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)