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World J Diabetes. Jul 10, 2015; 6(7): 912-926
Published online Jul 10, 2015. doi: 10.4239/wjd.v6.i7.912
Mechanisms of hypoglycemia unawareness and implications in diabetic patients
Iciar Martín-Timón, Francisco Javier del Cañizo-Gómez
Iciar Martín-Timón, Francisco Javier del Cañizo-Gómez, Section of Endocrinology, Hospital Universitario Infanta Leonor, Facultad de Medicina, Universidad Complutense, 28031 Madrid, Spain
Author contributions: Martín-Timón I and del Cañizo-Gómez FJ contributed equally to this work.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Francisco Javier del Cañizo-Gómez, Professor, Chief, Section of Endocrinology, Hospital Universitario Infanta Leonor, Facultad de Medicina, Universidad Complutense, Avda Gran Vía del Este 80, 28031 Madrid, Spain. fjcanizog@salud.madrid.org
Telephone: +34-91-1918000 Fax: +34-91-1918878
Received: August 1, 2014
Peer-review started: August 2, 2014
First decision: December 17, 2014
Revised: December 30, 2014
Accepted: March 30, 2015
Article in press: April 2, 2015
Published online: July 10, 2015
Processing time: 343 Days and 2.2 Hours
Abstract

Hypoglycemia unawareness (HU) is defined at the onset of neuroglycopenia before the appearance of autonomic warning symptoms. It is a major limitation to achieving tight diabetes and reduced quality of life. HU occurs in approximately 40% of people with type 1 diabetes mellitus (T1DM) and with less frequency in T2DM. Though the aetiology of HU is multifactorial, possible mechanisms include chronic exposure to low blood glucose, antecedent hypoglycaemia, recurrent severe hypoglycaemia and the failure of counter-regulatory hormones. Clinically it manifests as the inability to recognise impeding hypoglycaemia by symptoms, but the mechanisms and mediators remain largely unknown. Prevention and management of HU is complex, and can only be achieved by a multifactorial intervention of clinical care and structured patient education by the diabetes team. Less know regarding the impact of medications on the development or recognition of this condition in patients with diabetes. Several medications are thought to worsen or promote HU, whereas others may have an attenuating effect on the problem. This article reviews recent advances in how the brain senses and responds to hypoglycaemia, novel mechanisms by which people with insulin-treated diabetes develop HU and impaired counter-regulatory responses. The consequences that HU has on the person with diabetes and their family are also described. Finally, it examines the evidence for prevention and treatment of HU, and summarizes the effects of medications that may influence it.

Keywords: Hypoglycemia unawareness; Impaired awareness of hypoglycemia; Hypoglycemia associated autonomic failure; Diabetes mellitus; Counter-regulation

Core tip: This review describes novel mechanisms by which people with insulin-treated diabetes develop hypoglycemia unawareness (HU), the consequences that HU has on the person with diabetes and their family, the evidence for prevention and treatment of HU, and the effects of medications that may influence it.