Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus

2006 ◽  
Vol 291 (5) ◽  
pp. R1283-R1287 ◽  
Author(s):  
Zhentao Song ◽  
Vanessa H. Routh
Keyword(s):  
Insulin Injection ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Saline Control ◽  
Sprague Dawley ◽  
Glucose Levels ◽  
Extracellular Glucose ◽  
Glucose Sensitivity ◽  
Sense And Respond ◽  
Recurrent Hypoglycemia

Recurrent hypoglycemia blunts the brain's ability to sense and respond to subsequent hypoglycemic episodes. Glucose-sensing neurons in the ventromedial hypothalamus nucleus (VMN) are well situated to play a role in hypoglycemia detection. VMN glucose-inhibited (GI) neurons, which decrease their firing rate as extracellular glucose increases, are extremely sensitive to decreased extracellular glucose. We hypothesize that recurrent hypoglycemia decreases the glucose sensitivity of VMN GI neurons. To test our hypothesis, 14- to 21-day-old Sprague-Dawley rats were subcutaneously injected with regular human insulin (4 U/kg) or saline (control) for three consecutive days. Blood glucose levels 1 h after insulin injection on day 3 were significantly lower than on day 1, reflecting an impaired ability to counteract hypoglycemia. On day 4, the glucose sensitivity of VMN GI neurons was measured using conventional whole cell current-clamp recording. After recurrent insulin-induced hypoglycemia, VMN GI neurons only responded to a glucose decrease from 2.5 to 0.1, but not 0.5, mM. Additionally, lactate supplementation also decreased glucose sensitivity of VMN GI neurons. Thus our findings suggest that decreases in glucose sensitivity of VMN GI neurons may contribute to the impairments in central glucose-sensing mechanisms after recurrent hypoglycemia.

scholarly journals Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose

2009 ◽  
Vol 296 (5) ◽  
pp. E1101-E1109 ◽  
Author(s):  
Victoria E. Cotero ◽  
Vanessa H. Routh
Keyword(s):  
Energy Homeostasis ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Hypothalamic Nucleus ◽  
Compensatory Mechanisms ◽  
Glucose Levels ◽  
Compound C ◽  
Obesity And Diabetes ◽  
Extracellular Glucose ◽  
Pi3k Signaling Pathway

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the KATP channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 μM). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.

Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus

2007 ◽  
Vol 292 (4) ◽  
pp. R1418-R1428 ◽  
Author(s):  
Debra D. Canabal ◽  
Zhentao Song ◽  
Joseph G. Potian ◽  
Annie Beuve ◽  
Joseph J. McArdle ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Action Potential ◽  
Insulin Signaling ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
No Production ◽  
Obesity And Diabetes ◽  
Action Potential Frequency ◽  
Extracellular Glucose ◽  
Potential Frequency

Glucose-sensing neurons in the ventromedial hypothalamus (VMH) are involved in the regulation of glucose homeostasis. Glucose-sensing neurons alter their action potential frequency in response to physiological changes in extracellular glucose, insulin, and leptin. Glucose-excited neurons decrease, whereas glucose-inhibited (GI) neurons increase, their action potential frequency when extracellular glucose is reduced. Central nitric oxide (NO) synthesis is regulated by changes in local fuel availability, as well as insulin and leptin. NO is involved in the regulation of food intake and is altered in obesity and diabetes. Thus this study tests the hypothesis that NO synthesis is a site of convergence for glucose, leptin, and insulin signaling in VMH glucose-sensing neurons. With the use of the NO-sensitive dye 4-amino-5-methylamino-2′,7′-difluorofluorescein in conjunction with the membrane potential-sensitive dye fluorometric imaging plate reader, we found that glucose and leptin suppress, whereas insulin stimulates neuronal nitric oxide synthase (nNOS)-dependent NO production in cultured VMH GI neurons. The effects of glucose and leptin were mediated by suppression of AMP-activated protein kinase (AMPK). The AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) increased both NO production and neuronal activity in GI neurons. In contrast, the effects of insulin on NO production were blocked by the phosphoinositide 3-kinase inhibitors wortmannin and LY-294002. Furthermore, decreased glucose, insulin, and AICAR increase the phosphorylation of VMH nNOS, whereas leptin decreases it. Finally, VMH neurons express soluble guanylyl cyclase, a downstream mediator of NO signaling. Thus NO may mediate, in part, glucose, leptin, and insulin signaling in VMH glucose-sensing neurons.

scholarly journals Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes

2009 ◽  
Vol 296 (6) ◽  
pp. R1702-R1708 ◽  
Author(s):  
X. Fan ◽  
Y. Ding ◽  
S. Brown ◽  
L. Zhou ◽  
M. Shaw ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Protein Kinase ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Rodent Model ◽  
Saline Control ◽  
Chronic Hyperglycemia ◽  
Bb Rats ◽  
Amp Activated Protein Kinase

