Cystic Fibrosis-Related Diabetes: From bed to bench and back again
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Transcript of Cystic Fibrosis-Related Diabetes: From bed to bench and back again
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Andrea Kelly, MD MSCEDivision of Pediatric Endocrinology & Diabetes
Children’s Hospital of PhiladelphiaPerelman School of Medicine at University of Pennsylvania2013 North American Cystic Fibrosis Conference
Cystic Fibrosis-Related Diabetes: From bed to bench
and back again
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Disclosures: none
Objectives:• Present case study• Review associations of
hyperglycemia/insulin secretion defects with CF-relevant outcomes
• Review CFRD Guidelines• Review recent clinical research
initiatives
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Considerations
Insulin secretion defects are present early and are progressive in CF
Understanding the mechanisms underlying defective insulin secretion may permit development of interventions that interrupt progression to diabetes
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Cystic fibrosis related diabetes (CFRD) is Common!
Moran et al. Diabetes Care 2009
Prev
alen
ce (%
)
Age (years)
FH= fasting hyperglycemia
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Bismuth et al. J Pediatr 2008 Necker-Enfants Malades Hospital
1988-2005 Children & young adults
109M/128F
Serial oral glucose tolerance test (OGTT)
IGT=impaired glucose toleranceAge (years)
Surv
ival
rate
%Lu
ng tr
ansp
lant
rate
%
CFRDage <18y __ >18y ---
CFRDage <18y __ >18y ---
IGTage <15y __ >15y ---
IGTage <15y __ >15y ---
CFRD & even earlier glucose abnormalities -- worse survival and greater likelihood of lung transplant
Age (years)
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CFRD & Quality of Life
Tierney et al. Journal of Clinical Nursing 2008. Adults
“It was something that you didn’t want to accept because it’s an acceptance of the disease progressing … I had to wrestle with the fact that it was a progression of the CF.”
CHOP—some pediatric patients and their parents“She takes better care of her diabetes than her CF.”
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BM
I (ye
ars)
xx
x xx
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
Decreasing BMI% despite pancreatic enzyme doses daytime nutritional supplementation frequency of overnight enteral feeds
Decreasing FEV1%-predicted 100%95% over previous year
Age (years)
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CFF 2010 Consensus StatementCFRD Screening in Healthy Outpatients
Annual Screening with an oral glucose tolerance test (OGTT) starting by age 10y
5080
110140170200230260
Plas
ma
Glu
cose
(mg/
dL)
0 15 30 45 60 75 90 105 120 135
Time (min)Glucola (1.75 g/kg) PO
Max=75 g
*
Plasma glucose (PG)PG0 PG1 PG2
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14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
5080110140170200230260
Plas
ma
Glu
cose
(mg/
dL)
0 15 30 45 60 75 90 105 120 135
Time (min)
NGT*
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14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
5080110140170200230260
Plas
ma
Glu
cose
(mg/
dL)
0 15 30 45 60 75 90 105 120 135
Time (min)
IGT
NGT*
CFRD
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OGTT Glucose Tolerance Categories
Plasma glucose (PG) mg/dL
Fasting 2-hoursNormal <100 <140
Impaired fasting glucose 100-125Impaired glucose
tolerance (IGT) 140-199
Diabetes ≥126 ≥200
Indeterminate PG2<140PG1 ≥200
Moran et al. Diabetes Care 2010
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14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
5080110140170200230260
Plas
ma
Glu
cose
(mg/
dL)
0 15 30 45 60 75 90 105 120 135
Time (min)
IGT
NGT*
CFRD
Indeterminate
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52% at least one BG>200 >200
