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Insulin production and resistance in cystic fibrosis: Effect of age, disease activity, and genotype

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Abstract

Aim: To assess the major determinants of glucose tolerance between age, genotype, and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF-related diabetes (CFRD). Subjects and methods: One hundred and nineteen patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. Homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose/insulin ratio (FGIR) were calculated as indices of IR and insulinogenic index as a marker of pancreatic β-cell function. All patients underwent an oral glucose tolerance test, and 57 underwent an IVGTT for the calculation of first-phase (FPIR) and acute insulin responses (AIR). Results: The F508del homozygous patients had an increased chance of developing impaired glucose tolerance (IGT) and significantly lower FPIR, decreased HOMA-IR, and insulinogenic index. Heterozygote F508del patients had an increased chance of having normal glucose tolerance. HOMA-IR, FGIR, and insulinogenic index did not change with age or clinical score. HOMA-IR correlated with FPIR. FPIR correlated positively with insulinogenic index. AIR correlated negatively with FGIR, and positively with C-reactive protein. In multiple linear regression analyses, glucose tolerance was related to the age-group, and to the HOMA-IR and insulinogenic indexes. Conclusions: IGT and CFRD were related mainly to genotype, although, as expected, the prevalence increased with age. The data suggested a possible combined contribution of insulin deficiency, β-cell function, and reduced insulin sensitivity to the onset of CFRD; however, further studies are warranted to better elucidate this aspect.

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References

  1. FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993, 122: 1–9.

    Article  PubMed  CAS  Google Scholar 

  2. Costa M, Potvin S, Berthiaume Y, et al. Diabetes: a major co-morbidity of cystic fibrosis. Diab Metab 2005, 31: 221–32.

    Article  CAS  Google Scholar 

  3. Brennan AL, Geddes DM, Gyi KM, Baker EH. Clinical importance of cystic fibrosis-related diabetes. J Cystic Fibrosis 2004, 3: 209–22.

    Article  CAS  Google Scholar 

  4. Schaedel C, de Monestrol I, Hjelte L, et al. Predictors of deterioration of lung function in cystic fibrosis. Pediatc Pulmonol 2002, 33: 483–91.

    Article  CAS  Google Scholar 

  5. Hardin DS, Moran A. Diabetes Mellitus in cystic fibrosis. Endocrinol Metab Clin North Am 1999, 28: 787–800.

    Article  PubMed  CAS  Google Scholar 

  6. Mohan K, Miller H, Dyce R, et al. Mechanisms of glucose intolerance in cystic fibrosis. Diabet Med 2009, 26: 582–8.

    Article  PubMed  CAS  Google Scholar 

  7. Tofé S, Moreno JC, Máiz L, Alonso M, Escobar H, Barrio R. Insulin-secretion abnormalities and clinical deterioration related to impaired glucose tolerance in cystic fibrosis. Eur J Endocrinol 2005, 152: 241–7.

    Article  PubMed  CAS  Google Scholar 

  8. Cucinotta D, De Luca F, Gigante A, et al. No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study. Eur J Endocrinol 1994, 130: 253–8.

    Article  PubMed  CAS  Google Scholar 

  9. Lombardo F, De Luca F, Rosano M, et al. Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia. Eur J Endocrinol 2003, 149: 53–9.

    Article  PubMed  CAS  Google Scholar 

  10. Lanng S. Glucose intolerance in cystic fibrosis patients. Paediatr Resp Rev 2001, 2: 253–9.

    Article  CAS  Google Scholar 

  11. Street ME, Ziveri MA, Spaggiari C, et al. Inflammation is a modulator of the IGF-IGFBP system inducing reduced bioactivity of IGFs in Cystic Fibrosis. Eur J Endocrinol 2006, 154: 47–52.

    Article  PubMed  CAS  Google Scholar 

  12. Austin A, Kalhan SC, Orenstein D, Nixon P, Arslanian S. Roles of insulin resistance and β-cell dysfunction in the pathogenesis of glucose intolerance in cystic fibrosis. J Clin Endocrinol Metab 1994, 79: 80–5.

    PubMed  CAS  Google Scholar 

  13. Hardin DS, Leblanc A, Marshall G, Seilheimer DK. Mechanisms of insulin resistance in cystic fibrosis. Am J Physiol Endocrinol Metab 2001, 281: E1022–8.

    PubMed  CAS  Google Scholar 

  14. Moran A, Hardin D, Rodman D, et al. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus. A consensus conference report. Diabetes Res Clin Prac 1999, 45: 61–73.

    Article  CAS  Google Scholar 

  15. Bismuth E, Laborde K, Taupin P, et al. Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis. J Pediatr 2009, 152: 540–5.

    Article  CAS  Google Scholar 

  16. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract 2009, 15: 469–74.

    Article  PubMed  Google Scholar 

  17. Shwachman H, Kulczycki LL. Long-term study of one hundred five patients with cystic fibrosis; studies made over a five- to fourteen-year period. AMA J Dis Child 1958, 96: 6–15.

    Article  PubMed  CAS  Google Scholar 

  18. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969, 44: 291–303.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Marshall WA, Tanner J. Variations in pattern of pubertal changes in boys. Arch Dis Child 1970, 45: 13–23.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Cacciari E, Milani S, Balsamo A, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 2006, 29: 581–93.

    Article  PubMed  CAS  Google Scholar 

  21. Polgar G, Promadhat V. Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia: WB Saunders, 1971.

    Google Scholar 

  22. Adler AI, Shine BS, Chamnan P, Haworth CS, Bilton D. Genetic determinants and epidemiology of cystic fibrosis-related diabetes: results from a British cohort of children and adults. Diabetes Care 2008, 31: 1789–94.

