients with CF (≥18 years) from the MCFC underwent

a 2-h OGTT screening and were classified according to conventional criteria (ADA and CFF), based on their OGTT plasma glucose values, as having NGT (G0 ≤7.0 mmol/L and G2 ≤7.7 mmol/L), INDET (G0 ≤7.0 mmol/L and G2 ≤7.7 mmol/L, but G1 ≥11.1 mmol/L), impaired glucose tolerance (G0 ≤7.0 mmol/L and G2 ≥7.8 mmol/L, and ≤11.0 mmol/L) or de novo CFRD (G2 ≥11.1 mmol/L) – G0 is fasting plasma glucose, G1 is 1-hour glucose during OGTT, and G2 is 2-h glucose during OGTT Reference Coriati A, Ziai S, Azar M, et al. Characterization of patients with cystic fibrosis presenting an indeterminate glucose tolerance (INDET). J Cyst Fibros. 2016;15(1):127-132. 24

Key Findings

• Studies show an impaired insulin response in children and adolescents with CF in

comparison with the normal rapid insulin response to a glucose load, observed in healthy controls; instead, patients with CF display a delayed and diminished insulin response1-3 Additional Information

• The figure shows insulin levels during OGTT in patients with CF who had normal

glucose tolerance or abnormal glucose tolerance (which included impaired fasting glucose [IFG], impaired glucose tolerance [IGT], IFG/IGT, and diabetes as determined by the American Diabetes Association criteria) compared with healthy adolescents as a reference group3

• The study subjects were part of a total clinic population of 208 patients with CF

receiving care at Cincinnati Children's Hospital Medical Center in 2004. The reference group of adolescent subjects included 13 subjects with a male/female ratio of 3:10 enrolled in a previous study of glucose metabolism. These subjects were free of chronic medical conditions and were not receiving medication at the time of evaluation References 1. Kelly A, Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros. 2013;12(4):318-331. 2. Barrio R. Management of endocrine disease: cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues. Eur J Endocrinol. 2015;172(4):R131-R141 3. Elder DA, Wooldridge JL, Dolan LM, D'Alessio DA. Glucose tolerance, insulin secretion, and insulin sensitivity in children and adolescents with cystic fibrosis and no prior history of diabetes. J Pediatr. 2007;151(6):653-658.

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• There is also evidence for an impaired incretin response in patients with CF
• Compared with healthy subjects, patients with CF are prone to rapid gastric

emptying following a high-fat/high-carbohydrate meal, with profound impairment in secretion of incretins GLP-1 and GIP, a deficient insulin response to glycemia, and postprandial glycemic excursions

• Fasting GLP-1 tended to be lower than controls with or without enzyme

supplementation, whereas postprandial GLP-1 was significantly lower than controls (left figure), and this could be reversed by pancreatic enzyme

• supplementation. Similarly, plasma GIP was lower than controls

postprandially (right figure), and this could be only partially restored with enzyme supplementation, remaining lower than healthy subjects Reference Kuo P, Stevens JE, Russo A, et al. Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis--effects of pancreatic enzyme supplementation. J Clin Endocrinol Metab. 2011;96(5):E851-E855. 26

Key Points

• Euglycemic clamp studies have generally demonstrated a normal insulin

sensitivity in non-diabetic patients with CF, although insulin resistance has been observed and may be related to illness and inflammation or glucocorticoid use. Overall, however, peripheral insulin resistance is modest in CFRD1,2

• Liver insulin resistance, characterized by increased hepatic glucose

production, either in the fasting state and in response to insulin infusions,

• ccurs in patients with CF with diabetes, as well as those with normal

fasting glucose levels References

• 1. Moran A, Becker D, Casella SJ, et al. Epidemiology, pathophysiology, and

prognostic implications of cystic fibrosis-related diabetes: a technical

• review. Diabetes Care. 2010;33(12):2677-2683.
• 2. Barrio R. Management of endocrine disease: Cystic fibrosis-related

diabetes: novel pathogenic insights opening new therapeutic avenues. Eur J Endocrinol. 2015;172(4):R131-R141. 27

