CF Related Diabetes
ADEU
November 2010
Cystic Fibrosis
 Genetic disorder


Exocrine pancreas dysfunction
Autosomal recessive inheritance

Several identified genes
 Presentation

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
Newborn screening
Failure to thrive in infancy
Chronic pulmonary disease in older individuals
Cystic Fibrosis
 Treatment

Nutritional support



High caloric diet- carbohydrate and protein
Exocrine pancreatic enzymes
Pulmonary toilet

Monitor and aggressively treat pulmonary infection
 Course
Failure to thrive/ poor growth
 Progressive pulmonary disease
 Diabetes
 Early death due to pulmonary disease
 Genetic testing has demonstrated significant variability in
presentation and course

History of CF
 1980s
 Children and Teens died of respiratory failure
 Diabetes was a pre-morbid event
 1990s
 Aggressive nutritional support
 Extended lifespan
 Increased incidence of diabetes
 <25% of patients with CFRD reach age of 30 years vs
60% of those without
 2000s
 Increased life span, Average life expectancy 37.4 yrs
 Impact of diabetes?
Incidence of CFRD
 CFRD increases with age



2% children
19% adolescents
40-50% adults
 Normal OGTT (standard definition)


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60% children
30% of adults 20-40 years
20% of adults > 40 years
CFRD – Etiology
 Originally hypothesized to be due to fibrosis
and destruction of islet cells in pancreas

Autopsy data demonstrated that CF patients
with AND without diabetes had the same islet
cell mass
 Family history of type 2 diabetes increases
the risk of CFRD

Genetic predisposition towards type 2
diabetes?
Impact of Diabetes in CF
 Insulin deficiency
 Catabolic state- malnutrition
 Until recently focus has been here
 Hyperglycemia
 Airway glucose concentrations increased
 Immune function
 Long term complications
 Microvascular disease in CFRD is less common and
less severe in CF
 Not described in CF patients without fasting
hyperglycemia
Impact of Diabetes on CF patients
 CF patients die of pulmonary disease rather
than atherosclerotic cardiac disease
 Insulin deficiency



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Poor nutrition is linked to decline in pulmonary
function
Insulin is anabolic involved in conservation of
lean body mass and weight
Patients with IGT (on OGTT) have more rapid
decline in pulmonary function than NGT
CFRD without fasting hyperglycemia is bad
prognostic indicator
Definition of CFRD
 Same as the ADA definition

Oral glucose tolerance test


Glucose load is low compared to normal intake
Random glucose over 200mg/dl and
symptoms

Overnight tube feedings may make it hard to see
symptoms
 Is this the best or right definition for CF?
CFRD- how to define it?
 “Normal glucose tolerance” on OGTT


Increased 30, 60, and 90 minute glucoses
Increase area under the curve glucose
 CGMS

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Mean glucose levels higher in CF (106 vs 92
mg/dl)
33% of CF patients had a glucose >200 mg/dl
(vs 5% of control patients) / day
Risk of Diabetes in CF
 Family history of type 2 diabetes increases risk to CF
patients

OR- 3.1 (p = 0.009)
 Sibling-twin data from a study on type 2 diabetes
demonstrated genetic component

Concordance rate for monozygotic twins higher than
dizygotic twins or sib pairs (p=0.002)
 Genetic variant associated with Type 2 commonly
found in CFRD


Presence associated with earlier age of diagnosis of
diabetes
TCF7L2 = transcriprtion factor 7-like 2
Etiology of CFRD
 Originally thought to be due to purely
mechanical issues


Destruction of pancreas, loss of ß cell mass
Autopsy data demonstrated essentially
equivalent mass in non-diabetic CF and
diabetic CF patients
 Autopsy data demonstrated amyloid deposits
similar to that seen in type 2 DM patients but
not in type 1 nor in pancreatitis patients
Hyperglycemia in CF
 OGTT demonstrates glucose “area under the curve”
is higher in non-diabetic CF patients than controls
matched for for age and BMI

Higher 30, 60 and 90 minute glucose levels
 CGMS demonstrates CF patients with normal OGTT
have “diabetic” glucose values in normal life


Average glucose higher (106 vs 92 mg/dl)
33% of CF patients had one or more glucose over 200
mg/dl vs 5% of controls
 Hgb A1C and OGTT may underestimate glucose
abnormalities in CF patients
Hyperglycemia in CF
 Blood glucose over 144 mg/dl associated with
increased airway glucose levels

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CGMS demonstrates levels higher than this 50% of the
time in CFRD, 6% of the time in CF with normal GT,
and 1% of the time in controls
Staph aureus and Pseudomonas growth was
accelerated when cultured in a similar glucose
environment
 Potential impact: increased bacterial growth,
increased glycation products, increased inflammatory
process, decrased immune function
CFRD
 Increases with age


2% of children, 50% of adults
At younger ages, more individuals have
normal fasting glucose (CFRD FH-)
 Mortality is decreasing (1992-7 vs 2003-8)


Pre-screening, mortality was 20% within 5
years of diagnosis, now 3%
Lung function continues to be worse in CFRD
patients
When to Treat CFRD
 Macrovascular complications really aren’t seen in CF
 Microvascular complications are seen in CFRD FH+
 What about CFRD FH Multicenter trial of CFRD FH-, IGT
 Oral replaglinide, pre-meal insulin aspart, oral placebo
 End point BMI
 Pre-treatment BMI decreased in all groups, reversed in
insulin group only
 No difference in pulmonary function over 1 year but
study time frame is likely too short to see difference
Diagnosis and Treatment
 Oral glucose tolerance test


End point
Area under the curve?
 CFRD FH+

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Basal-bolus insulin similar to type 1 DM
Consider Insulin pump
 CFRD FH

Watch BMI trajectory
Consider pre-meal bolus insulin
Summary
 CFRD is a significant contributor to burden of
disease in CF

Increased illness, earlier death
 CFRD may look more like type 2 diabetes
than type 1 and may have identifiable risk
factors
 Appropriate diagnosis and timing of
intervention is a work in progress
 Therapy is classic basal-bolus insulin