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Original Research

Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes

Hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial

  1. Lalantha Leelarathna, MRCP1,
  2. Stuart A. Little, MRCP2,
  3. Emma Walkinshaw, MRCP3,
  4. Horng Kai Tan, MRCP4,
  5. Alexandra Lubina-Solomon, MD3,
  6. Kavita Kumareswaran, PHD1,
  7. Annette P. Lane, GCGI2,
  8. Thomas Chadwick, PHD5,
  9. Sally M. Marshall, MD2,
  10. Jane Speight, PHD6,7,8,
  11. Daniel Flanagan, MD4,
  12. Simon R. Heller, MD3,
  13. James A.M. Shaw, PHD2⇑ and
  14. Mark L. Evans, MD1⇑
  1. 1Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, U.K.
  2. 2Institute of Cellular Medicine, Newcastle University, Newcastle, U.K.
  3. 3School of Medicine and Biomedical Sciences, Sheffield University, Sheffield, U.K.
  4. 4Department of Diabetes, Derriford Hospital, Plymouth, U.K.
  5. 5Newcastle Clinical Trials Unit, Institute of Health and Society, Newcastle University, Newcastle, U.K.
  6. 6AHP Research, Hornchurch, U.K.
  7. 7Australian Centre for Behavioural Research in Diabetes, Diabetes Australia–Victoria, Melbourne, Victoria, Australia
  8. 8Centre for Mental Health and Wellbeing Research, School of Psychology, Deakin University, Burwood, Victoria, Australia
  1. Corresponding author: Mark L. Evans, mle24{at}cam.ac.uk, or James A.M. Shaw, jim.shaw{at}newcastle.ac.
  1. M.L.E. and J.A.M.S. contributed equally to this article as lead investigators for the clamp substudy and overall HypoCOMPaSS trial, respectively.

Diabetes Care 2013 Dec; 36(12): 4063-4070. https://doi.org/10.2337/dc13-1004
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Abstract

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial.

RESEARCH DESIGN AND METHODS Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies.

RESULTS After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420–780] vs. 710 [460–1,260], P = 0.02; metanephrine, 2,412 [−3,026 to 7,279] vs. 5,180 [−771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation.

CONCLUSIONS Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

Footnotes

  • Clinical trial reg. nos. ISRCTN52164803, www.isrctn.org, and EudraCT2009-015396-27, http://eudract.ema.europa.eu/.

  • This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc13-1004/-/DC1.

  • Received April 27, 2013.
  • Accepted July 14, 2013.
  • © 2013 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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Diabetes Care: 36 (12)

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Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes
Lalantha Leelarathna, Stuart A. Little, Emma Walkinshaw, Horng Kai Tan, Alexandra Lubina-Solomon, Kavita Kumareswaran, Annette P. Lane, Thomas Chadwick, Sally M. Marshall, Jane Speight, Daniel Flanagan, Simon R. Heller, James A.M. Shaw, Mark L. Evans
Diabetes Care Dec 2013, 36 (12) 4063-4070; DOI: 10.2337/dc13-1004

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Restoration of Self-Awareness of Hypoglycemia in Adults With Long-Standing Type 1 Diabetes
Lalantha Leelarathna, Stuart A. Little, Emma Walkinshaw, Horng Kai Tan, Alexandra Lubina-Solomon, Kavita Kumareswaran, Annette P. Lane, Thomas Chadwick, Sally M. Marshall, Jane Speight, Daniel Flanagan, Simon R. Heller, James A.M. Shaw, Mark L. Evans
Diabetes Care Dec 2013, 36 (12) 4063-4070; DOI: 10.2337/dc13-1004
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