Key Points

• Patients with CF and abnormal glucose tolerance do not appropriately suppress protein breakdown in

response to insulin; therefore, this mechanism of preserving protein mass is defective in people with CF.1 Suppression of fat breakdown is also reduced in people with CF and impaired glucose tolerance2

• These findings suggest that even well-nourished, clinically stable patients with CF with relatively

modest abnormalities in insulin secretion experience abnormal substrate metabolism that may negatively impact their overall health and nutritional status2 Additional Information

• Patients and controls in the protein metabolism study were matched on age, sex, weight, height, BMI,

and lean body mass. Patients with CF had been diagnosed in the previous 6 months with either IGT (n=6) or CFRD without fasting hyperglycemia (n=6)1

• Protein turnover was studied on the first day in the fasting state and was repeated on the third day

during insulin infusion using infusion of stable isotopes of leucine, tyrosine, and phenylalanine1

• Baseline fasting insulin levels and protein metabolism were normal in patients with CF and did not

differ from control subjects. The degree of suppression of all 3 protein synthesis markers was significantly lower between patients with CF and controls1

• A similar study using isotope-labeled free fatty acid (FFA) infused and measured at baseline (fasted)

and under euglycemic, hyperinsulinemic clamp to mimic the postprandial state showed reduced suppression of lipolysis in patients with CF with IGT vs controls, although the differences were not significant (P=0.08)2 References 1. Moran A, Milla C, Ducret R, Nair KS. Protein metabolism in clinically stable adult cystic fibrosis patients with abnormal glucose tolerance. Diabetes. 2001;50(6):1336-1343. 2. Moran A, Basu R, Milla C, Jensen MD. Insulin regulation of free fatty acid kinetics in adult cystic fibrosis patients with impaired glucose tolerance. Metabolism. 2004;53(11):1467-1472.

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Key Point

• Genes other than CFTR influence the risk of CFRD in patients with CF

Additional Information

• In a genome-wide association study, conducted in some 3059 individuals

with CF, including 644 with CFRD, single nucleotide polymorphisms (SNPs) in the SLC26A9 gene were significantly associated with CFRD, with an

• verall hazard ratio of 1.38 (P= - 3.6 x 10-8)
• SLC26A9 SNPs modify risk of CFRD independently of meconium ileus, liver

disease, and female sex

• Four other risk alleles were identified in patients with CF that are also

associated with susceptibility to type 2 diabetes

• There was a combined impact of these risk alleles, such that, when

stratified by a 5-SNP risk score, CFRD prevalence increased from 11% among those with zero or 1 risk allele to 40% for those with 8 or 9 risk alleles Reference Blackman SM, Commander CW, Watson C, et al. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes. 2013;62(10):3627-3635. 29

• Treatment guidelines for CFRD have been recommended by the International

Society for Pediatric and Adolescent Diabetes

• Categories of abnormal glucose tolerance have been outlined for patients with CF

and include normal, indeterminate, or impaired glucose tolerance, and CFRD with

• r without fasting hyperglycemia; nearly 2/3 of patients with CFRD do not have

fasting hyperglycemia

• The 2-hour OGTT is the screening method of choice, and patients with CF without

CFRD should begin being screened annually by 10 years of age; the use of A1c is unreliable in the diagnosis of CFRD and is not recommended as a diagnostic tool

• Insulin is the treatment of choice for patients with CFRD, and use of oral

antidiabetic agents is not recommended. Plasma glucose monitoring and treatment should have the goal of maintaining levels in accordance with American Diabetes Association guidelines for other persons with diabetes

• The Cystic Fibrosis Foundation evidence-based guidelines for nutrition in patients

with CF should be followed by persons with CFRD and moderate weekly aerobic exercise is recommended Reference Moran A, Pillay K, Becker DJ, et al. ISPAD Clinical Practice Consensus Guidelines

• 2014. Management of cystic fibrosis-related diabetes in children and adolescents.

