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

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.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to information security but are available from the corresponding author on reasonable request.

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

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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.

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.

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Contributions

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.

Corresponding author

Correspondence to Steven E. Kahn.

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Aitken, M.L., Szkudlinska, M.A., Boyko, E.J. et al. Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis. Diabetologia 63, 1055–1065 (2020). https://doi.org/10.1007/s00125-020-05096-6

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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