Transcript PowerPoint Slides

Cystic Fibrosis-Related Diabetes:
From bed to bench and back again
Andrea Kelly, MD MSCE
Division of Pediatric Endocrinology & Diabetes
Children’s Hospital of Philadelphia
Perelman School of Medicine at University of Pennsylvania
2013 North American Cystic Fibrosis Conference
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!
Prevalence (%)
FH= fasting
hyperglycemia
Age (years)
Moran et al. Diabetes Care 2009
Lung transplant rate %
Survival rate %
CFRD & even earlier glucose abnormalities - worse survival and greater likelihood of
lung transplant
1988-2005
Children & young adults
109M/128F
CFRD
age <18y __
>18y ---
Age (years)
CFRD
age <18y __
>18y ---
IGT
age <15y __
>15y ---
Age (years)
Serial oral glucose
tolerance test (OGTT)
IGT=impaired
glucose tolerance
IGT
age <15y __
>15y ---
Bismuth et al. J Pediatr 2008
Necker-Enfants Malades Hospital
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.”
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
 pancreatic enzyme doses
 daytime nutritional
supplementation
 frequency of overnight enteral
feeds
Decreasing FEV1%-predicted
BMI (years)
Decreasing BMI% despite
x xx
x
x
100%95% over previous year
Age (years)
CFF 2010 Consensus Statement
CFRD Screening in Healthy Outpatients
Plasma Glucose (mg/dL)
Annual Screening with an oral glucose tolerance test
(OGTT) starting by age 10y
260
230
200
170
140
Plasma glucose (PG)
110
80
PG1
* PG0
PG2
50
0
15
30
45
60
75
90
105 120 135
Time (min)
Glucola (1.75 g/kg) PO
Max=75 g
Plasma Glucose (mg/dL)
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
260
230
200
170
140
110
80
NGT
*
50
0
15
30
45
60
75
Time (min)
90
105 120 135
Plasma Glucose (mg/dL)
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
260
230
CFRD
200
170
IGT
140
110
80
NGT
*
50
0
15
30
45
60
75
Time (min)
90
105 120 135
OGTT Glucose
Tolerance Categories
Normal
Plasma glucose (PG) mg/dL
Fasting
<100
Impaired fasting glucose
Impaired glucose
tolerance (IGT)
100-125
Diabetes
≥126
Indeterminate
Moran et al. Diabetes Care 2010
2-hours
<140
140-199
≥200
PG2<140
PG1 ≥200
Plasma Glucose (mg/dL)
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
260
230
CFRD
200
170
IGT
140
Indeterminate
110
80
NGT
*
50
0
15
30
45
60
75
Time (min)
90
105 120 135
NGT (n=22)
36% at least one glucose
>200 mg/dL
Glucose (mg/dL)
Continuous Glucose Monitoring in CF
*
*
52% at least one BG>200 >200
CFRD (n=10)
Post meal glucose > 200
mg/dL is common
Moreau et al. Horm Meta Res 2008
Glucose (mg/dL)
Insulin secretion defects are evident even
IGT (n=17)
in the setting of “NGT”
**
*
*
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
Annual CFRD Screening with OGTT
Age
9y 6mo 12y 3mo
Plasma Glucose (PG), PG0
99
106
mg/dL
PG1
169
188
PG2
139
116
Glucose Tolerance
NGT
NGT
Category
14y 8mo
121
220
194
IGT
NGT: PG2<140 mg/dL
IGT:
PG2 140-199 mg/dL
CFRD: PG2 >200 mg/dL
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
Annual CFRD Screening with OGTT
Age
9y 6mo 12y 3mo
Plasma Glucose (PG), PG0
99
106
mg/dL
PG1
169
188
PG2
139
116
Glucose Tolerance
NGT
NGT
Category
14y 8mo
121
220
194
IGT
NGT: PG2<140 mg/dL
IGT:
PG2 140-199 mg/dL
CFRD: PG2 >200 mg/dL
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
Annual CFRD Screening with OGTT
Age
9y 6mo 12y 3mo
Plasma Glucose (PG), PG0
99
106
mg/dL
PG1
169
188
PG2
139
116
Glucose Tolerance
NGT
NGT
Category
14y 8mo
121
220
194*
IGT
NGT: PG2<140 mg/dL
IGT:
PG2 140-199 mg/dL
