Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

Cryer, Philip E.

doi:10.1056/nejmra1215228

Cited by 371 publications

(312 citation statements)

References 78 publications

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“…hypoglycemia | autonomic nervous system | synaptic plasticity | adrenal | chromaffin cells F ailure to avoid hypoglycemia can lead to dysphoria, ventricular arrhythmia, and even sudden death (1). That these effects are rare and observed only in response to prolonged fasting or severe insulin-induced hypoglycemia is because of the remarkable effectiveness of the counter-regulatory response (CRR).…”

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Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

Wang

Whim

2016

Proc. Natl. Acad. Sci. U.S.A.

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During fasting, activation of the counter-regulatory response (CRR) prevents hypoglycemia. A major effector arm is the autonomic nervous system that controls epinephrine release from adrenal chromaffin cells and, consequently, hepatic glucose production. However, whether modulation of autonomic function determines the relative strength of the CRR, and thus the ability to withstand food deprivation and maintain euglycemia, is not known. Here we show that fasting leads to altered transmission at the preganglionic → chromaffin cell synapse. The dominant effect is a presynaptic, long-lasting increase in synaptic strength. Using genetic and pharmacological approaches we show this plasticity requires neuropeptide Y, an adrenal cotransmitter and the activation of adrenal Y5 receptors. Loss of neuropeptide Y prevents a fasting-induced increase in epinephrine release and results in hypoglycemia in vivo. These findings connect plasticity within the sympathetic nervous system to a physiological output and indicate the strength of the final synapse in this descending pathway plays a decisive role in maintaining euglycemia.hypoglycemia | autonomic nervous system | synaptic plasticity | adrenal | chromaffin cells F ailure to avoid hypoglycemia can lead to dysphoria, ventricular arrhythmia, and even sudden death (1). That these effects are rare and observed only in response to prolonged fasting or severe insulin-induced hypoglycemia is because of the remarkable effectiveness of the counter-regulatory response (CRR). This sensory-motor homeostatic feedback loop detects a fall in blood glucose through central and peripheral receptors and initiates a neuronal, endocrine, and behavioral response that restores euglycemia (2). One of the principal effector arms of the CRR is the sympatho-adrenal branch of the autonomic nervous system. Hypoglycemia elevates sympathetic activity, increasing hepatic glucose production and the release of gluconeogenic substrates while suppressing insulin and potentiating glucagon secretion (3, 4).During fasting, these autonomic actions are mediated by epinephrine, which enters the systemic circulation after release from adrenal neuroendocrine chromaffin cells and by norepinephrine, secreted directly onto target tissues from postganglionic sympathetic neurons. The importance of sympathetic activity, and in particular circulating epinephrine in the CRR, is illustrated by the poor recovery from insulin-induced hypoglycemia when the release of this hormone is suppressed during hypoglycemia-associated autonomic failure (5, 6), and by recent work showing that deletion of melanocortin 4 receptors from preganglionic sympathetic neurons leads to elevated levels of blood glucose (7).Given the involvement of the sympathetic nervous system in the CRR, modulation of autonomic activity is thus likely to alter the ability to respond to a hypoglycemic challenge. However, unlike in the CNS, where long-lasting changes in synaptic strength are known to be associated with functional consequences (8-10), whether the output ...

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confidence: 99%

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

Wang

Whim

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Approximately 25% of patients with type 1 diabetes have lost the capacity to timely detect hypoglycemia, a condition referred to as impaired awareness of hypoglycemia (IAH) (1). IAH increases the risk for severe, potentially hazardous hypoglycemia up to sixfold (2) and is usually the end result of a process of habituation to recurrent hypoglycemia (1).…”

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“…IAH increases the risk for severe, potentially hazardous hypoglycemia up to sixfold (2) and is usually the end result of a process of habituation to recurrent hypoglycemia (1).…”

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Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

et al. 2016

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Brain lactate may be involved in the development of impaired awareness of hypoglycemia (IAH), a condition that affects approximately 25% of patients with type 1 diabetes and increases the risk of severe hypoglycemia. The aim of this study was to investigate the effect of acute hypoglycemia on brain lactate concentration in patients with IAH as compared with those with normal awareness of hypoglycemia (NAH) and healthy control subjects (n = 7 per group). After an overnight fast, all subjects underwent a two-step hyperinsulinemic euglycemic (5.0 mmol/L)-hypoglycemic (2.8 mmol/L) glucose clamp. Brain lactate concentrations were measured continuously with 1 H-MRS using a specific lactate detection method. Hypoglycemia generated symptoms in patients with NAH and healthy control subjects but not in patients with IAH. Brain lactate fell significantly by ∼20% in response to hypoglycemia in patients with type 1 diabetes with IAH but remained stable in both healthy control subjects and in patients with NAH. The fall in brain lactate is compatible with increased brain lactate oxidation providing an alternative fuel source during hypoglycemia, which may contribute to the impaired detection of hypoglycemia.

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“…23 Another factor favoring a dysregulation of the counter is the [page 12] [Italian Journal of Medicine 2015; 9:549] presence of autonomic neuropathy. 24 Although there are no studies in hospitalized patients, it is very likely that the diabetic autonomic neuropathy may be a significant risk factor for hypoglycemia in diabetic inpatients. Insulin therapy is elective in the hospital for blood glucose control.…”

Section: Risk Factors Of Hypoglycemiamentioning

confidence: 99%

The clinical impact of hypoglycemia in hospitalized patients

Borzı̀

Fontanella

2015

Ital J Med

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Hypoglycemia is a very common problem, mostly in frail, severely ill, older hospitalized patients. Hypoglycemia has been implicated in the development of adverse clinical outcomes, including an increased mortality. Fear of iatrogenic hypoglycemia remains an obstacle to adequate inpatient glycemic control. It may be considered as a marker of disease, rather than cause in itself of undesirable events. Several factors, such as treatment with exogenous insulin, mismatch between insulin administration and meal intake with the loss of normal counter regulatory responses, place patients with diabetes at higher risk for hypoglycemia than the ones without diabetes. In this review we discuss the causes and predictors of hypoglycemia in non-critically ill hospitalized patients and how to prevent them. Subcutaneous insulin with basal-bolus regimen rather than sliding scale and the use of analogues may minimize hypoglycemic events. In-patient glycemic management should be patient-centered, following the current guidelines, and aimed to prevent hypoglycemic events.Correspondence: Andrea Fontanella, Dipartimento di Medicina, Ospedale del Buon Consiglio Fatebenefratelli, via Manzoni 220, 80123 Napoli, Italy. E-mail: andreafontanella52@gmail.com Key words: hypoglycemia, diabetes, non-critical illness, inpatients.Received for publication: 6 October 2014. Accepted for publication: 3 December 2014.This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0).

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Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

Cited by 371 publications

References 78 publications

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

The clinical impact of hypoglycemia in hospitalized patients

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