Pediatr Diabetes. 2014;15(Suppl 20):65-76.

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Key Point

• Several hypotheses have been proposed for the mechanism of CFRD pathogenesis

Additional Information

• Pancreatic destruction leads to loss of islet cells, fibrosis, and amyloid deposits in islets1
• Defective CFTR activity leads to insufficient depolarization and Ca2+ mobilization in response to

glucose in cultured β-cells2

• β-cells synthesize large amounts of protein. Chronic accumulation of misfolded CFTR may
• verwhelm the β-cell proteolytic degradation pathways, leading to sustained endoplasmic reticulum

stress responses (unfolded protein response, endoplasmic reticulum–associated protein degradation) and β-cell apoptosis3

• A chronic inflammatory state produced by oxidative stress, reactive oxygen species production,4

elevated pro-inflammatory cytokines,1 defective fat-soluble antioxidant absorption, and possibly vitamin D deficiency contribute to β-cell destruction and dysfunction and insulin resistance1,4

• Defective incretin secretion in CF may also contribute to inadequate β-cell function
• Insulin sensitivity is normal in patients with CF in most studies,1,5 and in studies showing reduced

insulin sensitivity, issues of study populations, methods, and interpretation may be factors5

• Insulin resistance in CF may develop because of abnormal localization of the GLUT-4 glucose

transporter and/or elevated TNF-α levels6 References 1. Barrio R. Management of endocrine disease: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues. Eur J Endocrinol. 2015;172(4):R131-R141. 2. Guo JH, Chen H, Ruan YC, et al. Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR. Nat Commun. 2014;5:4420. 3. Ali BR. Is cystic fibrosis-related diabetes an apoptotic consequence of ER stress in pancreatic cells? Med Hypotheses. 2009;72(1):55-57. 4. Galli F, Battistoni A, Gambari R, et al. Oxidative stress and antioxidant therapy in cystic fibrosis. Biochim Biophys Acta. 2012;1822(5):690-713. 5. Kelly A, Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros. 2013;12(4):318-331. 6. Hardin DS, Leblanc A, Marshall G, Seilheimer DK. Mechanisms of insulin resistance in cystic

• fibrosis. Am J Physiol Endocrinol Metab. 2001;281(5):E1022-E1028.

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Key Point

• Even patients with CF and normal peripheral insulin sensitivity as measured

by glucose disposal in response to insulin have defective insulin responses related to suppression of protein breakdown, hepatic glucose production, and lipolysis1-3 Additional Information

• These studies were performed using isotope-labeled amino acids that are

not synthesized by the body (leucine, phenylalanine, tyrosine),1 glucose,2 or palmitate3 as tracers to assess insulin action in muscle, liver, and fat tissues, respectively

• Euglycemic, hyperinsulinemic, and hyperglycemic clamp protocols were

used to determine the effects of insulin1-3 References

• 1. Moran A, Milla C, Ducret R, Nair KS. Protein metabolism in clinically stable

adult cystic fibrosis patients with abnormal glucose tolerance. Diabetes. 2001;50(6):1336-1343.

• 2. Moran A, Pyzdrowski KL, Weinreb J, et al. Insulin sensitivity in cystic
• fibrosis. Diabetes. 1994;43(8):1020-1026.
• 3. Moran A, Basu R, Milla C, Jensen MD. Insulin regulation of free fatty acid

kinetics in adult cystic fibrosis patients with impaired glucose tolerance.

• Metabolism. 2004;53(11):1467-1472.