CFRD: PG2 >200 mg/dL
A brief review: Insulin signals the fed-state
Intestine
Pancreatic
β-cells
Food Insulin Deficiency:
potent
anabolic
hormone
Evokes
a catabolic
state 
Compromised nutritional status
Blood
GlucoseHyperglycemia:
Direct implications for
Insulin
lung & immune function
Adipose
Glucose Glucose
Liver
Incretin secretion augment insulin secretion
Intestinal
Neuroendocrine
cells
I
(Incretins: GLP-1 GIP)
Pancreatic
β-cells
glucose
fatty acids
amino acids
glucose
Insulin 
Food
Insulin Secretion Defects
Underlie all Forms of Diabetes
Insulin deficiency
Islets
Genetics
T2DM
CFRD
relative
deficient
Insulin Secretion Defects
Underlie all Forms of Diabetes
Insulin deficiency
Islets
T2DM
CFRD
relative
deficient
β-cell apoptosis
inherent β-cell defect
Genetics
Insulin Secretion Defects
Underlie all Forms of Diabetes
Insulin deficiency
Islets
T2DM
CFRD
relative
deficient
β-cell apoptosis
Destruction extending from
pancreatic exocrine damage
inherent β-cell defect
Genetics
Insulin Secretion Defects
Underlie all Forms of Diabetes
Insulin deficiency
Islets
T2DM
CFRD
relative
deficient
β-cell apoptosis
Destruction extending from
pancreatic exocrine damage
inherent β-cell defect
inherent β-cell defect
Genetics
β-cell
Insulin Secretion Defects
Underlie all Forms of Diabetes
Insulin deficiency
Islets
Genetics
T2DM
CFRD
relative
deficient
β-cell apoptosis
Destruction extending from
pancreatic exocrine damage
inherent β-cell defect
inherent β-cell defect
TCF7L2
TCF7L2
β-cell
Defects in Insulin Secretion & Glucose Excursion are
Present in the Setting of “Normal” Glucose Tolerance
OGTT Plasma Glucose
288
252
216
180
144
108
72
OGTT C-peptide (insulin secretion)
C-Peptide (nmol/L)
324
Time (min)
C-Peptide (nmol/L)
Plasma Glucose (mg/dL)
Moran et al. J Peds 1991
Controls
PI-CF w/o CFRD
Time (min)
IV Glucose Tolerance Test
(Dextrose 20 g IV bolus)
Time (min)
C-Peptide to IV Glucose
324
C-Peptide (nmol/L)
Plasma Glucose (mg/dL)
OGTT Plasma Glucose
288
252
216
180
144
108
OGTT C-peptide (insulin secretion)
Controls
PI-CF w/o CFRD
(nmol/L)
C-Peptide
C-Peptide (nmol/L)
72
•Loss
of (min)
early insulinTime
secretionhyperglycemia
Time
(min)
•Animal models
IV Glucose Tolerance Test
(Dextrose 20 g IV bolus)
Time (min)
C-Peptide to IV Glucose
Absolute Insulin Response
(μIU/mL)
ACUTE INSULIN
RESPONSE (uU/ml)
Mechanisms of insulin secretion defects
200
Glucose Potentiated Arginine
Stimulation Test
CF PI-NGT
Normal
180
160
140
120
100
80
60
40
20
0
100
Arginine
5g IV
150
200
250
300
350
KATP
channel
glucose
Plasma Glucose (mg/dl)
Plasma glucose (mg/dL)
ATP
ADP

VDCC
insulin
secretory
granules
Absolute Insulin Response
(μIU/mL)
ACUTE INSULIN
RESPONSE (uU/ml)
Mechanisms of insulin secretion defects
200
Glucose Potentiated Arginine
Stimulation Test
CF PI-NGT
Normal
180
160
140
120
100
80
60
40
20
Glucose clamp 230 mg/dL
0
100
Arginine
5g IV
150
200
250
300
350
KATP
channel
glucose
Plasma Glucose (mg/dl)
Arginine
5g IV
Plasma glucose (mg/dL)
ATP
ADP

VDCC
insulin
secretory
granules
Absolute Insulin Response
(μIU/mL)
ACUTE INSULIN
RESPONSE (uU/ml)
Mechanisms of insulin secretion defects
200
Glucose Potentiated Arginine
Stimulation Test
CF PI-NGT
Normal
180
160
140
120
100
80
60
40
20
340 mg/dL
Glucose clamp 230 mg/dL
0
100
Arginine
5g IV
150
200
250
Plasma Glucose (mg/dl)
Arginine
5g IV
300
350
glucose
KATP
channel
Arginine
5g IV
Plasma glucose (mg/dL)
ATP
ADP

VDCC
insulin
secretory
granules
Absolute Insulin Response
