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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 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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  1. 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

  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! FH= fasting hyperglycemia Prevalence (%) Age (years) Moran et al. Diabetes Care 2009

  5. 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

  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.”

  7. 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)

  8. 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

  9. 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)

  10. 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)

  11. Moran et al. Diabetes Care 2010

  12. 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)

  13. 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

  14. 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

  15. 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. 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. 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

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

  19. Insulin Secretion Defects Underlie all Forms of Diabetes

  20. Insulin Secretion Defects Underlie all Forms of Diabetes

  21. Insulin Secretion Defects Underlie all Forms of Diabetes

  22. Insulin Secretion Defects Underlie all Forms of Diabetes β-cell

  23. Insulin Secretion Defects Underlie all Forms of Diabetes β-cell

  24. 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

  25. 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

  26. 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

  27. 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)

  28. 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

  29. 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)

  30. 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)

  31. 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)

  32. 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

  33. 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

  34. More information about our patient

  35. 14y 8mo old male with pancreatic insufficient CF and “abnormal” OGTT HbA1C== 7.5

  36. 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

  37. 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)

  38. 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)

  39. “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

  40. The Goal Hyperglycemia WorseningPulmonary function Nutritional status Insulin Deficiency

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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)

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