I.c.v. administration of the nonsteroidal glucocorticoid receptor antagonist, CP-472555, prevents exacerbated hypoglycemia during repeated insulin administration

Kale, Ajay; Paranjape, Sachin A.; Briski, Karen P.

doi:10.1016/j.neuroscience.2006.02.041

Cited by 52 publications

(32 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5), and thus we were unable to fully assess the role of portal vein hypoglycemia per se. That peak norepinephrine was not impacted by antecedent hypoglycemia is consistent with other reports for both rats and humans (11,28,36,43). However, there was a significant delay in the onset of the norepinephrine response, similar to that observed for epinephrine.…”

Section: Discussionsupporting

confidence: 90%

“…This has ranged from as few as two episodes the day before (41,43) to as much as 3-4 wk of daily insulin-induced hypoglycemia (20,38). The duration of antecedent hypoglycemic exposure in these previous reports appears to have been at least 2 h/episode (18,20,25,28,38,41,43,48). Thus the single 30-min antecedent hypoglycemic episode (45 min if one includes the time between the hypoglycemic threshold and nadir) employed in the current study appears to be the shortest antecedent exposure to date in a study involving rodents.…”

Section: Discussionmentioning

confidence: 98%

“…With one exception (36), all groups studying antecedent hypoglycemia in the rat have employed protocols involving multiple hypoglycemic insults before testing (18,20,25,28,38,41,43,48). This has ranged from as few as two episodes the day before (41,43) to as much as 3-4 wk of daily insulin-induced hypoglycemia (20,38).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Matveyenko

Bohland

Saberi

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Matveyenko AV, Bohland MA, Saberi M, Donovan CM. Portal vein hypoglycemia is essential for full induction of hypoglycemiaassociated autonomic failure with slow-onset hypoglycemia. Am J Physiol Endocrinol Metab 293: E857-E864, 2007. First published July 17, 2007; doi:10.1152/ajpendo.00283.2007.-Antecedent hypoglycemia leads to impaired counterregulation and hypoglycemic unawareness. To ascertain whether antecedent portal vein hypoglycemia impairs portal vein glucose sensing, thereby inducing counterregulatory failure, we compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the counterregulatory response to subsequent hypoglycemia. Male Wistar rats were chronically cannulated in the carotid artery (sampling), jugular vein (glucose and insulin infusion), and mesenteric vein (glucose infusion). On day 1, the following three distinct antecedent protocols were employed: 1) HYPO-HYPO: systemic hypoglycemia (2.52 Ϯ 0.11 mM); 2) HYPO-EUG: systemic hypoglycemia (2.70 Ϯ 0.03 mM) with normalization of portal vein glycemia (portal vein glucose ϭ 5.86 Ϯ 0.10 mM); and 3) EUG-EUG: systemic euglycemia (6.33 Ϯ 0.31 mM). On day 2, all groups underwent a hyperinsulinemic-hypoglycemic clamp in which the fall in glycemia was controlled so as to reach the nadir (2.34 Ϯ 0.04 mM) by minute 75. Counterregulatory hormone responses were measured at basal (Ϫ30 and 0) and during hypoglycemia (60 -105 min). Compared with EUG-EUG, antecedent hypoglycemia (HYPO-HYPO) significantly blunted the peak epinephrine (10.44 Ϯ 1.35 vs. 15.75 Ϯ 1.33 nM: P ϭ 0.01) and glucagon (341 Ϯ 16 vs. 597 Ϯ 82 pg/ml: P ϭ 0.03) responses to next-day hypoglycemia. Normalization of portal glycemia during systemic hypoglycemia on day 1 (HYPO-EUG) prevented blunting of the peak epinephrine (15.59 Ϯ 1.43 vs. 15.75 Ϯ 1.33 nM: P ϭ 0.94) and glucagon (523 Ϯ 169 vs. 597 Ϯ 82 pg/ml: P ϭ 0.66) responses to day 2 hypoglycemia. Consistent with hormonal responses, the glucose infusion rate during day 2 hypoglycemia was substantially elevated in HYPO-HYPO (74 Ϯ 12 vs. 49 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ; P ϭ 0.03) but not HYPO-EUG (39 Ϯ 7 vs. 49 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 : P ϭ 0.36). Antecedent hypoglycemia local to the portal vein is required for the full induction of hypoglycemiaassociated counterregulatory failure with slow-onset hypoglycemia. glucose sensor; sympathoadrenal; counterregulation INTENSIVE INSULIN REPLACEMENT therapy has proven to be an effective tool in the reduction of mean plasma glycemia and subsequent prevention of microvascular and macrovascular complications in patients with type 1 diabetes (T1DM) and late-stage type 2 diabetes (14, 34). However, intensive glucose management is associated with increased frequency of iatrogenic hypoglycemia (14), which results in increased morbidity and has been described as the major obstacle in the management of the disease (6). In diabetes, hypoglycemia results from imperfect insulin replacement combined with an impaired sympathoadrenal response, absent glucagon secretion, a...

