Advertisement

Diabetologia

pp 1–11 | Cite as

Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis

  • Moira L. Aitken
  • Magdalena A. Szkudlinska
  • Edward J. Boyko
  • Debbie Ng
  • Kristina M. Utzschneider
  • Steven E. KahnEmail author
Article
First Online:

Abstract

Aims/hypothesis

The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF).

Methods

A 3 h 75 g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3 mmol/l with or without symptoms or glucose <3.9 mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed.

Results

The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10 mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8 pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05 nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135 min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3 mmol/l at 180 min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5 mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1 ml min−1 m−2, p = 0.074 based on values until 120 min [n = 14]; 512 ± 18.9 vs 438 ± 15.5 ml min−1 m−2, p = 0.006 based on values until 180 min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISRfasting: 50.8 ± 3.2 vs 74.0 ± 5.9 pmol min−1 m−2, p = 0.002; ISROGTT: 44.9 ± 5.0 vs 63.4 ± 5.2 nmol/m2, p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5 pmol min−1 m−2 [mmol/l]−1, p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180 min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2 mmol/l, respectively.

Conclusions/interpretation

Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction.

Keywords

Adrenaline Cortisol Cystic fibrosis Epinephrine Glucagon Glucagon-like peptide-1 (GLP-1) Glucose Glucose-dependent insulinotropic peptide (GIP) Growth hormone Hypoglycaemia Incretins Insulin Noradrenaline Norepinephrine Oral glucose tolerance test 

Abbreviations

CF

Cystic fibrosis

CFRD

CF-related diabetes

CFTR

CF transmembrane conductance regulator

CTRC

Clinical and Translational Research Centers

DIo

Oral disposition index

FEV1

Forced expiratory volume in the first second

GIP

Glucose-dependent insulinotropic peptide

GLP-1

Glucagon-like peptide-1

HAAF

Hypoglycaemia-associated autonomic failure

iAUC

Incremental AUC

IGT

Impaired glucose tolerance

ISR

Insulin secretion rate

This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

The authors wish to thank the participants for their time and effort in addressing this important clinical problem. We appreciate the advice of A. Mari (Institute of Neuroscience, National Research Council, Padova, Italy) regarding the mathematical modelling and discussions with R. Singh (Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA) and K. Morgenthaler (Colorado Clinical and Translational Sciences Institute, University of Colorado Denver, Aurora, CO, USA) regarding the catecholamine assays. The support of B. Ramsey, S. Heltshe and S. McNamara (all at Seattle Children’s Research Institute, University of Washington, Seattle, WA, USA) during the performance of the study is greatly appreciated.

Contribution statement

SEK designed the study and all authors acquired data. SEK, EJB and KMU analysed the data and all authors participated in interpreting it. SEK drafted and all other authors reviewed/edited the manuscript and gave final approval for its publication. SEK and EJB had access to all the data and are guarantors of the work.

Funding

This study was supported in part by a Pilot and Feasibility Award to SEK from the University of Washington Cystic Fibrosis Research and Translation Center (NIH grant P30 DK089507) and the Diabetes Research Center at the University of Washington (NIH grant P30 DK017047). Additional support to SEK, KMU and EJB was provided by the Department of Veterans Affairs. MAS was supported by NIH grant T32 DK007247. The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Supplementary material

125_2020_5096_MOESM1_ESM.pdf (318 kb)
ESM Figure (PDF 317 kb)

