Cystic fibrosis related diabetes from bed to bench and back again
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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.

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Cystic Fibrosis-Related Diabetes: From bed to bench and back again

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Cystic fibrosis related diabetes from bed to bench and back again

Cystic Fibrosis-Related Diabetes: From bed to bench and back again

Andrea Kelly, MD MSCEDivision of Pediatric Endocrinology & DiabetesChildren’s Hospital of PhiladelphiaPerelman School of Medicine at University of Pennsylvania2013 North American Cystic Fibrosis Conference


Disclosures none

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

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 from bed to bench and back again

Cystic fibrosis related diabetes (CFRD) is Common!

FH= fasting hyperglycemia

Prevalence (%)

Age (years)

Moran et al. Diabetes Care 2009


Cystic fibrosis related diabetes from bed to bench and back again

CFRD & even earlier glucose abnormalities -- worse survival and greater likelihood of lung transplant

1988-2005

Children & young adults

109M/128F

Serial oral glucose

tolerance test (OGTT)

IGT=impaired

glucose tolerance

Survival rate %

CFRD

age <18y __

>18y ---

IGT

age <15y __

>15y ---

Age (years)

Age (years)

CFRD

age <18y __

>18y ---

IGT

age <15y __

>15y ---

Lung transplant rate %

Bismuth et al. J Pediatr 2008

Necker-EnfantsMalades Hospital


Cfrd quality of life

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

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

BMI (years)

x

x

x

x

x

Age (years)


Cff 2010 consensus statement cfrd screening in healthy outpatients

AnnualScreening with an oral glucose tolerance test (OGTT) starting by age 10y

CFF 2010 Consensus StatementCFRD Screening in Healthy Outpatients

260

230

200

170

140

Plasma glucose (PG)

Plasma Glucose (mg/dL)

110

PG1

PG2

PG0

*

80

50

120

0

15

30

45

60

75

90

105

135

Time (min)

Glucola (1.75 g/kg) PO

Max=75 g


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt1

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

260

230

200

170

Plasma Glucose (mg/dL)

140

110

NGT

*

80

50

0

15

30

45

60

75

90

105

120

135

Time (min)


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt2

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

260

230

CFRD

200

170

IGT

Plasma Glucose (mg/dL)

140

110

NGT

*

80

50

0

15

30

45

60

75

90

105

120

135

Time (min)


Cystic fibrosis related diabetes from bed to bench and back again

Moran et al. Diabetes Care 2010


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt3

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

260

230

CFRD

200

170

IGT

Plasma Glucose (mg/dL)

140

Indeterminate

110

NGT

*

80

50

0

15

30

45

60

75

90

105

120

135

Time (min)


Cystic fibrosis related diabetes from bed to bench and back again

Continuous Glucose Monitoring in CF

*

NGT (n=22)

*

36% at least one glucose

>200 mg/dL

Glucose (mg/dL)

Insulin secretion defects areevident even in the setting of “NGT”

IGT (n=17)

52% at least one BG>200 >200

CFRD (n=10)

Post meal glucose > 200 mg/dL is common

*

*

*

*

Glucose (mg/dL)

Moreau et al. Horm Meta Res 2008


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt4

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

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 ogtt5

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

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 ogtt6

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

NGT: PG2<140 mg/dL

IGT: PG2 140-199 mg/dL

CFRD: PG2 >200 mg/dL


Cystic fibrosis related diabetes from bed to bench and back again

A brief review: Insulin signals the fed-state

Insulin Deficiency:

Evokes a catabolic state 

Compromised nutritional status

Hyperglycemia:

Direct implications for

lung & immune function

Intestine

Food

potent anabolic hormone

Blood

Pancreatic

β-cells

Glucose

Glucose

Fatty acids

Insulin

Adipose

Glucose

Glucose

Liver


Cystic fibrosis related diabetes from bed to bench and back again

Incretin secretion augment insulin secretion

I

(Incretins: GLP-1 GIP)

glucose

fatty acids

amino acids

Intestinal

Neuroendocrine cells

Insulin 

Food

glucose

Pancreatic

β-cells


Cystic fibrosis related diabetes from bed to bench and back again

Insulin Secretion Defects Underlie all Forms of Diabetes


Cystic fibrosis related diabetes from bed to bench and back again

Insulin Secretion Defects Underlie all Forms of Diabetes


Cystic fibrosis related diabetes from bed to bench and back again

Insulin Secretion Defects Underlie all Forms of Diabetes


Cystic fibrosis related diabetes from bed to bench and back again

Insulin Secretion Defects Underlie all Forms of Diabetes

β-cell


Cystic fibrosis related diabetes from bed to bench and back again

Insulin Secretion Defects Underlie all Forms of Diabetes

β-cell


Cystic fibrosis related diabetes from bed to bench and back again

Defects in Insulin Secretion & Glucose Excursion are Present in the Setting of “Normal” Glucose Tolerance

Moran et al. J Peds 1991

OGTT Plasma Glucose

OGTT C-peptide (insulin secretion)

324

288

252

216

180

144

108

72

Controls

C-Peptide (nmol/L)

Plasma Glucose (mg/dL)

PI-CF w/o CFRD

Time (min)

Time (min)

IV Glucose Tolerance Test

(Dextrose 20 g IV bolus)

C-Peptide (nmol/L)

C-Peptide (nmol/L)

Time (min)

C-Peptide to IV Glucose


Cystic fibrosis related diabetes from bed to bench and back again

OGTT Plasma Glucose

OGTT C-peptide (insulin secretion)

324

288

252

216

180

144

108

72

Controls

C-Peptide (nmol/L)