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Matveyenko

Bohland

Saberi

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…Blood glucose levels were measured using an AccuCheck Advantage glucometer (Roche Diagnostics, Indianapolis, IN), as described [Kale et al, 2006]. Dissected brains were snap-frozen in liquid nitrogen-cooled isopentane.…”

Section: Methodsmentioning

confidence: 99%

Role of dorsal vagal complex A2 noradrenergic neurons in hindbrain glucoprivic inhibition of the luteinizing hormone surge in the steroid-primed ovariectomized female rat: Effects of 5-thioglucose on A2 functional biomarker and AMPK activity

Ibrahim

Briski

2014

Neuroscience

Self Cite

View full text Add to dashboard Cite

Neuro-glucostasis is required for normal expression of the steroid positive-feedback - induced preovulatory pituitary luteinizing hormone (LH) surge, a critical element of female reproduction. Glucoprivic signals from the caudal hindbrain restrain this surge, but the cellular source of this stimulus is unclear. Norepinephrine (NE) exerts well-defined stimulatory effects on the reproductive neuroendocrine axis. Our studies show that medullary A2 noradrenergic neurons are both estrogen- and glucoprivic-sensitive. Here, we investigated the premise that the LH surge is inhibited by A2 cell reactivity to hindbrain glucopenia and diminished preoptic NE neurotransmission. Estradiol- and progesterone-primed ovariectomized (OVX) female rats were injected into the caudal fourth ventricle (CV4) with the glucose anti-metabolite, 5-thioglucose (5TG) or saline (SAL) prior to onset of the LH surge. Pretreatment by intra-CV4 delivery of the selective catecholamine neurotoxin, 6-OHDA, attenuated LH output, but prevented inhibition by 5TG. 5TG modified patterns of steroid feedback-associated Fos staining of A2, but not other medullary catecholamine cell groups. Intra-preoptic administration of the alpha1-adrenergic receptor agonist, methoxamine, elicited site-specific reversal of hindbrain glucoprivic suppression of gonadotropin-releasing hormone (GnRH) neuron Fos labeling and LH release. Western blotting of laser-microdissected A2 neurons revealed glucoprivic stimulation of Fos, but inhibition of the catecholamine synthetic enzyme, dopamine-β-hydroxylase; 5TG also diminished A2 estrogen receptor (ER)-α and progesterone receptor profiles, but augmented ER-β protein. Intriguingly, A2 AMPK activity was decreased in 5TG-treated rats, despite down-regulation of GLUT3 and no change in MCT2 protein expression. Rostral preoptic GnRH neurons also exhibited decreased AMPK activation simultaneous with apparent reduction of neuropeptide signaling to the pituitary. The present studies demonstrate that hindbrain glucoprivation inhibits the LH surge, in part, by reducing preoptic noradrenergic input, and furthermore implicate A2 neurons as a source of this altered signal. Results also suggest that AMPK sensor deactivation does not supersede the impact of pharmacological inhibition of glucose catabolism on A2 cell function nor afferent signaling of hindbrain glucopenia on GnRH neurons. Further studies are needed to determine if decreased AMPK activation in these cell populations reflect compensatory gain in positive energy balance and/or direct effects of estrogen on AMPK.

show abstract

“…Blood glucose levels were measured using an AccuCheck Advantage glucometer (Roche Diagnostics, Indianapolis, IN) as previously described (26). Plasma glucagon and corticosterone concentrations were determined by radioimmunoassay, as previously reported (7,44).…”

Section: Blood Analyte Measurementsmentioning

confidence: 99%

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

Gujar

Ibrahim

Tamrakar

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.

show abstract

I.c.v. administration of the nonsteroidal glucocorticoid receptor antagonist, CP-472555, prevents exacerbated hypoglycemia during repeated insulin administration

Cited by 52 publications

References 18 publications

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Role of dorsal vagal complex A2 noradrenergic neurons in hindbrain glucoprivic inhibition of the luteinizing hormone surge in the steroid-primed ovariectomized female rat: Effects of 5-thioglucose on A2 functional biomarker and AMPK activity

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

Contact Info

Product

Resources

About