The effects of recurrent hypoglycaemia and opioid antagonists on the adrenal catecholamine synthetic capacity in a rat model of HAAF

Senthilkumaran, Manjula; Bobrovskaya, Larisa

doi:10.1016/j.autneu.2017.12.004

Cited by 9 publications

(20 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notwithstanding clinical studies demonstrating the potential of naloxone in improving the sympathoadrenal and symptomatic response to hypoglycemia, the exact mechanisms mediating this effect remain unknown. Conflicting findings in rodent models of HAAF indicate that intraperitoneal injection of 5 mg/kg naloxone 15 min before 10 U/kg insulin injections did not restore plasma epinephrine levels after subsequent hypoglycemia (48). Our measurements of plasma epinephrine are comparable to those of Senthilkumaran and Bobrovskaya (48) despite the fact that we lowered the dose of naloxone to 1 mg/kg to prevent any potential nonspecific effects (13).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we used a rodent model of HAAF (adapted from Ref. 48) to determine whether repeated insulin-induced hypoglycemia reduced the activation of C1 and C3 medullary neurons. Our specific aims were to determine whether 1 ) a 3-day repeated hypoglycemia protocol reduces C1 and C3 neuronal activation and 2 ) a hypoglycemia prevention protocol or 3 ) injection of naloxone during antecedent hypoglycemia in HAAF rats can restore C1 and C3 neuronal activation and epinephrine release after subsequent hypoglycemia.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Kakall

Kavurma

Cohen

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed “hypoglycemia-associated autonomic failure” (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250–300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia ( n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia ( n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 ( n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 ( n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 ( n = 4; 12 ± 3%, P < 0.05) and C3 ( n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Kakall

Kavurma

Cohen

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…) and insulin‐induced hypoglycaemia (Senthilkumaran et al . ; Senthilkumaran & Bobrovskaya ). Overall the results from these studies suggest that physiological changes in TH phosphorylation in vivo are substantially delayed when compared to the in situ studies.…”

Section: Acute and Prolonged Th Phosphorylation Changes In Specific Cmentioning

confidence: 99%

“…In vivo studies on rat adrenals included the use of the psychological stressors social defeat (Ong et al 2011a) and immobilisation (Ong et al 2011b), the physical stressor electrical footshock (Ong et al 2014), or the metabolic stressors 2DG ) and insulin-induced hypoglycaemia (Senthilkumaran et al 2016;Senthilkumaran & Bobrovskaya 2017). Overall the results from these studies suggest that physiological changes in TH phosphorylation in vivo are substantially delayed when compared to the in situ studies.…”

Section: Adrenal Medullamentioning

confidence: 99%

Tyrosine hydroxylase phosphorylation in vivo

Dunkley

Dickson

2019

Journal of Neurochemistry

View full text Add to dashboard Cite

Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in the synthesis of the catecholamines dopamine, noradrenaline and adrenaline. One of the major mechanisms for controlling the activity of TH is protein phosphorylation. TH is phosphorylated at serine residues 8, 19, 31 and 40. There have been a number of previous reviews focused on TH phosphorylation in vitro and in situ. This review on TH phosphorylation in vivo has three main sections focusing on: (1) the methods used to investigate TH phosphorylation in vivo, including the animals used, the sacrifice procedures, the tissue preparation, the measurement of TH protein levels and TH phosphorylation and the measurement of TH activation. (2) The regulation of TH phosphorylation and its consequences in vivo, including the kinases and phosphatases acting on TH, the stoichiometry of TH phosphorylation, the proteins that bind TH and TH subcellular location. (3) The acute and prolonged TH phosphorylation changes in specific catecholaminergic tissues, including the adrenal medulla, the nigrostriatal pathway and the mesolimbic pathway.

show abstract

“…Before additional translational work is done in this area, it will be important for these results to be confirmed by others, particularly since work by Senthilkumaran and Bobrovskaya (15) recently reported that recurrent hypoglycemia actually increased tyrosine hydroxylase protein while reducing the epinephrine response in a rat model, a response that is opposite to that seen by Ma et al In humans, recurrent hypoglycemia not only reduces the amount of epinephrine released from the adrenal medulla in response to hypoglycemia, but also reduces the glucose threshold that elicits that response (4). Presumably, that change in threshold is based on alterations present in the glucose-sensing neurons, but future work should determine whether changes in adrenal SNA occurs in a glucose concentration-dependent fashion and whether the glucose concentration required to elicit chromaffin cell catecholamine release is higher in animals exposed to a single episode of hypoglycemia as opposed to recurrent episodes prior to sacrifice.…”

Section: Consequences Of Recurrent Hypoglycemia Versus a Single Hypogmentioning

confidence: 90%

Beyond the brain: do peripheral mechanisms develop impaired awareness of hypoglycemia?

Seaquist¹

2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

The mechanisms responsible for the development of the impaired awareness of hypoglycemia often seen in insulin-treated patients with diabetes remain uncertain, but cerebral adaptations to recurrent hypoglycemia are frequently hypothesized. In this issue of the JCI, Ma et al. demonstrate that neuropeptide Y (NPY) secretion from adrenal chromaffin cells persists during exposure to recurrent hypoglycemia and activation of the sympathetic nerves at the same time that epinephrine secretion is reduced. This results in the inhibition of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. These observations suggest that a peripheral mechanism downstream from the brain contributes to the development of impaired awareness of hypoglycemia.

show abstract

The effects of recurrent hypoglycaemia and opioid antagonists on the adrenal catecholamine synthetic capacity in a rat model of HAAF

Cited by 9 publications

References 38 publications

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Tyrosine hydroxylase phosphorylation in vivo

Beyond the brain: do peripheral mechanisms develop impaired awareness of hypoglycemia?

Contact Info

Product

Resources

About