IGT (n=17)
NGT (n=22)36% at least one glucose
>200 mg/dL
CFRD (n=10)Post meal glucose > 200
mg/dL is common* * *
**
*
Moreau et al. Horm Meta Res 2008
Continuous Glucose Monitoring in CF
Glu
cose
(mg/
dL)
Glu
cose
(mg/
dL)
Insulin secretion defects are evident even in the setting of “NGT”
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Annual CFRD Screening with OGTTAge
9y 6mo 12y 3mo 14y 8moPlasma Glucose (PG),
mg/dLPG0 99 106 121PG1 169 188 220PG2 139 116 194
Glucose Tolerance Category
NGT NGT IGT
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
NGT: PG2<140 mg/dLIGT: PG2 140-199 mg/dLCFRD: PG2 >200 mg/dL
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Annual CFRD Screening with OGTTAge
9y 6mo 12y 3mo 14y 8moPlasma Glucose (PG),
mg/dLPG0 99 106 121PG1 169 188 220PG2 139 116 194
Glucose Tolerance Category
NGT NGT IGT
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
NGT: PG2<140 mg/dLIGT: PG2 140-199 mg/dLCFRD: PG2 >200 mg/dL
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Annual CFRD Screening with OGTTAge
9y 6mo 12y 3mo 14y 8moPlasma Glucose (PG),
mg/dLPG0 99 106 121PG1 169 188 220PG2 139 116 194*
Glucose Tolerance Category
NGT NGT IGT
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
NGT: PG2<140 mg/dLIGT: PG2 140-199 mg/dLCFRD: PG2 >200 mg/dL
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GlucoseBlood
Intestine Food
A brief review: Insulin signals the fed-state
Insulin
Liver
Glucose
Pancreaticβ-cells
Glucose
GlucoseAdipose
Fatty acids
potent anabolic hormone
Insulin Deficiency:Evokes a catabolic state Compromised nutritional
status
Hyperglycemia:Direct implications for lung & immune function
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IntestinalNeuroendocrine cells
glucose fatty acidsamino acids
Incretin secretion augment insulin secretion
Pancreaticβ-cells
I(Incretins: GLP-1 GIP)
Insulin
Food
glucose
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T2DM CFRD
Insulin deficiency relative deficient
Islets
Genetics
Insulin Secretion Defects Underlie all Forms of
Diabetes
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T2DM CFRD
Insulin deficiency relative deficient
Islets β-cell apoptosis
inherent β-cell defectGenetics
Insulin Secretion Defects Underlie all Forms of
Diabetes
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T2DM CFRD
Insulin deficiency relative deficient
Islets β-cell apoptosis
inherent β-cell defect
Destruction extending from pancreatic exocrine damage
Genetics
Insulin Secretion Defects Underlie all Forms of
Diabetes
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T2DM CFRD
Insulin deficiency relative deficient
Islets β-cell apoptosis
inherent β-cell defect
Destruction extending from pancreatic exocrine damage
inherent β-cell defectGenetics
Insulin Secretion Defects Underlie all Forms of
Diabetes
β-cell
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T2DM CFRD
Insulin deficiency relative deficient
Islets β-cell apoptosis
inherent β-cell defect
Destruction extending from pancreatic exocrine damage
inherent β-cell defectGenetics TCF7L2 TCF7L2
Insulin Secretion Defects Underlie all Forms of
Diabetes
β-cell
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ControlsPI-CF w/o CFRD
Defects in Insulin Secretion & Glucose Excursion are Present in the Setting of “Normal” Glucose
ToleranceMoran et al. J Peds 1991OGTT Plasma GlucoseOGTT C-peptide (insulin secretion)
324
288
252
216
180
144
108
72C-
Pept
ide
(nm
ol/L
)
Plas
ma
Gluc
ose
(mg/
dL)
C-Peptide to IV Glucose
C-Pe
ptid
e (n
mol
/L)
C-Pe
ptid
e (n
mol
/L)
IV Glucose Tolerance Test(Dextrose 20 g IV bolus)
Time (min) Time (min)
Time (min)
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ControlsPI-CF w/o CFRD
OGTT Plasma GlucoseOGTT C-peptide (insulin secretion)324
288
252
216
180
144
108