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Key Point

• Insulin deficiency and hyperglycemia may contribute to pulmonary function decline in several ways

Additional Information

• A study presented at NACFC 2015 examined the impact of glucose and insulin on airway tight

junction barrier using normal and CF epithelial cell experimental models; they found that insulin negatively and specifically affected the airway epithelia in CF compared with normal cells, especially in the presence of high glucose. Their results suggest that the negative effects of insulin and glucose in CF airway epithelia may allow leakage of metabolites into the airway, supporting the growth of pathogenic microbes leading to airway exacerbations1

• Other studies have suggested that aberrant glucose metabolism in the airway epithelia of patients

with CF foster pathogenic bacterial growth, including Pseudomonas aeruginosa, Staphylococcus Sp, and S. maltophilia2-4

• Inflammatory responses in patients with CF may also be linked to enhanced lymphocyte responses

and infiltration into the lungs as a result of ongoing hyperglycemia5

• There is evidence that the receptor for advanced glycation end products (RAGE) is active in the

airways but not the vascular compartment of patients with CF and CFRD, and this correlates with lung function; RAGE may thus be another contributor to the enhanced inflammatory state that is present in CF and to a greater degree in CFRD6 References 1. Molina SA et al. NACFC 2015. Abstract 150. 2. Hameed S, Jaffé A, Verge CF. Advances in the detection and management of cystic fibrosis related

• diabetes. Curr Opin Pediatr. 2015;27(4):525-533.

3. Fothergill JL. ECFC 2015. Abstract ePS06.1. 4. Garnett JP, Gray MA, Tarran R, et al. Elevated paracellular glucose flux across cystic fibrosis airway epithelial monolayers is an important factor for Pseudomonas aeruginosa growth. PLoS One. 2013;8(10):e76283. 5. Ziai S, Coriati A, Gauthier MS, Rabasa-Lhoret R, Richter MV. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis? Diabetes Res Clin Pract. 2014;105(1):22-29. 6. Mulrennan S, Baltic S, Aggarwal S, et al. The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes. Sci Rep. 2015;5:8931.

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Key Points

• Glucose excursions were significantly different between patients with CF

and CFRD without FH compared with those with NGT or IGT (P<0.0001)

• The peak insulin level was quantitatively similar in all groups, but the timing
• f the peak was increasingly delayed as glucose tolerance worsened.

Patients with CFRD had significantly lower insulin excursion (measured as the area under the curve) than those with IGT or NGT (P<0.05) Additional Information

• Between January 1992 and December 1995, the OGTT was performed on

195 nondiabetic patients with CF aged 5 years or older who were patients followed at the University of Minnesota CF Center

• The OGTT was not performed for patients with CFRD with FH, patients who

had been hospitalized for acute illness in the preceding 2 months, or patients who were not fasting Reference Moran A, Doherty L, Wang X, Thomas W. Abnormal glucose metabolism in cystic fibrosis. J Pediatr. 1998;133(1):10-17. 43

Key Point

• Defects in the insulin secretory response in CF may relate in part to loss of islets

and islet cells Additional Information

• In qualitative autopsy assessments of patients with CF (n=17), patients with CFRD

had reduced numbers of islets over time (top graph) and the highest levels of exocrine pancreas atrophy and fat replacement. Ages shown are mean ± SD1

• However, degree of fibrosis was not necessarily different in patients with CF when

comparing the patients with or without CFRD2

• A reduction in β-cell mass has also been reported in mice with the F508del CFTR

mutation, relative to their wild-type counterparts. Whereas there was no difference

• bserved at 11 weeks, a reduction in β-cell mass was observed at 18 weeks,

becoming significant at 24 weeks (bottom graph)3 References

• 1. Iannucci A, Mukai K, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis:

an immunohistochemical study. Hum Pathol. 1984;15(3):278-284.

• 2. Barrio R. Management of endocrine disease: Cystic fibrosis-related diabetes:

novel pathogenic insights opening new therapeutic avenues. Eur J Endocrinol. 2015;172(4):R131-R141.

• 3. Fontés G, Ghislain J, Benterki I, et al. The ΔF508 mutation in the cystic fibrosis

transmembrane conductance regulator is associated with progressive insulin resistance and decreased functional β-cell mass in mice. Diabetes. 2015;64(12):4112-4122.