References

  1. 1.
    Cystic Fibrosis Foundation (2017) Cystic Fibrosis Foundation patient registry: 2016 annual data report. Cystic Fibrosis Foundation, Bethesda, MDGoogle Scholar
  2. 2.
    Battezzati A, Battezzati PM, Costantini D et al (2007) Spontaneous hypoglycemia in patients with cystic fibrosis. Eur J Endocrinol 156(3):369–376.  https://doi.org/10.1530/eje.1.02344 CrossRefPubMedGoogle Scholar
  3. 3.
    Radike K, Molz K, Holl RW, Poeter B, Hebestreit H, Ballmann M (2011) Prognostic relevance of hypoglycemia following an oral glucose challenge for cystic fibrosis-related diabetes. Diabetes Care 34(4):e43.  https://doi.org/10.2337/dc10-2286 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mannik LA, Chang KA, Annoh PQK et al (2018) Prevalence of hypoglycemia during oral glucose tolerance testing in adults with cystic fibrosis and risk of developing cystic fibrosis-related diabetes. J Cyst Fibros 17(4):536–541.  https://doi.org/10.1016/j.jcf.2018.03.009 CrossRefPubMedGoogle Scholar
  5. 5.
    Armaghanian N, Markovic TP, Brand-Miller JC, Bye PTP, Moriarty CP, Steinbeck KS (2018) Hypoglycaemia in cystic fibrosis: an analysis of a single centre adult cystic fibrosis clinic. J Cyst Fibros 17(4):542–547.  https://doi.org/10.1016/j.jcf.2017.11.015 CrossRefPubMedGoogle Scholar
  6. 6.
    Hirsch IB, Janci MM, Goss CH, Aitken ML (2013) Hypoglycemia in adults with cystic fibrosis during oral glucose tolerance testing. Diabetes Care 36(8):e121–e122.  https://doi.org/10.2337/dc12-1859 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    American Diabetes Association (1997) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197CrossRefGoogle Scholar
  8. 8.
    Moran A, Brunzell C, Cohen RC et al (2010) Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 33(12):2697–2708.  https://doi.org/10.2337/dc10-1768 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    International Hypoglycaemia Study Group (2017) Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 60(1):3–6.  https://doi.org/10.1007/s00125-016-4146-6 CrossRefGoogle Scholar
  10. 10.
    Jiang NS, Machacek D, Wadel OP (1976) Further study on the two-column plasma catecholamine assay. Mayo Clin Proc 51(2):112–116PubMedGoogle Scholar
  11. 11.
    Kahn SE, Prigeon RL, McCulloch DK et al (1993) Quantification of the relationship between insulin sensitivity and β-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42:1663–1672CrossRefGoogle Scholar
  12. 12.
    Utzschneider KM, Prigeon RL, Faulenbach MV et al (2009) Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care 32(2):335–341.  https://doi.org/10.2337/dc08-1478 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mari A, Schmitz O, Gastaldelli A, Oestergaard T, Nyholm B, Ferrannini E (2002) Meal and oral glucose tests for assessment of β-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 283:E1159–E1166CrossRefGoogle Scholar
  14. 14.
    Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ (2001) A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 24(3):539–548CrossRefGoogle Scholar
  15. 15.
    Moheet A, Ode KL (2018) Hypoglycaemia in patients with cystic fibrosis- harbinger of poor outcomes or innocent bystander? J Cyst Fibros 17(4):428–429.  https://doi.org/10.1016/j.jcf.2018.05.012 CrossRefPubMedGoogle Scholar
  16. 16.
    Sacca L, Sherwin R, Hendler R, Felig P (1979) Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans. J Clin Invest 63(5):849–857.  https://doi.org/10.1172/JCI109384 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rizza RA, Cryer PE, Gerich JE (1979) Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest 64(1):62–71.  https://doi.org/10.1172/JCI109464 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cryer PE (2013) Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 369(4):362–372.  https://doi.org/10.1056/NEJMra1215228 CrossRefPubMedGoogle Scholar
  19. 19.
    Mohan V, Alagappan V, Snehalatha C, Ramachandran A, Thiruvengadam KV, Viswanathan M (1985) Insulin and C-peptide responses to glucose load in cystic fibrosis. Diabete Metab 11(6):376–379PubMedGoogle Scholar
  20. 20.
    Moran A, Diem P, Klein DJ, Levitt MD, Robertson RP (1991) Pancreatic endocrine function in cystic fibrosis. J Pediatr 118(5):715–723.  https://doi.org/10.1016/s0022-3476(05)80032-0 CrossRefPubMedGoogle Scholar
  21. 21.
    Lanng S, Thorsteinsson B, Roder ME et al (1993) Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance. Acta Endocrinol 128(3):207–214.  https://doi.org/10.1530/acta.0.1280207 CrossRefPubMedGoogle Scholar
  22. 22.
    Sheikh S, Gudipaty L, De Leon DD et al (2017) Reduced β-cell secretory capacity in pancreatic-insufficient, but not pancreatic-sufficient, cystic fibrosis despite normal glucose tolerance. Diabetes 66(1):134–144.  https://doi.org/10.2337/db16-0394 CrossRefPubMedGoogle Scholar
  23. 23.
    Hull RL, Gibson RL, McNamara S et al (2018) Islet interleukin-1β immunoreactivity is an early feature of cystic fibrosis that may contribute to β-cell failure. Diabetes Care 41(4):823–830.  https://doi.org/10.2337/dc17-1387 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Havel PJ, Mundinger TO, Taborsky GJ Jr (1996) Pancreatic sympathetic nerves contribute to increased glucagon secretion during severe hypoglycemia in dogs. Am J Phys 270(1 Pt 1):E20–E26.  https://doi.org/10.1152/ajpendo.1996.270.1.E20 CrossRefGoogle Scholar
  25. 25.
    Edlund A, Pedersen MG, Lindqvist A, Wierup N, Flodstrom-Tullberg M, Eliasson L (2017) CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells. Sci Rep 7(1):90.  https://doi.org/10.1038/s41598-017-00098-8 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444(7121):840–846.  https://doi.org/10.1038/nature05482 CrossRefPubMedGoogle Scholar
  27. 27.
    Kilberg MJ, Sheikh S, Stefanovski D et al (2019) Dysregulated insulin in pancreatic insufficient cystic fibrosis with post-prandial hypoglycemia. J Cyst Fibros.  https://doi.org/10.1016/j.jcf.2019.07.006
  28. 28.
    Campfield LA, Smith FJ (1983) Neural control of insulin secretion: interaction of norepinephrine and acetylcholine. Am J Phys 244(5):R629–R634.  https://doi.org/10.1152/ajpregu.1983.244.5.R629 CrossRefGoogle Scholar
  29. 29.
    Nauck MA, Heimesaat MM, Behle K et al (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87(3):1239–1246.  https://doi.org/10.1210/jcem.87.3.8355 CrossRefPubMedGoogle Scholar
  30. 30.
    Johnson DD, Dorr KE, Swenson WM, Service FJ (1980) Reactive hypoglycemia. JAMA 243(11):1151–1155CrossRefGoogle Scholar
  31. 31.
    Brun JF, Fedou C, Mercier J (2000) Postprandial reactive hypoglycemia. Diabetes Metab 26(5):337–351PubMedGoogle Scholar
  32. 32.
    Porcellati F, Pampanelli S, Rossetti P et al (2003) Counterregulatory hormone and symptom responses to insulin-induced hypoglycemia in the postprandial state in humans. Diabetes 52(11):2774–2783.  https://doi.org/10.2337/diabetes.52.11.2774 CrossRefPubMedGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020

Authors and Affiliations

  1. 1.Division of Pulmonary, Critical Care and Sleep Medicine, Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleUSA
  3. 3.Division of General Internal Medicine, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleUSA

Personalised recommendations

Cite article

Buy options