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
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
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
Cystic fibrosis related diabetes (CFRD) is Common!
Moran et al. Diabetes Care 2009
Prev
alen
ce (%
)
Age (years)
FH= fasting hyperglycemia
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)
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.”
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)
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
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*
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
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
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
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”
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
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
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
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
IntestinalNeuroendocrine cells
glucose fatty acidsamino acids
Incretin secretion augment insulin secretion
Pancreaticβ-cells
I(Incretins: GLP-1 GIP)
Insulin
Food
glucose
T2DM CFRD
Insulin deficiency relative deficient
Islets
Genetics
Insulin Secretion Defects Underlie all Forms of
Diabetes
T2DM CFRD
Insulin deficiency relative deficient
Islets β-cell apoptosis
inherent β-cell defectGenetics
Insulin Secretion Defects Underlie all Forms of
Diabetes
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
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
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
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)
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
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
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
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
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
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
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
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
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
More information about our patient
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
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
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
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
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
Hyperglycemia
Insulin Deficiency
Worsening Pulmonary function
Nutritional status
The Goal
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
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
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
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
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)