72C-
Pept
ide
(nm
ol/L
)
Plas
ma
Gluc
ose
(mg/
dL)
C-Peptide to IV Glucose
C-Pe
ptid
e (n
mol
/L)
C-Pe
ptid
e (n
mol
/L)
IV Glucose Tolerance Test(Dextrose 20 g IV bolus)
Time (min) Time (min)
Time (min)
• Loss of early insulin secretionhyperglycemia
• Animal models
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100 150 200 250 300 3500
20
40
60
80
100
120
140
160
180
200
AC
UTE
INS
ULI
N R
ES
PO
NS
E (u
U/m
l)
Plasma Glucose (mg/dl)
CF PI-NGT Normal
Abs
olut
e In
sulin
Res
pons
e (μ
IU/m
L)
Plasma glucose (mg/dL)
Arginine5g IV
Glucose Potentiated Arginine Stimulation Test
Mechanisms of insulin secretion defects
ATP ADP
glucoseKATP
channel
VDCC
secretorygranulesinsulin
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100 150 200 250 300 3500
20
40
60
80
100
120
140
160
180
200
AC
UTE
INS
ULI
N R
ES
PO
NS
E (u
U/m
l)
Plasma Glucose (mg/dl)
CF PI-NGT Normal
Abs
olut
e In
sulin
Res
pons
e (μ
IU/m
L)
Plasma glucose (mg/dL)
Arginine5g IV
Arginine5g IV
Glucose clamp 230 mg/dL
Glucose Potentiated Arginine Stimulation Test
Mechanisms of insulin secretion defects
ATP ADP
glucoseKATP
channel
VDCC
secretorygranulesinsulin
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100 150 200 250 300 3500
20
40
60
80
100
120
140
160
180
200
AC
UTE
INS
ULI
N R
ES
PO
NS
E (u
U/m
l)
Plasma Glucose (mg/dl)
CF PI-NGT Normal
Abs
olut
e In
sulin
Res
pons
e (μ
IU/m
L)
Plasma glucose (mg/dL)
Arginine5g IV
Arginine5g IV
Arginine5g IV
340 mg/dLGlucose clamp 230 mg/dL
Glucose Potentiated Arginine Stimulation Test
Mechanisms of insulin secretion defects
ATP ADP
glucoseKATP
channel
VDCC
secretorygranulesinsulin
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100 150 200 250 300 3500
20
40
60
80
100
120
140
160
180
200
AC
UTE
INS
ULI
N R
ES
PO
NS
E (u
U/m
l)
Plasma Glucose (mg/dl)
CF PI-NGT Normal
Abs
olut
e In
sulin
Res
pons
e (μ
IU/m
L)
Plasma glucose (mg/dL)
Arginine5g IV
Arginine5g IV
Arginine5g IV
340 mg/dLGlucose clamp 230 mg/dL
Glucose Potentiated Arginine Stimulation Test
Mechanisms of insulin secretion defects
Healthy lean controlsPI-CF NGT OGTT PG1<200 mg/dL PG2<140 mg/L
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And, β-cell Sensitivity to Glucose is Preserved
Glucose threshold for ½ maximal insulin secretion
100 150 200 250 300 3500
20
40
60
80
100
120
140
160
180
200
AC
UTE
INS
ULI
N R
ES
PO
NS
E (u
U/m
l)
Plasma Glucose (mg/dl)
CF PI-NGT Normal
Abs
olut
e In
sulin
Res
pons
e (μ
IU/m
L)
Plasma glucose (mg/dL)
Healthy Lean Controls CF with NGT
p = 0.84
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Glucose threshold for ½ maximal insulin secretion
100 150 200 250 300 3500
20
40
60
80
100
120
140
160
180
200
AC
UTE
INS
ULI
N R
ES
PO
NS
E (u
U/m
l)
Plasma Glucose (mg/dl)
CF PI-NGT Normal
Abs
olut
e In
sulin
Res
pons
e (μ
IU/m
L)
Plasma glucose (mg/dL)
Healthy Lean Controls (n=12)CF with NGT (n=10)
preserved
p = 0.84
Insulin deficiency is NOT due to an altered glucose threshold for insulin
secretion
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Pancreatic enzyme replacement & plasma glucose
Kuo P et al. JCEM 2011;96:E851-E855
BG Insulin
Glucagon GLP-1
EnzymesPlaceboHealthy
Insulin Insulin BG
GLP-1 GIP
Healthy ControlsCF Enzymes Placebo
GIP
BG Insulin Mixed meal tolerance test
Blo
od G
luco
se(m
g/dL
)
Plas
ma
GLP
-1(n
mol
/L) GLP-1
Plas
ma
GIP
(pm
ol/L
)Time (min)Time (min)
Time (min)Time (min)Pancreatic exocrine insufficiency & maldigestion can contribute to defective insulin secretion &
hyperglycemia
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Ivacaftor--Insulin & Incretin Secretion
Case series (n=5) variable improvements in glucose excursion and insulin secretion following 5 weeks of ivacaftor (Bellin Ped Diabetes 2013)
Does ivacaftor have a direct effect upon • Islet or β-cell function?• Intestinal incretin-secreting neuroendocrine
cells?
