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Potential approaches to prevent hypoglycemia-associated autonomic failure
  1. Eric Lontchi-Yimagou1,
  2. Jee Young You1,
  3. Michelle Carey1,2,
  4. Ilan Gabriely1,
  5. Harry Shamoon1,
  6. Meredith Hawkins1
  1. 1Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, USA
  2. 2Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, Maryland, USA
  1. Correspondence to Professor Meredith Hawkins, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; meredith.hawkins{at}


Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to ‘hypoglycemia-associated autonomic failure’ (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.

  • diabetes mellitus
  • diabetes complications
  • hypoglycemia
  • disease management

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  • Contributors ELY conceived of the idea for this review paper, and ELY and JYY did the majority of the literature review and writing. MC, HS, and MH contributed to the literature review and analysis, critical revision, and editing. IG contributed ideas and inspiration.

  • Funding This work was supported by grants from the National Institute of Health (DK069861 and DK48321), by the Einstein-Montefiore NIH CTSA Grant UL1TR001073 from the National Center for Research Resources (NCRR) and the Einstein-Mt. Sinai Diabetes Research Center (5P30DK020541-41). Its contents are solely the responsibility of the authors and do not necessarily represent the official views or policies of the FDA, NCRR, or NIH.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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