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Diabetologia

pp 1–11 | Cite as

Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in non-diabetic recurrently hypoglycaemic rats

  • Rawad Farhat
  • Gong Su
  • Anne-Sophie Sejling
  • Nicholas Knight
  • Simon J. Fisher
  • Owen ChanEmail author
Article

Abstract

Aims/hypothesis

This study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent counterregulatory failure and the development of impaired awareness of hypoglycaemia (IAH) in recurrently hypoglycaemic rats.

Methods

Sprague Dawley rats were implanted with vascular catheters and intracranial guide cannulas targeting the ventromedial hypothalamus (VMH). These animals underwent either three bouts of insulin-induced hypoglycaemia or received three saline injections (control group) over 3 days. A subgroup of recurrently hypoglycaemic animals was treated with carvedilol. The next day, the animals underwent a hypoglycaemic clamp with microdialysis without carvedilol treatment to evaluate changes in central lactate and hormone levels. To assess whether carvedilol prevented IAH, we treated rats that had received repeated 2-deoxyglucose (2DG) injections to impair their awareness of hypoglycaemia with carvedilol and measured food intake in response to insulin-induced hypoglycaemia as a surrogate marker for hypoglycaemia awareness.

Results

Compared with the control group, recurrently hypoglycaemic rats had a ~1.7-fold increase in VMH lactate and this was associated with a 75% reduction in the sympathoadrenal response to hypoglycaemia. Treatment with carvedilol restored VMH lactate levels and improved the adrenaline (epinephrine) responses. In 2DG-treated rats compared with control animals receiving saline, food intake was reduced in response to hypoglycaemia and increased with carvedilol treatment.

Conclusions/interpretation

We conclude that carvedilol may be a useful therapy to prevent counterregulatory failure and improve IAH.

Keywords

Carvedilol Counterregulatory failure Impaired hypoglycaemia awareness Lactate Recurrent hypoglycaemia Ventromedial hypothalamus (VMH) β-blocker 

Abbreviations

2DG

2-Deoxyglucose

β2AR

β2-Adrenergic receptor

GIR

Glucose infusion rate

HAAF

Hypoglycaemia-associated autonomic failure

IAH

Impaired awareness of hypoglycaemia

MCT

Monocarboxylic acid transporter

qRT-PCR

Quantitative RT-PCR

VMH

Ventromedial hypothalamus

Notes

Contribution statement

RF, GS, AS and NK researched the data. OC conceptualised and designed the studies. SJF developed the 2DG IAH rodent model. RF and OC drafted the manuscript. RF, GS, AS, NK, SJF and OC reviewed, revised and approved the final manuscript. OC is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

The authors are grateful for the generosity of the agencies that helped fund this study: the JDRF (3-SRA-2017-487-S-B), the National Institutes of Health (R01 DK099315) and the University of Utah’s Diabetes and Metabolism Research Center. NK was supported by the Undergraduate Research Opportunities Program at the University of Utah.

Duality of interest

The authors declare that there is no duality of interest associated with the manuscript.

Supplementary material

125_2018_4802_MOESM1_ESM.pdf (459 kb)
ESM Fig.1 (PDF 458 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Rawad Farhat
    • 1
  • Gong Su
    • 1
    • 2
  • Anne-Sophie Sejling
    • 3
  • Nicholas Knight
    • 1
  • Simon J. Fisher
    • 1
  • Owen Chan
    • 1
    Email author
  1. 1.Division of Endocrinology, Metabolism and Diabetes, Department of Internal MedicineUniversity of UtahSalt Lake CityUSA
  2. 2.Beijing An Zhen HospitalCapital Medical UniversityBeijingChina
  3. 3.Novo-Nordisk A/SSøborgDenmark

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