CFF Pilot Study (n=10): 16 wks ivacaftor• GPA studies of insulin secretion• Mixed meal tolerance tests—incretin secretion• OGTT
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More information about our patient
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Annual CFRD Screening with Oral Glucose Tolerance Test (OGTT)Age
9y 6mo 12y 3mo 14y 8moPlasma Glucose (PG),
mg/dL (mmoL)PG0 99 (5.5) 106 (5.8) 121 (6.7)PG1 169 (9.4) 188 (10.4) 220 (12.2)PG2 139 (7.7) 116 (6.4) 194* (10.7)
Glucose Tolerance Category
NGT NGT CFRD
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
HbA1C== 7.5
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Hyperglycemia during overnight enteral feeds
Blo
od G
luco
se (m
g/dL
)14 y 8 mo old male with pancreatic
insufficient CF & IGT by OGTT
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 690
50
100
150
200
250
300
350
NIGHT DAY NIGHT
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Age (years)
BM
I (ye
ars)
xx
x xx
• HbA1C==5.9%• BMI improved• FEV1%-predicted improved to
100% 105%xxx
Insulin initiatedB
MI (
year
s)
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
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Age (years)
BM
I (ye
ars)
xx
x xx
• FEV1%-predicted improved to 100% 105%
• HbA1C==5.9%
xxx
Insulin initiatedB
MI (
year
s)
14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT
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J. . .going about his life with CFRD
“Caring for a child with CFRD can be challenging. . . nutrition, med’s & treatments must be the most important part of your child’s daily routine to assure his/her well being. As a parent of a child with CF, I feel we must help them build a positive outlook, stay active and enjoy life”—Jeffrey’s mom
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Hyperglycemia
Insulin Deficiency
Worsening Pulmonary function
Nutritional status
The Goal
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Screening: • Can be a challenge—adherence!• Alternatives
– Random glucose– Continuous glucose monitoring– Does it need to be yearly (if OGTT is completely
normal)?• 50g glucose challenge test as an initial screen for
CFRD (Sheikh-CFF Fellowship; Phillips multi-center CFF study)– No fasting– Glucose at 1 hour
Ongoing Challenges and Questions
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What is the Role of Earlier Treatment: • CF relevant outcomes (BMI, pulmonary function, survival)• β-cell preservation• With insulin?
– What formulation? What dose?• Another agent? Preferably oral!
• RCT of sitagliptin ( an oral agent that inhibits incretin breakdown) (Stecenko-NIH)
pulmonary function, oxidative stress, conversion to CFRD in CF-IGT
Ongoing Challenges and Questions
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Mechanism: • impact of acute incretin infusion and chronic incretin-
based therapy upon insulin secretion (Kelly/Rickels-NIH)
• glucose and insulin secretion in infants and toddlers with CF (Ode/Engelhardt)
• Environmental/lifestyle/nutritional therapies that may hasten progression to CFRD
Ongoing Challenges and Questions
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Many questions remain
Animal models will hopefully provide additional insights into the mechanisms
underlying insulin secretion defects
Defective insulin secretion is common early in CF
Preserving residual β-cell function is an important
consideration
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It takes a villageCHOP PennCF Center CF CenterRon Rubenstein (Director) Denis Hadjiliadis (Director)Chris Kubrak Dan Dorgin
Saba Sheikh Endocrinology & DiabetesEndocrinology & Diabetes Mike Rickels Diva De Leon Nora RosenfeldShayne Dougherty Amy Peleckis
Lalitha Gudipaty
Center for Applied Genomics: Struan GrantPENN & CHOP CTRCPENN Diabetes & Endocrine Research CoreCystic Fibrosis Foundation and NIDDKAntoinette Moran, MD (University of MN)