1 2 3 4 5 6 7 8 9 10 Several hypotheses have been - PDF document

1

2

3

4

5

6

7

8

9

10

• Several hypotheses have been proposed for the mechanism of CFRD pathogenesis – Pancreatic destruction leads to loss if islet cells, fibrosis, and amyloid deposits in islets 1 – Defective CFTR activity led to insufficient depolarization and Ca 2+ mobilization in response to glucose in cultured β-cells 2 – β-cells synthesize large amounts of protein. Chronic accumulation of misfolded CFTR may overwhelm the β-cell proteolytic degradation pathways leading to sustained endoplasmic reticulum stress responses (unfolded protein response, endoplasmic reticulum-associated protein degradation) and β-cell apoptosis 3 – A chronic inflammatory state produced by oxidative stress, ROS production, 4 elevated pro-inflammatory cytokines, 1 defective fat-soluble antioxidant absorption, and possibly vitamin D deficiency contribute to β- cell destruction and dysfunction and insulin resistance 1,4 – Insulin sensitivity is normal in patients with CF in most studies, 1,5 and in studies showing reduced insulin sensitivity, issues of study populations, methods, and interpretation may be factors 5 – Insulin resistance in CF may develop because of abnormal localization of the GLUT-4 glucose transporter and/or elevated tumor necrosis factor alpha (TNF-α) levels 6 References 1. Barrio R. Eur J Endocrinol . 2015;172(4):R131-R141. 2. Guo JH et al. Nat Commun . 2014;5:4420. 3. Ali BR. Med Hypotheses . 2009;72(1):55-57. 4. Galli F et al. Biochimica et Biophysica Acta. 2012;1822(5):690-713. 5. Mohan K et al. Diabet Med . 2009;26(6):582-588. 6. Hardin DS et al. Am J Physiol Endocrinol Metab . 2001;281(5):E1022-E1028. 11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

• Normal: Lumen of the pancreatic duct with balanced fluid volume and pH 1 • CF: Pancreatic ducts are obstructed with viscous secretions, leading to inability to secrete digestive enzymes into the gut 2,3 References 1. Pandol SJ. The Exocrine Pancreas . San Rafael (CA): Morgan & Claypool Life Sciences; 2010. 2. Wilschanski M et al. Gut . 2007;56(8):1153-1163. 3. Derichs N. Eur Respir Rev . 2013;22(127):58-65. 29

30

31

32

33

34

35

36

37

38

39

40

• PAP is proposed as a less costly alternative to the DNA testing or IRT retesting after the initial elevated IRT test results in newborns 1,2 • Blood from neonatal samples (pinpricks/bloodspots) are analyzed using ELISA method 2 • According to one proposed screening strategy (France), all newborns are tested for IRT. Newborns with IRT >50 ng/mL are tested for PAP. Those with PAP >1.8 ng/mL and those with PAP >1.0 ng/mL and IRT > 100 ng/mL are recalled for sweat testing 2 References 1. Sarles J et al. Arch Dis Child Fetal Neonatal Ed. 1999;80(2):F118- F122. 2. Sarles J et al. J Pediatr. 2005;147(3):302-305. 41

• Wireless motility capsule system – Measures pH and transit time – Use of pH capsule devise is limited in young children and infants due to its size Reference Bodewes FA et al. J Cyst Fibros . 2015;14(2):169-177. 42

43

44

45

46

47

48

49

50

51

52

53