cystic fibrosis related diabetes from bed to bench and back again
Download
Skip this Video
Download Presentation
Cystic Fibrosis-Related Diabetes: From bed to bench and back again

Loading in 2 Seconds...

play fullscreen
1 / 46

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


  • 112 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Cystic Fibrosis-Related Diabetes: From bed to bench and back again' - malise


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
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

slide4

Cystic fibrosis related diabetes (CFRD) is Common!

FH= fasting hyperglycemia

Prevalence (%)

Age (years)

Moran et al. Diabetes Care 2009

slide5

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)

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)

slide14

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

slide18

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

slide19

Incretin secretion augment insulin secretion

I

(Incretins: GLP-1 GIP)

glucose

fatty acids

amino acids

Intestinal

Neuroendocrine cells

Insulin 

Food

glucose

Pancreatic

β-cells

slide25

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

slide26

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

slide27

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

slide28

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)

slide29

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

slide30

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)

slide31

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)

slide32

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)

slide33

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
slide37

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)

slide40

“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

slide41

The Goal

Hyperglycemia

WorseningPulmonary function

Nutritional status

Insulin Deficiency

slide42

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
slide43

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

slide44

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

CHOP Penn

CF CenterCF Center

Ron Rubenstein (Director) Denis Hadjiliadis (Director)

Chris Kubrak Dan Dorgin

Saba Sheikh Endocrinology & Diabetes

Endocrinology & Diabetes Mike Rickels

Diva De Leon Nora Rosenfeld

Shayne Dougherty Amy 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)

ad