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• There is evidence that the defect in insulin secretion observed in patients with CF results in

part from a global insufficiency of the β-cell response to glucose, and that defective CFTR is involved in the reduced response

• In mouse and human β-cells, antagonists of CFTR block insulin secretion as well as an

ATP-sensitive and cyclic AMP-dependent current. In this model, CFTR was also shown to be a likely regulator of the chloride channel Anoctamin 1 (ANO1), and inhibition of CFTR was found to decrease exocytosis in mouse and human β-cells1

• A model has been proposed whereby high glucose increases intracellular ATP causing

depolarization and a subsequent influx of intracellular calcium, ultimately triggering

• exocytosis. CFTR via ANO1-mediated chloride influx and/or other mechanisms improves

cyclic AMP-dependent granular priming and exocytosis1

• Support for this hypothesis is provided by studies that have shown that the silencing of

CFTR using small hairpin RNA inhibits the secretion of insulin by 70%, rendering the β-cells less able to respond to glucose stimuli relative to control treated cells2

• Similarly, studies of mice harboring the F508del-CFTR mutation, the most common type of

CFTR mutation, also show that CFTR is required for glucose induced whole cell currents, membrane depolarizations, electrical bursts or action potentials, and calcium oscillations, as well as insulin secretion3 References 1. Edlund A, Esguerra JL, Wendt A, Flodström-Tullberg M, Eliasson L. CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells. BMC Med. 2014;12:87. 2. Ntimbane T, Mailhot G, Spahis S, et al. CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response. Am J Physiol Endocrinol Metab. 2016;310(3):E200-E212. 3. Guo JH, Chen H, Ruan YC, et al. Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR. Nat Commun. 2014;5:4420.

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Key Points

• Ali has proposed a model whereby increased β-cell apoptosis occurs as a

result of chronic stress on the endoplasmic reticulum due to the chronic presence of an aberrantly folded CFTR in islet cells

• In this model, the unfolded protein response in the endoplasmic reticulum of

pancreatic cells is thought to result in a persistent apoptotic signal and cell death

• Because the β-cells of the pancreas have a highly developed endoplasmic

reticulum and an important protein secretory function, it is believed that they may be especially sensitive to endoplasmic reticulum–related stresses and subsequent apoptosis, and this may be one mechanism accounting for β- cell death and the development of diabetes

• Support for this hypothesis comes from the finding that patients with CF and

Class II CFTR mutations, which are non-functional and are retained in the endoplasmic reticulum, are some 20 times more likely to develop CFRD than are patients with Class IV CFTR mutations, which are appropriately trafficked to the cell surface

• The findings suggest that the CFRD phenotype is not merely a result of

CFTR nonfunction, but instead results from β-cell apoptosis as a result of aberrant CFTR folding and resulting endoplasmic reticulum stress Reference Ali BR. Is cystic fibrosis-related diabetes an apoptotic consequence of ER stress in pancreatic cells? Med Hypotheses. 2009;72(1):55-57. 40

• In epithelial cells of patients with CF, defects in CFTR function may lead to a redox

imbalance and abnormally high levels of reactive oxygen species; this could be due to defects in glutathione metabolism, reduced intake of antioxidants as a result of malnutrition, and inflammatory damage to the lungs, pancreas, and liver, all of which may contribute to systemic inflammation and oxidative stress1

• Results from a β-cell model system further suggest a protective effect of CFTR in β-cells, in

that silencing of the CFTR using small hairpin RNA (shRNA) resulted in impaired insulin secretion, and this condition was exacerbated by oxidative stress. Reduced insulin secretion by β-cells in this model system may have been a result of abnormal ATP production, β-oxidation of fatty acids, apoptosis, and inflammation2

• High mobility group box 1 protein (HMGB1), which plays an important role in inflammatory

responses, also appears to be progressively elevated in relation to worsening glycemic status in patients with CF.3 Whereas serum concentrations of HMGB1 were similar in normal age-matched controls or patients with CF and normal glucose tolerance, as shown in the figure, levels were slightly elevated in patients with CF and impaired glucose tolerance, and became significantly elevated in those with CFRD

• In vitro experiments confirmed that the loss of CFTR function resulted in the increased

HMGB1 expression and insulin reduced HMGB1 mRNA and protein levels3 References 1. Galli F, Battistoni A, Gambari R, et al. Oxidative stress and antioxidant therapy in cystic

• fibrosis. Biochim Biophys Acta. 2012;1822(5):690-713.

