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Cystic Fibrosis Related
diabetes
By
Abdulmajeed AlSubaihin
Clinical Fellow
Pediatric Endocrinology
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Presentation Outline
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Introduction
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Pathophysiology
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Clinical impact
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Management guidelines
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
Cystic Fibrosis is an autosomal recessive disease caused by
mutations in CFTR Gene on chromosome 7
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The most common life limiting genetic condition in
Caucasians.
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Ratjen F. N Engl J Med 2006;354:291-293.
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Clinical Features
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Pulmonary disease
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Hepatobiliary disease
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Pancreatic insufficiency
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Pancreatitis
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Meconium ileus and distal ileal obstruction
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Nephrolitihiasis
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Rectal prolapse
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Infertility
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Cystic fibrosis–related diabetes (CFRD) is the most common
comorbidity in subjects with cystic fibrosis (CF)
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Prevalence
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The Cystic Fibrosis Foundation Patient Registry, which
collects information from 22,732 people with CF of all ages in
the United States and Canada, has shown that the diagnoses
of glucose intolerance and diabetes in CF are becoming
more prevalent
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Prevalence
Moran et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical
review. Diabetes Care. 2010 Dec;33(12):2677-83
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Pathophysiology
Yung et al Cystic fibrosis-related diabetes: the role of
peripheral insulin resistance and beta-cell dysfunction.
Diabet Med. 2002 Mar;19(3):221-6.
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Pathophysiology
Hardin et al. J Pediatr. Insulin resistance is associated with decreased clinical status in cystic fibrosis
1997 Jun;130(6):948-56
.
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Hardin et al. J Pediatr. Insulin resistance is associated with decreased clinical status in cystic fibrosis
1997 Jun;130(6):948-56
.
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DF508 cells had lower membrane resting potentials
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Glibenclamide failed to induce depolarization when CFTR is inhibited
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In Vitro Glucose Challenge
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Impaired first phase response
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In Vivo Glucose Challenge
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Nelson Textbook of Pediatrics
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VX-809 rescue
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Trust me I’ve tried
that out and it seems
to be working
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2 siblings, 24 and 21 years of age, CF (DF508/S549R), with
INDET and CFRD respectively, treated Ivacaftor for 16
weeks. Not on insulin or glucose lowering drugs.
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48 CF patients (CFRD =19) compared to 18 healthy controls
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Age range 23-52 years
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All fasted overnight and received a standard meal at the test
time.
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Serial GLP-1 levels were taken
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CFRD patients were instructed to hold insulin during the fast
time.
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None had T1DM related Autoantibodies
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Difference is not statistically
significant
CFRD vs Controls (AUC, P= 0.001)
CF vs Controls (AUC, P= 0.02)
CFRD vs CF (AUC, P=0.06)
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Lek et al, Current Diabetes Reviews, 2010
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CFRD is part of a spectrum
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CFRD spectrum
FP
NGT
1h
2h
< 11.1 mmol/L
<7.8 mmol/L
IGT
≥ 7.8 and
< 11.1 mmol/L
Indet
≥ 11.1 mmol/L
< 7.8 mmol/L
CFRD -FH
< 7 mmol/L
≥11.1 mmol/L
CFRD +FH
≥ 7 mmol/L
≥11.1 mmol/L
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Clinical Impact
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Cystic Fibrosis Foundation Patient Registry reported that
people with CF and diabetes have a 6-fold greater mortality
rate than people without diabetes.
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Similarly to type 2 DM, 10 year duration of CFRD is
associated with:
50% risk of mild neuropathy
16% risk of Retinopathy
14% risk of Neuropathy
Schwarzenberg et al. Microvascular complications in cystic fibrosis– related
diabetes. Diabetes Care2007
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Clinical Impact
Finkelstein et al. Diabetes Mellitus Associated with Cystic Fibrosis. J Pediatr. 1988 Mar;112(3):373-7.
