Hypoglycemia unawareness

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Abstract

Iatrogenic hypoglycemia is the limiting factor in the glycemic control of diabetes. It causes recurrent symptomatic and sometimes, at least temporally, disabling episodes in most people with type 1 diabetes, as well as in many with advanced type 2 diabetes. Furthermore, iatrogenic hypoglycemia precludes maintenance of euglycemia during the lifetime of a person with diabetes and thus full realization of the well established benefits of glycemic control. In this article I discuss the clinical problem of hypoglycemia in diabetes from the perspective of pathophysiology. First, the syndromes of defective glucose counterregulation and hypoglycemia without warning symptoms (known as hypoglycemia unawareness) are described, followed by the unifying concept of Hypoglycemia-Associated Autonomie Failure (HAAF). The concept of hypoglycemia-associated autonomie failure in diabetes posits that recurrent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness and thus leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. The clinical relevance of this phenomenon is now well established, but the mechanisms and mediators remain largely unknown. The short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The ultimate goal of lifelong maintenance of euglycemia in patients with diabetes remains elusive because of the pharmacokinetic imperfections of all current glucose-lowering therapies and the resulting barrier of hypoglycemia. Nonetheless, it is now possible both to improve the control of glycemia and to reduce the frequency of hypoglycemia in many people with diabetes. These results can be accomplished by recognizing the problem of hypoglycemia applying the principles of aggressive glycemic therapy and reducing the risk factors of hypoglycemia in people with diabetes.

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      Anderbro et al., highlighted a complex relationship between hypoglycaemic episodes and fear and anxiety, showing that patients adopt strategies to avoid hypoglycaemic episodes (2010). Much of the research already available has a strong medical focus and explores the clinical interventions healthcare professionals could implement (Martin-Timon et al., 2015; Bakatselos, 2011). This literature is important for the treatment and management of the clinical condition, however Elliot and Rankin (2014) express concerns regarding the requirement to consider the psychological needs of both the patient and SO.

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      The responses ‘always’ and ‘usually’ indicate a normal awareness; i.e., knowing that hypoglycemia symptoms are associated with low blood sugar levels. The response ‘occasionally’ denotes impaired awareness, and ‘never’ denotes severely impaired awareness, whereby participants had impaired or complete loss of the ability to recognize or sense typical symptoms of hypoglycemia, which results from an impaired counter-regulatory mechanism and has been shown to increase the risk of future episodes of hypoglycemia [18,19]. Categories of hypoglycemia recorded in the questionnaire and patient diary included: non-severe hypoglycemia (defined as an event managed by the patient alone); severe hypoglycemia (defined, based on the American Diabetes Association definition, as any hypoglycemic event requiring assistance of another person to administer carbohydrate, glucagon or other resuscitative actions) [20]; and nocturnal hypoglycemia (any event occurring between midnight and 6:00 AM).

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      A deteriorated adrenalin response in type 1 diabetes is associated with an unawareness of hypoglycemia, and the hypoglycemic nadir is significantly lower in patients who are unaware than in patients who are aware [30]. Furthermore, hypoglycemia causes hypoglycemia-associated autonomic failure and a further defect of counterregulatory hormone secretion, leading to a vicious cycle of recurrent hypoglycemia [31–34]. In fact, CVR-R tended to be lower in patients with gastrointestinal dysmotility than in patients without it (2.44 ± 1.39 vs. 3.76 ± 1.88%, p = 0.062).

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      Those with recent antecedent hypoglycemia are predisposed.27,28 Affected individuals have loss of forewarning symptoms of hypoglycemia and decreased response to those symptoms, and thus are at increased risk of hypoglycemia.27,28 In one study, adults with type 1 diabetes and impaired awareness of hypoglycemia exhibited twice the frequency of all episodes of hypoglycemia over a 4-week monitoring period, compared with those with normal awareness (mean ± standard deviation, 7.9 ± 5.4 episodes vs 3.7 ± 3.6 episodes, P = .003).29

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