    Article  PubMed Central  PubMed  Google Scholar 

  23. de Gracia J, Mata F, Alvarez A, et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax 2005, 60: 558–63.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Uwaifo GI, Fallon EM, Chin J, Elberg J, Parikh SJ, Yanovski JA. Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care 2002, 25: 2081–7.

    Article  PubMed  CAS  Google Scholar 

  25. Caumo A, Luzi L. First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am J Physiol Endocrinol Metab 2004, 287: E371–85.

    Article  PubMed  CAS  Google Scholar 

  26. Andreozzi F, Laratta E, Cardellini M, et al. Plasma interleukin-6 levels are independently associated with insulin secretion in a cohort of Italian-Caucasian nondiabetic subjects. Diabetes 2006, 55: 2021–4.

    Article  PubMed  CAS  Google Scholar 

  27. Lorini R, Vanelli M. Normal values of first-phase insulin response to intravenous glucose in healthy Italian children and adolescents. Diabetologia 1996, 39: 370–1.

    Article  PubMed  CAS  Google Scholar 

  28. Katz A, Nambi SS, Mather K. et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000, 85: 2402–10.

    Article  PubMed  CAS  Google Scholar 

  29. Vuguin P, Saenger P, Dimartino-Nardi J. Fasting glucose insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche. J Clin Endocrinol Metab 2001, 86: 4618–21.

    Article  PubMed  CAS  Google Scholar 

  30. Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005, 146: 681–7.

    Article  PubMed  CAS  Google Scholar 

  31. Costa M, Potvin S, Hammana I, et al. Increased glucose excursion in cystic fibrosis and its association with a worse clinical status. J Cyst Fibros 2007, 6: 376–83.

    Article  PubMed  CAS  Google Scholar 

  32. Koch C, Rainisio M, Madessani U, et al; Investigators of the European Epidemiologic Registry of Cystic Fibrosis. Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: Data from the European epidemiologic registry of cystic fibrosis. Pediatr Pulmonol 2001, 32: 343–50.

    Article  PubMed  CAS  Google Scholar 

  33. Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatr 1994, 8: 849–53.

    Article  Google Scholar 

  34. Cook JS, Hoffman RP, Stene MA, Hansen JR. Effects of maturational stage on insulin sensitivity during puberty. J Clin Endocrinol Metab 1993, 77: 725–30.

    PubMed  CAS  Google Scholar 

  35. Canale-Zambrano JC, Poffenberger MC, Cory SM, Humes DG, Haston CK. Intestinal phenotype of variable-weight cystic fibrosis knockout mice. Am J Physiol Gastrointest Liver Physiol 2007, 293: G222–9.

    Article  PubMed  CAS  Google Scholar 

  36. Dobson L, Sheldon CD, Hattersley AT. Conventional measures underestimate glycaemia in cystic fibrosis patients. Diab Med 2004, 21: 691–6.

    Article  CAS  Google Scholar 

  37. Godbout A, Hammana I, Potvin S, et al. No relationship between mean plasma glucose and glycated haemoglobin in patients with cystic fibrosis-related diabetes. Diab Metab 2008, 34: 568–73.

    Article  CAS  Google Scholar 

  38. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 2006, 103: 2334–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Antigny F, Norez C, Cantereau A, Becq F, Vandebrouck C. Abnormal spatial diffusion of Ca 2+ in F508del-CFTR airway epithelial cells. Respir Res 2008, 9: 70.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Street ME, Volta C, Ziveri MA, Viani I, Bernasconi S. Markers of insulin sensitivity in placentas and cord serum of intrauterine growth-restricted newborns. Clin Endocrinol (Oxf) 2009, 71: 394–9.

    Article  CAS  Google Scholar 

  41. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 2003, 52: 2784–9.

    Article  PubMed  CAS  Google Scholar 

  42. Fasshauer M, Kralisch S, Klier M, et al. Insulin resistance-inducing cytokines differentially regulate SOCS mRNA via growth factor- and Jak/Stat-signaling pathway in 3T3-L1 adipocytes. J Endocrinol 2004, 181: 129–38.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Paediatrics, University Hospital of Parma, Via Gramsci, 14, 43100, Parma, Italy

    M. E. Street MD, PhD, C. Spaggiari, M. A. Ziveri, C. Volta, I. Viani, G. L. Grzincich, C. Sartori, M. Zanzucchi, C. Terzi, G. Pisi, E. Zanetti & S. Bernasconi

  2. Department of Statistics, University of Parma, Parma, Italy

    M. Rossi

  3. Department of Paediatrics, University Federico II, Naples, Italy

    V. Raia

  4. Department of Paediatrics, Federal University of Parana, Curitiba, Brazil

    E. Zanetti & M. C. S. Boguszewski

  5. Department of Paediatrics, FCM/UNICAMP, Campinas, Brazil

    T. O. Kamoi

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  1. M. E. Street MD, PhD
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  2. C. Spaggiari
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  3. M. A. Ziveri
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  4. M. Rossi
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  5. C. Volta
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  6. I. Viani
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  7. G. L. Grzincich
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  16. S. Bernasconi
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Corresponding author

Correspondence to M. E. Street MD, PhD.

Additional information

Data from this study were presented as an oral presentation at the LWPES/ESPE 8th joint meeting, New York September 9–12, 2009.

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Street, M.E., Spaggiari, C., Ziveri, M.A. et al. Insulin production and resistance in cystic fibrosis: Effect of age, disease activity, and genotype. J Endocrinol Invest 35, 246–253 (2012). https://doi.org/10.3275/7628

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