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Clinical Impact
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Cross-sectional
analysis of 7566
people enrolled in the
European
Epidemiologic
Registry of Cystic
Fibrosis (ERCF)
found that FEV1 %
predicted was lower
in people with
diabetes than in those
without diabetes at all
ages
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Lanng et al Eur J Pediatr
(1992) 151 : 684-687
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Lanng et al, Acta Paediatr 83:
849-53. 1994
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Glucose and Lung Function
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High glucose concentration on mucosal surfaces and
bacterial colonization.
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Hyperglycemia induced inflammatory response
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Clinical Features
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Screening
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Screening of CFRD gains its importance as:
CFRD has an insidious course
CFRD does not usually present with florid clinical diabetes
picture (polyuria, polydipsia, DKA)
Impact of CFRD on pulmonary functions and outcome begins
in the prediabetes phase.
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Screening
Screening Tool
Hgb A1C
Limitations
Not sufficiently sensitive for diagnosis of CFRD, low
positive predictive value
Random Glucose Low sensitivity
Fructosamine
Low sensitivity
Urine Glucose
Low Sensitivity
CGM
Intermittent hyperglycemia is of unknown clinical
significance
FPG
Identifies only 50% of CFRD patients
Self monitoring
(SMBG)
International Organization for Standardization only
requires that 95% of readings be within 20% of the
actual glucose level
Adapted from: Moran et al. Clinical Care Guidelines for Cystic Fibrosis–Related Diabetes DIABETES CARE, VOLUME 33, NUMBER
12, DECEMBER 2010
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Screening-OGTT
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Advantages:
Correlated with pulmonary outcomes
Predicted microvascular complications and early death
Identified patients who benefited from insulin therapy
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Disadvantages:
Variability of results
Combersome
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Screening- OGTT
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2h OGTT as per WHO recommendation( 1.75 gram/Kg,
maximum = 75 grams)
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Following 8 hours of fasting, water is allowed
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To be done at baseline, 6 weeks following last CF
exacerbation.
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Screening is recommended annualy starting at 10 years of
age
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Screening- Frequently ill
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CF patients with acute pulmonary exacerbation requiring
intravenous antibiotics and/or systemic glucocorticoids
should be screened for CFRD by monitoring fasting and 2-h
postprandial plasma glucose levels for the first 48 h. If
elevated blood glucose levels are found by SMBG, the results
must be confirmed by a certified laboratory.
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Screening- Continuous Drip
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Screening for CFRD by measuring mid- and immediate
postfeeding plasma glucose at the time of gastrostomy tube
feeding initiation and then monthly at home.
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Elevated glucose levels detected by SMBG must be
confirmed by a certified laboratory.
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Screening- Pregnancy
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Women with CF who are planning a pregnancy or confirmed
pregnant should be screened for preexisting CFRD with a 2-h
75-g fasting OGTT if they have not had a normal CFRD screen in
the last 6 months.
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Screening for gestational diabetes mellitus is recommended at
both 12–16 weeks’ and 24–28 weeks’ using a 2-h 75-g OGTT with
blood glucose measures at 0, 1, and 2 h.
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Screening for CFRD using a 2-h 75-g fasting OGTT is
recommended 6–12 weeks after the end of the pregnancy in
women with gestational diabetes mellitus>
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7mmol/l
11.1mmol/l
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Management
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Multidisciplinary setting
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Insulin therapy is the first line of management
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No evidence supporting one insulin regimen. Insulin
regimens are to be individualized.
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No evidence supporting oral agents.
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Patients on insulin should perform SMBG at least 3 times per
day.
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Follow up quarterly with HgbA1c
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Goal Hgb A1c is =< 7%
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Conclusion
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CFRD remains the most common CF comorbidity.
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Mechanisms include insulin insufficiency due to reduced
beta cell mass and possibly some insensitivity to glucose at
the beta cell surface.
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CFRD outcomes are not limited to Micro/Macrovascular
complications of diabetes, it also involves
pulmonary/nutritional status.
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Screening is recommended by using 2h OGTT.
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Treatment is recommended using insulin at CFRD phase with
or without fasting hyperglycemia.
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Thank you