Plasma Glucose (mg/dL)

PI-CF w/o CFRD

  • Loss of early insulin secretionhyperglycemia

  • Animal models

Time (min)

Time (min)

IV Glucose Tolerance Test

(Dextrose 20 g IV bolus)

C-Peptide (nmol/L)

C-Peptide (nmol/L)

Time (min)

C-Peptide to IV Glucose


Cystic fibrosis related diabetes from bed to bench and back again

Mechanisms of insulin secretion defects

Glucose Potentiated Arginine Stimulation Test

Absolute Insulin Response

(μIU/mL)

KATP channel

glucose

Arginine

5g IV

Plasma glucose (mg/dL)

ATP

ADP

VDCC

secretory

granules

insulin


Cystic fibrosis related diabetes from bed to bench and back again

Mechanisms of insulin secretion defects

KATP channel

glucose

Glucose Potentiated Arginine Stimulation Test

ATP

ADP

Absolute Insulin Response

(μIU/mL)

VDCC

secretory

granules

Glucose clamp 230 mg/dL

insulin

Arginine

5g IV

Arginine

5g IV

Plasma glucose (mg/dL)


Cystic fibrosis related diabetes from bed to bench and back again

Mechanisms of insulin secretion defects

Glucose Potentiated Arginine Stimulation Test

Absolute Insulin Response

(μIU/mL)

340 mg/dL

Glucose clamp 230 mg/dL

KATP channel

glucose

Arginine

5g IV

Arginine

5g IV

Arginine

5g IV

Plasma glucose (mg/dL)

ATP

ADP

VDCC

secretory

granules

insulin


Cystic fibrosis related diabetes from bed to bench and back again

Mechanisms of insulin secretion defects

Glucose Potentiated Arginine Stimulation Test

Healthy lean controls

PI-CF NGT

OGTT PG1<200 mg/dL

PG2<140 mg/L

Absolute Insulin Response

(μIU/mL)

340 mg/dL

Glucose clamp 230 mg/dL

Arginine

5g IV

Arginine

5g IV

Arginine

5g IV

Plasma glucose (mg/dL)


Cystic fibrosis related diabetes from bed to bench and back again

And, β-cell Sensitivity to Glucose is Preserved

Glucose threshold for ½ maximal insulin secretion

Healthy Lean Controls

CF with NGT

Absolute Insulin Response

(μIU/mL)

p = 0.84

Plasma glucose (mg/dL)


Cystic fibrosis related diabetes from bed to bench and back again

Glucose threshold for ½ maximal insulin secretion

Healthy Lean Controls (n=12)

CF with NGT (n=10)

preserved

Absolute Insulin Response

(μIU/mL)

Insulin deficiency is NOT due to an altered glucose threshold for insulin secretion

p = 0.84

Plasma glucose (mg/dL)


Cystic fibrosis related diabetes from bed to bench and back again

Pancreatic enzyme replacement & plasma glucose

Insulin

Insulin

BG

Mixed meal tolerance test

Insulin

BG

Enzymes

Placebo

Healthy

Insulin

BG

Healthy Controls

CF

Enzymes

Placebo

Blood Glucose

(mg/dL)

Pancreatic exocrine insufficiency & maldigestion can contribute to defective insulin secretion & hyperglycemia

Time (min)

Time (min)

GIP

Glucagon

GLP-1

GLP-1

GIP

GLP-1

Plasma GIP (pmol/L)

Plasma GLP-1

(nmol/L)

Time (min)

Time (min)

Kuo P et al. JCEM 2011;96:E851-E855


Ivacaftor insulin incretin secretion

Ivacaftor--Insulin & Incretin Secretion

Case series (n=5) variable improvements in glucose excursion and insulin secretion following 5 weeks of ivacaftor(BellinPed 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 wksivacaftor

  • GPA studies of insulin secretion

  • Mixed meal tolerance tests—incretin secretion

  • OGTT


More information about our patient

More information about our patient


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt7

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

HbA1C== 7.5


Cystic fibrosis related diabetes from bed to bench and back again

14 y 8 mo old male with pancreatic insufficient CF & IGT by OGTT

Hyperglycemia during overnight enteral feeds

Blood Glucose (mg/dL)

NIGHT DAY NIGHT


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt8

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

  • HbA1C==5.9%

  • BMI improved

  • FEV1%-predicted improved to 100%  105%

x

x

BMI (years)

BMI (years)

x

x

x

x

x

x

Insulin initiated

Age (years)


14y 8mo old male with pancreatic insufficient cf and abnormal ogtt9

14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

  • FEV1%-predicted improved to 100%  105%

  • HbA1C==5.9%

x

x

BMI (years)

BMI (years)

x

x

x

x

x

x

Insulin initiated

Age (years)


Cystic fibrosis related diabetes from bed to bench and back again

“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

J. . .going about his life with CFRD


Cystic fibrosis related diabetes from bed to bench and back again

The Goal

Hyperglycemia

WorseningPulmonary function

Nutritional status

Insulin Deficiency


Cystic fibrosis related diabetes from bed to bench and back again

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


Cystic fibrosis related diabetes from bed to bench and back again

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


Cystic fibrosis related diabetes from bed to bench and back again

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


Many questions remain

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 t akes a village

It takes a village

CHOPPenn

CF CenterCF Center

Ron Rubenstein (Director)Denis Hadjiliadis (Director)

Chris KubrakDan Dorgin

Saba SheikhEndocrinology & Diabetes

Endocrinology & DiabetesMike Rickels

Diva De LeonNora Rosenfeld

Shayne DoughertyAmy Peleckis

LalithaGudipaty

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)


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