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

2. 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

3. 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

4. Cystic fibrosis related diabetes (CFRD) is Common! Moran et al. Diabetes Care 2009 Prevalence (%) Age (years) FH= fasting hyperglycemia

5. 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 tolerance Age (years) Survival rate % Lung transplant rate % CFRD age <18y __ >18y --- CFRD age <18y __ >18y --- IGT age <15y __ >15y --- IGT age <15y __ >15y --- CFRD & even earlier glucose abnormalities - - worse survival and greater likelihood of lung transplant Age ( years )

6. 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.”

8. BMI (years) x x xx x 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 FEV 1 %-predicted 100%  95% over previous year Age (years)

9. CFF 2010 Consensus Statement CFRD Screening in Healthy Outpatients Annual Screening with an oral glucose tolerance test (OGTT) starting by age 10y 50 80 110 140 170 200 230 260 Plasma Glucose (mg/dL) 0153045607590105 120 135 Time (min) Glucola (1.75 g/kg) PO Max=75 g * Plasma glucose (PG) PG0 PG1PG2

10. 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT 50 80 110 140 170 200 230 260 Plasma Glucose (mg/dL) 0153045607590105120135 Time (min) NGT *

11. 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT 50 80 110 140 170 200 230 260 Plasma Glucose (mg/dL) 0153045607590105120135 Time (min) IGT NGT * CFRD

12. OGTT Glucose Tolerance Categories Plasma glucose (PG) mg/dL Fasting2-hours Normal<100<140 Impaired fasting glucose100-125 Impaired glucose tolerance (IGT) 140-199 Diabetes≥126≥200 Indeterminate PG2<140 PG1 ≥200 Moran et al. Diabetes Care 2010

13. 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT 50 80 110 140 170 200 230 260 Plasma Glucose (mg/dL) 0153045607590105120135 Time (min) IGT NGT * CFRD Indeterminate

14. 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 Glucose (mg/dL) Insulin secretion defects are evident even in the setting of “NGT”

15. Annual CFRD Screening with OGTT Age 9y 6mo12y 3mo14y 8mo Plasma Glucose (PG), mg/dL PG099106121 PG1169188220 PG2139116194 Glucose Tolerance Category NGT IGT 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

16. Annual CFRD Screening with OGTT Age 9y 6mo12y 3mo14y 8mo Plasma Glucose (PG), mg/dL PG099106121 PG1169188220 PG2139116 194 Glucose Tolerance Category NGT IGT 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

17. Annual CFRD Screening with OGTT Age 9y 6mo12y 3mo14y 8mo Plasma Glucose (PG), mg/dL PG099106121 PG1 169188220 PG2139116194* Glucose Tolerance Category NGT IGT 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

18. Glucose Blood Intestine Food A brief review: Insulin signals the fed-state Insulin Liver Glucose Pancreatic β-cells Glucose Adipose Fatty acids potent anabolic hormone Insulin Deficiency: Evokes a catabolic state  Compromised nutritional status Hyperglycemia: Direct implications for lung & immune function

19. Intestinal Neuroendocrine cells glucose fatty acids amino acids Incretin secretion augment insulin secretion Pancreatic β-cells I (Incretins: GLP-1 GIP) Insulin  Food glucose

20. T2DMCFRD Insulin deficiencyrelativedeficient Islets Genetics Insulin Secretion Defects Underlie all Forms of Diabetes

21. T2DMCFRD Insulin deficiencyrelativedeficient Isletsβ-cell apoptosis inherent β-cell defect Genetics Insulin Secretion Defects Underlie all Forms of Diabetes

22. T2DMCFRD Insulin deficiencyrelativedeficient Isletsβ-cell apoptosis inherent β-cell defect Destruction extending from pancreatic exocrine damage Genetics Insulin Secretion Defects Underlie all Forms of Diabetes

23. T2DMCFRD Insulin deficiencyrelativedeficient Isletsβ-cell apoptosis inherent β-cell defect Destruction extending from pancreatic exocrine damage inherent β-cell defect Genetics Insulin Secretion Defects Underlie all Forms of Diabetes β-cell

24. T2DMCFRD Insulin deficiencyrelativedeficient Isletsβ-cell apoptosis inherent β-cell defect Destruction extending from pancreatic exocrine damage inherent β-cell defect GeneticsTCF7L2 Insulin Secretion Defects Underlie all Forms of Diabetes β-cell

