Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure

Paranjape, Sachin A.; Vavaiya, Kamlesh K.; Kale, Ajay; Briski, Karen P.

doi:10.1016/j.regpep.2006.02.002

Cited by 25 publications

(17 citation statements)

References 20 publications

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“…As identified by other investigators and confirmed here, OX cells in the lateral hypothalamus/ perifornical region have significantly increased Fos-immunoreactivity after insulin injection [17][18][19]. OX neuron activation is to be expected in this model due to at least two mechanisms.…”

Section: Discussionsupporting

confidence: 88%

“…The functional neuroanatomy of arousal has been extensively studied in this species [35], and there have been several Fos-mapping studies related to sleep and arousal states [32,36,37,43]. Our data as well as previous studies demonstrating that insulin-induced hypoglycemia strongly stimulates Fos production in OX neurons [17][18][19] predict that hypoglycemia should increase wake time in rats. In this study, we indeed found a significant increase in waking during insulin-induced hypoglycemia.…”

Section: Discussionsupporting

confidence: 72%

“…Hypoglycemia in rats strongly activates neurons containing the wake-promoting peptide orexin (OX), also known as hypocretin [17][18][19] however, there have been no reports to date of the effects of hypoglycemia on sleep/wake measures in rats. In this study, we sought to characterize the interaction between hypoglycemia and sleep in rats studied in the afternoon, a diurnal time associated with increased time spent in sleep in rats.…”

Section: Introductionmentioning

confidence: 99%

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Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Tkacs

Pan

Sawhney

et al. 2007

Physiology & Behavior

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Hypoglycemia resulting from excess of exogenous or endogenous insulin elicits central nervous system activation that contributes to counterregulatory hormone secretion. In adult humans without diabetes, hypoglycemia occurring during sleep usually produces cortical activation with awakening. However, in adult humans with type 1 diabetes, hypoglycemic arousal appears blunted or absent. We hypothesized that insulin injection sufficient to produce hypoglycemia would induce awakening in adult male rats. Polysomnographic studies were carried out to characterize the effect of insulin injection on measures of sleep and waking during a circadian time of increased sleep. Compared to a baseline day, insulin treatment more than doubled the time spent awake, from 18.4 ± 2.6% after saline injection to 48.0 ± 5.5% after insulin. Insulin injection also reduced rapid eye movement sleep (REMS) from 27.3 ± 1.8% to 5.6 ± 1.3%. The percent of time in non-REM sleep (NREMS) sleep was not different between saline and insulin days, however, NREMS after insulin was fragmented, with increased number and decreased duration of episodes. These electrophysiological data indicate that insulin-induced hypoglycemia is an arousing stimulus in rats, as in nondiabetic adult humans. We also studied the effect of insulin on activation of selected arousal-related neurons using immunohistochemical detection of Fos. Fos-immunoreactivity increased in orexin (OX) neurons after insulin, from 8.7 ± 4.9% after saline injection to 37 ± 9% after insulin. Basal forebrain cholinergic nuclei also showed increased Fos-immunoreactivity after insulin. These correlated behavioral and histological data provide targets for future studies of the neural pathways underlying hypoglycemic arousal.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Tkacs

Pan

Sawhney

et al. 2007

Physiology & Behavior

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“…Swanson, Elsevier 1999) served as dissections guides. Quantitative PCR (qPCR) was performed as previously described in our laboratory (Paranjape et al 2006). Total RNA was isolated from micropunched tissue with MELT Total RNA isolation kit reagents (cat.…”

Section: Methodsmentioning

confidence: 99%

Effects of Caudal Fourth Ventricular Lactate Infusion on Hypoglycemia-Associated MCT2, GLUT3, GLUT4, GCK, and Sulfonylurea Receptor-1 Gene Expression in the Ovariectomized Female Rat LHA and VMH: Impact of Estradiol