2. Ntimbane T, Mailhot G, Spahis S, et al. CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response. Am J Physiol Endocrinol Metab. 2016;310(3):E200-E212. 3. Montanini L, Cirillo F, Smerieri A, et al. HMGB1 is increased by CFTR loss of function, is lowered by insulin, and increases in vivo at onset of CFRD. J Clin Endocrinol Metab. 2016;101(3):1274-1281.

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Key Point

• Inflammatory mechanisms may play a role in insulin sensitivity of patients

with CF relative to normal subjects Additional Information

• Studies have shown an increased level of some inflammatory mediators

such as tumor necrosis factor (TNF)-alpha in patients with CF (n=38) compared with normal control volunteers (n=28). Patients with CF with impaired glucose tolerance, or diabetes, also tended to have higher TNF levels than did those with CF and normal glucose tolerance (respective values, 120, 130, and 90 pg/mL; not significant). There were no differences in plasma interleukin (IL)-6, or IL-1 levels between the patients with CF and the controls in this study1

• Peripheral insulin resistance may also play a role, specifically in the setting
• f acute pulmonary illness or with the use of glucocorticoids2

References

• 1. Hardin DS, Leblanc A, Marshall G, Seilheimer DK. Mechanisms of insulin

resistance in cystic fibrosis. Am J Physiol Endocrinol Metab. 2001;281(5):E1022-E1028.

• 2. Barrio R. Management of endocrine disease: Cystic fibrosis-related

diabetes: novel pathogenic insights opening new therapeutic avenues. Eur J Endocrinol. 2015;172(4):R131-R141. 42

• There is evidence for a reduced insulin sensitivity and defective peripheral insulin response in CF
• Studies examining insulin secretion and sensitivity in mice with the F508del mutation have shown

that, in young F508del mutant mice, insulin secretion is normal and insulin sensitivity is increased; however, as the mutant mice age, they develop a progressive deficit in beta cell mass, in addition to insulin resistance, compared with their wild-type counterparts. At 24 weeks of age, insulin sensitivity index was significantly lower in the F508del mice compared with wild-type mice. This supports findings of increased CFRD with age in patients with CF1

• The glucose transporter protein GLUT-4 is required for insulin mediated glucose disposal, and

translocation of GLUT-4 from the intracellular compartment to the cell surface is needed to ensure the normal transport of glucose into the cell.2 In patients with CF, an abnormal cellular localization has been found compared with BMI, age, and sex-matched control patients, in addition to abnormally high plasma levels of tumor necrosis factor, and this may in part account for peripheral insulin insensitivity2

• A reduced level of winged helix forkhead transcription factor (FOXO1) content, which is involved in

stimulating gluconeogenesis and inhibiting adipogenesis, has been shown in CF cells. In the fasting state (baseline), there was a reduced level of FOXO1 activity, and there was also a reduced level of FOXO1 inactivation in the presence of insulin. A reduced level of FOXO1 in CF compared with wild- type cells may be in part responsible for the characteristic features of insulin insensitivity such as reduced gluconeogenesis and increased adipogenesis3 References 1. Fontés G, Ghislain J, Benterki I, et al. The ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator is associated with progressive insulin resistance and decreased functional β- cell mass in mice. Diabetes. 2015;64(12):4112-4122. 2. Hardin DS, Leblanc A, Marshall G, Seilheimer DK. Mechanisms of insulin resistance in cystic

• fibrosis. Am J Physiol Endocrinol Metab. 2001;281(5):E1022-E1028.

3. Smerieri A, Montanini L, Maiuri L, Bernasconi S, Street ME. FOXO1 content is reduced in cystic fibrosis and increases with IGF-I treatment. Int J Mol Sci. 2014;15(10):18000-18022.

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