(μIU/mL)
ACUTE INSULIN
RESPONSE (uU/ml)
Mechanisms of insulin secretion defects
200
Glucose Potentiated Arginine
Stimulation Test
CF PI-NGT
Normal
180
Healthy lean controls
PI-CF NGT
160
140
OGTT PG1<200 mg/dL
PG2<140 mg/L
120
100
80
60
40
20
340 mg/dL
Glucose clamp 230 mg/dL
0
100
Arginine
5g IV
150
200
250
Plasma Glucose (mg/dl)
Arginine
5g IV
300
350
Arginine
5g IV
Plasma glucose (mg/dL)
And, β-cell Sensitivity to Glucose is
Preserved
Absolute Insulin Response
(μIU/mL)
ACUTE INSULIN
RESPONSE (uU/ml)
Glucose threshold for ½ maximal insulin secretion
200
180
Healthy Lean Controls
CF PI-NGT
CF with
NGT
Normal
160
140
120
100
80
60
40
20
0
100
150
200
250
300
Plasma Glucose (mg/dl)
p = 0.84
Plasma glucose (mg/dL)
350
Absolute Insulin Response
(μIU/mL)
ACUTE INSULIN
RESPONSE (uU/ml)
Glucose threshold for ½ maximal insulin secretion
200
180
Healthy Lean Controls (n=12)
CF PI-NGT
CF with
NGT (n=10)
Normal
160
preserved
140
120
100
Insulin deficiency is NOT due to an altered
glucose threshold for insulin secretion
80
60
40
20
0
100
150
200
250
300
Plasma Glucose (mg/dl)
p = 0.84
Plasma glucose (mg/dL)
350
Blood Glucose
(mg/dL)
Pancreatic enzyme replacement & plasma glucose
Insulin
BG
BG
Insulin
Insulin
Insulin
BG
Mixed meal
tolerance test
Enzymes
Placebo
Healthy
Controls
CF Healthy
Enzymes
Placebo
Plasma GLP-1
(nmol/L)
Plasma GIP (pmol/L)
Time (min)exocrine insufficiency
Time (min)
Pancreatic
& maldigestion can
GIP
Glucagon
GLP-1to defective insulin
GLP-1 secretion & hyperglycemia
contribute
GIP
GLP-1
Time (min)
Kuo P et al. JCEM 2011;96:E851-E855
Time (min)
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
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
Annual CFRD Screening with Oral Glucose Tolerance Test (OGTT)
Age
9y 6mo 12y 3mo 14y 8mo
Plasma Glucose (PG), PG0 99 (5.5) 106 (5.8) 121 (6.7)
mg/dL (mmoL)
PG1 169 (9.4) 188 (10.4) 220 (12.2)
PG2 139 (7.7) 116 (6.4) 194* (10.7)
Glucose Tolerance
NGT
NGT
CFRD
Category
HbA1C== 7.5
Blood Glucose (mg/dL)
14 y 8 mo old male with pancreatic
insufficient CF & IGT by OGTT
Hyperglycemia during overnight enteral feeds
350
300
250
200
150
100
50
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69
NIGHT
DAY
NIGHT
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
• HbA1C==5.9%
• FEV1%-predicted improved
to 100%  105%
(years)
BMI
BMI(years)
• BMI improved
x
x
x x xx
x
x
Insulin initiated
Age (years)
14y 8mo old male with pancreatic
insufficient CF and “abnormal” OGTT
(years)
BMI
BMI(years)
• FEV1%-predicted improved
to 100%  105%
• HbA1C==5.9%
x
x
x x xx
x
x
Insulin initiated
Age (years)
“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
J. life”—Jeffrey’s
. .going about
enjoy
mom his life with CFRD
The Goal
Hyperglycemia
Insulin
Deficiency
Worsening
Pulmonary function
Nutritional status
Ongoing Challenges and Questions
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 incretinbased 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
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 village
CHOP
Penn
CF Center
Ron Rubenstein (Director)
Chris Kubrak
CF Center
Denis Hadjiliadis (Director)
Dan Dorgin
Saba Sheikh
Endocrinology & Diabetes
Diva De Leon
Shayne Dougherty
Endocrinology & Diabetes
Mike Rickels
Nora Rosenfeld
Amy Peleckis
Lalitha Gudipaty
Center for Applied Genomics: Struan Grant
PENN & CHOP CTRC
PENN Diabetes & Endocrine Research Core
Cystic Fibrosis Foundation and NIDDK
Antoinette Moran, MD (University of MN)