Vavaiya

Briski

2007

J Mol Neurosci

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Cellular metabolic stasis is monitored in the lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH), the classically defined hypothalamic "anoretic" and "satiety" centers, respectively. Neuronal glucose (GLUT3, GLUT4) and monocarboxylate (MCT2) transporter genes are expressed in both sites, suggesting that glucose and lactate, a product of astrocytic glycolysis, may fuel aerobic respiration in local neurons. Evidence that glucose utilization in the hypothalamus, but not other brain regions, is reported to vary according to cyclic estradiol secretion suggests that this hormone may regulate uptake and/or catabolism of this fuel. We investigated the hypothesis that estradiol exerts site-specific regulatory effects on basal and insulin-induced hypoglycemia (IIH)-associated MCT2 and neuronal glucose transporter mRNA profiles, and expression of genes that encode the substrate sensor, glucokinase (GCK), and the sulfonylurea receptor-1 (SUR) subunit of the energy-dependent potassium channel, K(ATP), in the female rat LHA and VMH. As caudal fourth ventricular (CV4) lactate infusion intensifies hypoglycemia in this gender, we also examined whether demonstrable LHA and VMH gene responses to IIH are correspondingly amplified. MCT2, GLUT3, GLUT4, GCK, and SUR1 mRNA levels in the LHA and VMH did not differ between saline-injected ovariectomized (OVX) rats implanted with estradiol benzoate (EB) or oil (O). LHA: IIH had no impact on gene profiles, excluding SUR1, in EB-treated animals, but decreased these transcripts, with the exception of GCK, in OVX + O rats. CV4 lactate infusion in hypoglycemic OVX + EB animals suppressed each mRNA profile, but reversed IIH-associated reductions in MCT2, GLUT3, and GLUT4 gene expression in OVX + O. VMH: IIH increased MCT2 and GLUT4 transcripts in OVX + EB, but not OVX + O rats and decreased GCK mRNA in both groups. Lactate plus insulin treatment elevated VMH MCT2, GLUT3, SUR1, and GCK gene expression in EB- and O-implanted OVX rats, but augmentation of the former three profiles was greater in the presence of EB. The data show that LHA and VMH neurons exhibited dissimilar, estradiol-dependent adjustments in neuronal lactate and glucose transporter, GCK, and SUR1 gene expression during IIH, and that in the presence of estradiol, caudal hindbrain lactate infusion during IIH elicited divergent changes in MCT2, GLUT3, GCK, and SUR1 gene expression in the LHA and VMH, where these transcripts were, respectively, diminished or augmented. These results support the need to investigate the potential impact of site-specific adjustments in fuel uptake and KATP regulation of membrane voltage on general and specialized, e.g., chemosensory, neuronal functions.

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“…GAPDH gene expression was measured as a housekeeping gene control [Forward: 5′-ACAGCCGCATCTTCTTGTGC-3′; Reverse: 5′-GCC TCACCCCATTTGATGTT-3′]. Cycling parameters for quantitative real-time RT-PCR were as follows: initial denaturation at 95°C for 3 min, followed by 40 cycles of 1 min each (30 s at 95°C, followed by 30 s at 59°C for GCK and at 65°C for GAPDH), using described methods (Paranjape et al 2006;Vavaiya et al 2007). For each animal, measurements of individual gene transcript levels in each evaluated structure were analyzed by the 2 ΔΔC T method, and group means were evaluated by two-way ANOVA and Tukey's HSD test.…”

Section: Methodsmentioning

confidence: 99%

Adaptation of Glucokinase Gene Expression in the Rat Dorsal Vagal Complex in a Model for Recurrent Intermediate Insulin-Induced Hypoglycemia: Impact of Gender

2008

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Standard therapeutic management of insulin-dependent diabetes mellitus with intermediate-acting insulin poses a significant risk for iatrogenic hypoglycemia and associated hypoglycemia-associated autonomic failure. Gender differences in preservation of counterregulatory function during recurring hypoglycemia have been documented in the clinical setting. In rats, repeated induction of prolonged hypoglycemia by neutral protamine Hagadorn insulin (NPH) results in diminished neuronal transcriptional activation in several key metabolic loci in male, but not female rat brain, including the hindbrain dorsal vagal complex (DVC). Glucose is committed to glycolytic catabolism by hexokinase-mediated phosphorylation. The low-affinity, high K (m) hexokinase, glucokinase (GCK), monitors intracellular glucose levels in pancreatic beta cells, and is purported to fulfill a similar function in the CNS. GCK is expressed in the rat DVC, where mRNA is localized to neurons that exhibit electrophysiological sensitivity to glucose imbalance. The current study investigated the hypothesis that DVC GCK gene expression acclimates to RIIH in a gender-dependent manner. Quantitative real-time RT-PCR was used to evaluate GCK mRNA levels in microdissected DVC tissue obtained from male and female rats before or after one or serial doses of NPH. Basal DVC GCK transcripts were equal between ovariectomized (OVX) female rats implanted with estradiol benzoate (EB) or oil (O). Tissue mRNA levels were increased following a single NPH injection in both groups, but this response was greater in the presence of estrogen. Basal GCK gene expression was elevated by precedent insulin dosing in both O- and EB-implanted rats; however, transcripts were not modified relative to this adjusted baseline during subsequent NPH treatment in either group of females. While acute NPH treatment did not modify tissue transcript levels in orchidectomized (ORDX) or sham-ORDX rats, precedent NPH dosing increased basal GCK mRNA levels and further enhanced gene expression during ensuring hypoglycemia in sham males. These studies provide novel evidence for gender-dimorphic DVC GCK gene responses to single and serial intermediate-acting insulin administration. Further research is required to determine if and how stimulatory versus inhibitory transcriptional adaptation of this gene profile in male and female rats, respectively, impacts glucose-sensing functions in the DVC, and whether such adjustments may contribute to gender differences in magnitude of precedent hypoglycemic impairment of counterregulation.

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Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure

Cited by 25 publications

References 20 publications

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Effects of Caudal Fourth Ventricular Lactate Infusion on Hypoglycemia-Associated MCT2, GLUT3, GLUT4, GCK, and Sulfonylurea Receptor-1 Gene Expression in the Ovariectomized Female Rat LHA and VMH: Impact of Estradiol

Adaptation of Glucokinase Gene Expression in the Rat Dorsal Vagal Complex in a Model for Recurrent Intermediate Insulin-Induced Hypoglycemia: Impact of Gender

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