25. Controls PI-CF w/o CFRD Defects in Insulin Secretion & Glucose Excursion are Present in the Setting of “Normal” Glucose Tolerance Moran et al. J Peds 1991 OGTT Plasma GlucoseOGTT C-peptide (insulin secretion) 324 288 252 216 180 144 108 72 C-Peptide (nmol/L) Plasma Glucose (mg/dL) C-Peptide to IV Glucose C-Peptide (nmol/L) IV Glucose Tolerance Test (Dextrose 20 g IV bolus) Time (min)

26. Controls PI-CF w/o CFRD OGTT Plasma GlucoseOGTT C-peptide (insulin secretion) 324 288 252 216 180 144 108 72 C-Peptide (nmol/L) Plasma Glucose (mg/dL) C-Peptide to IV Glucose C-Peptide (nmol/L) IV Glucose Tolerance Test (Dextrose 20 g IV bolus) Time (min) Loss of early insulin secretion  hyperglycemia Animal models

27. Absolute Insulin Response (μIU/mL) Plasma glucose (mg/dL) Arginine 5g IV Glucose Potentiated Arginine Stimulation Test Mechanisms of insulin secretion defects  ATP ADP glucose K ATP channel  VDCC secretory granules insulin

28. Absolute Insulin Response (μIU/mL) Plasma glucose (mg/dL) Arginine 5g IV Arginine 5g IV Glucose clamp 230 mg/dL Glucose Potentiated Arginine Stimulation Test Mechanisms of insulin secretion defects

29. Absolute Insulin Response (μIU/mL) Plasma glucose (mg/dL) Arginine 5g IV Arginine 5g IV Arginine 5g IV 340 mg/dL Glucose clamp 230 mg/dL Glucose Potentiated Arginine Stimulation Test Mechanisms of insulin secretion defects

30. Absolute Insulin Response (μIU/mL) Plasma glucose (mg/dL) Arginine 5g IV Arginine 5g IV Arginine 5g IV 340 mg/dL Glucose clamp 230 mg/dL Glucose Potentiated Arginine Stimulation Test Mechanisms of insulin secretion defects Healthy lean controls PI-CF NGT OGTT PG1<200 mg/dL PG2<140 mg/L

31. And, β-cell Sensitivity to Glucose is Preserved Glucose threshold for ½ maximal insulin secretion Absolute Insulin Response (μIU/mL) Plasma glucose (mg/dL) Healthy Lean Controls CF with NGT p = 0.84

32. Glucose threshold for ½ maximal insulin secretion Absolute Insulin Response (μIU/mL) 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

33. Pancreatic enzyme replacement & plasma glucose Kuo P et al. JCEM 2011;96:E851-E855 BG Insulin GlucagonGLP-1 Enzymes Placebo Healthy Insulin BG GLP-1 GIP Healthy Controls CF Enzymes Placebo GIP BG Insulin Mixed meal tolerance test Blood Glucose (mg/dL) Plasma GLP-1 (nmol/L) GLP-1 Plasma GIP (pmol/L) Time (min) Pancreatic exocrine insufficiency & maldigestion can contribute to defective insulin secretion & hyperglycemia

34. 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

35. More information about our patient

36. Annual CFRD Screening with Oral Glucose Tolerance Test (OGTT) Age 9y 6mo12y 3mo14y 8mo Plasma Glucose (PG), mg/dL (mmoL) PG099 (5.5)106 (5.8)121 (6.7) PG1169 (9.4)188 (10.4)220 (12.2) PG2139 (7.7)116 (6.4)194* (10.7) Glucose Tolerance Category NGT CFRD 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT HbA1C== 7.5

37. Hyperglycemia during overnight enteral feeds Blood Glucose (mg/dL) 14 y 8 mo old male with pancreatic insufficient CF & IGT by OGTT NIGHT DAY NIGHT

38. Age (years) BMI (years) x x xx x HbA1C==5.9% BMI improved FEV 1 %-predicted improved to 100%  105% x x x Insulin initiated BMI (years) 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

39. Age (years) BMI (years) x x xx x FEV 1 %-predicted improved to 100%  105% HbA1C==5.9% x x x Insulin initiated BMI (years) 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT

40. 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

41. Hyperglycemia Insulin Deficiency Worsening Pulmonary function Nutritional status The Goal

42. 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

43. 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

44. 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

45. 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

46. It takes a village CHOPPennCF Center Ron Rubenstein (Director)Denis Hadjiliadis (Director) Chris KubrakDan Dorgin Saba SheikhEndocrinology & Diabetes Endocrinology & DiabetesMike Rickels Diva De LeonNora Rosenfeld Shayne DoughertyAmy 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)