In nondiabetic rodents, AMP-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. To address this issue, we used four groups of chronically catheterized male diabetic BB rats, a rodent model of autoimmune T1DM with established insulin—requiring diabetes (40 ± 4 pmol/l basal c-peptide). Two groups were subjected to 3 days of recurrent hypoglycemia (RH), while the other two groups were kept hyperglycemic [chronic hyperglycemia (CH)]. All groups subsequently underwent hyperinsulinemic hypoglycemic clamp studies on day 4 in conjunction with VMH microinjection with either saline (control) or AICAR (5-aminoimidazole-4-carboxamide) to activate AMPK. Compared with controls, local VMH application of AICAR during hypoglycemia amplified both glucagon [means ± SE, area under the curve over time (AUC/ t) 144 ± 43 vs. 50 ± 11 ng·l−1·min−1; P < 0.05] and epinephrine [4.27 ± 0.96 vs. 1.06 ± 0.26 nmol·l−1·min−1; P < 0.05] responses in RH-BB rats, and amplified the glucagon [151 ± 22 vs. 85 ± 22 ng·l−1·min−1; P < 0.05] response in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.

scholarly journals Extracellular Glucose in Rat Ventromedial Hypothalamus During Acute and Recurrent Hypoglycemia

Diabetes ◽  
2003 ◽  
Vol 52 (11) ◽  
pp. 2767-2773 ◽  
Author(s):  
M. G. de Vries ◽  
L. M. Arseneau ◽  
M. E. Lawson ◽  
J. L. Beverly
Keyword(s):  
Ventromedial Hypothalamus ◽  
Extracellular Glucose ◽  
Recurrent Hypoglycemia

scholarly journals Effects of Feeding-Related Peptides on Neuronal Oscillation in the Ventromedial Hypothalamus

2019 ◽  
Vol 8 (3) ◽  
pp. 292 ◽  
Author(s):  
Kamon Iigaya ◽  
Yoshino Minoura ◽  
Hiroshi Onimaru ◽  
Sayumi Kotani ◽  
Masahiko Izumizaki
Keyword(s):  
Sympathetic Nerve Activity ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Corticotropin Releasing Factor ◽  
Nerve Activity ◽  
Pituitary Adenylate Cyclase ◽  
Neuronal Oscillation ◽  
Extracellular Glucose ◽  
Frequency Changes ◽  
The Brain

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic nervous system. The VMH also expresses various receptors of the peptides related to feeding. However, it is not well-understood whether the action of feeding-related peptides mediates the activity of glucose-sensing neurons in the VMH. In the present study, we examined the effects of feeding-related peptides on the burst-generating property of the VMH. Superfusion with insulin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, and orexin increased the frequency of the VMH oscillation. In contrast, superfusion with leptin, cholecystokinin, cocaine- and amphetamine-regulated transcript, galanin, ghrelin, and neuropeptide Y decreased the frequency of the oscillation. Our findings indicated that the frequency changes of VMH oscillation in response to the application of feeding-related peptides showed a tendency similar to changes of sympathetic nerve activity in response to the application of these substances to the brain.

scholarly journals Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus

2011 ◽  
Vol 301 (6) ◽  
pp. R1815-R1820 ◽  
Author(s):  
Meredith B. Barnes ◽  
Marcus A. Lawson ◽  
J. Lee Beverly
Keyword(s):  
Blood Glucose ◽  
Plasma Glucose ◽  
Ventromedial Hypothalamus ◽  
First Episode ◽  
Initial Increase ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Interstitial Glucose ◽  
Recurrent Hypoglycemia ◽  
Glucose Threshold

Noradrenergic activity in the ventromedial hypothalamus (VMH) is increased and activates a sympathoadrenal response during hypoglycemia. How the rate at which hypoglycemia develops affects local glucose concentrations and norepinephrine (NE) release was evaluated by placing microdialysis probes into the VMH of male Sprague-Dawley rats receiving insulin (20 mU·kg−1·min−1) and variable glucose infusions. During a first episode of hypoglycemia, interstitial glucose concentrations in the VMH generally declined at the same rate as plasma glucose; however, the faster hypoglycemia developed, the greater the magnitude of the initial NE release in the VMH ( r2 = 0.72, P < 0.001). Following recurrent episodes of hypoglycemia, VMH glucose decreased at a slower rate than plasma glucose, and the initial NE release was attenuated at the same rates of blood glucose decline. The plasma glucose threshold for the initial NE release in VMH was similar for all groups (∼3.23 mM); however, the VMH glucose threshold was stimulated and was lower when blood glucose declined more slowly (0.86 ± 0.06 vs. 1.06 ± 0.04 mmol/l, P < 0.01). The timing of the initial increase in NE release in VMH corresponded with an increase in plasma epinephrine during the first episode of hypoglycemia but not following recurrent hypoglycemia. Although a decrease in VMH glucose concentration is required for noradrenergic activation in VMH, there does not appear to be a set glucose threshold within the VMH for activation of this response.

Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation

2007 ◽  
Vol 293 (3) ◽  
pp. E705-E712 ◽  
Author(s):  
Haiying Cheng ◽  
Ligang Zhou ◽  
Wanling Zhu ◽  
Ajin Wang ◽  
Chuyan Tang ◽  
...  
Keyword(s):  
Glucose Utilization ◽  
Glucose Production ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Endogenous Glucose Production ◽  
Corticotropin Releasing Factor ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Acute Hypoglycemia ◽  
Glucose Dynamics

Type 2 corticotropin-releasing factor (CRF) receptors (CRFR2) within the ventromedial hypothalamus (VMH), a key glucose-sensing region, play a major role in regulating the hormonal counterregulatory responses (CRRs) to acute hypoglycemia. The VMH expresses both subtypes of CRF receptors, CRFR1 and CRFR2. The objective of this study was to examine the role of the CRFR1 receptor in the VMH in the regulation of the CRR to acute hypoglycemia. To compare the hormonal CRR to hypoglycemia, awake and unrestrained Sprague-Dawley rats were bilaterally microinjected to the VMH with either 1) aECF, 2) CRF (1 pmol/side), 3) CRFR1 antagonist Antalarmin (500 pmol/side), or 4) CRF + Antalarmin prior to undergoing a hyperinsulinemic hypoglycemic (2.8 mM) clamp. A second series of studies also incorporated an infusion of [3H]glucose to allow the calculation of glucose dynamics. In addition the effect of CRFR1 antagonism in the paraventricular nucleus (PVN) was studied. Activation of VMH CRFR1 increased, whereas inhibition of CRFR1 suppressed hypoglycemia-induced CRRs. Inhibition of VMH CRFR1 also increased peripheral glucose utilization and reduced endogenous glucose production during hypoglycemia, whereas VMH CRF reduced peripheral glucose utilization. In contrast CRFR1 inhibition in the PVN blunted corticosterone but not epinephrine or glucagon CRR to hypoglycemia. In contrast to CRFR2 activation, CRFR1 activation within the VMH amplifies CRRs to acute hypoglycemia. The balance between these two opposing CRFRs in this key glucose-sensing region may play an important role in determining the magnitude of CRRs to acute hypoglycemia.

Dissociation of hypothalamic noradrenergic activity and sympathoadrenal responses to recurrent hypoglycemia

2004 ◽  
Vol 286 (5) ◽  
pp. R910-R915 ◽  
Author(s):  
Martin G. de Vries ◽  
Marcus A. Lawson ◽  
J. Lee Beverly
Keyword(s):  
Brain Area ◽  
Plasma Catecholamines ◽  
Ventromedial Hypothalamus ◽  
Hypothalamic Nucleus ◽  
First Episode ◽  
Sprague Dawley ◽  
Hypoglycemic Episode ◽  
Sprague Dawley Rats ◽  
Collateral Pathway ◽  
Recurrent Hypoglycemia

This study evaluated whether attenuation of sympathoadrenal responses to recurrent hypoglycemia is mediated by diminished noradrenergic activity in the hypothalamus. Male Sprague-Dawley rats received either once daily insulin (1.0 units/kg) injections or an equal administration of saline for 3 days. Both groups received an administration of insulin on the fourth day, during which blood glucose and plasma catecholamines were determined, and extracellular norepinephrine (NE) in the ventromedial hypothalamus (VMH) or paraventricular hypothalamic nucleus (PVN) was monitored with microdialysis. The peak response of plasma epinephrine to insulin-induced hypoglycemia (nadir ∼3.2 mmol/l) was significantly reduced during the fourth hypoglycemic episode (774 ± 134 pg/ml) compared with the first episode (2,561 ± 410 pg/ml, P < 0.001). Baseline levels of extracellular NE were elevated ∼25% ( P = 0.07) in the VMH and ∼46% ( P = 0.03) in the PVN after multiple hypoglycemic episodes. There was no difference in noradrenergic activity during the first or fourth hypoglycemic episode in either brain area. The reduced sympathoadrenal output after recurrent hypoglycemia is likely postsynaptic from hypothalamic NE release or is mediated via a collateral pathway.

scholarly journals Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose counterregulatory responses during hypoglycemia

2010 ◽  
Vol 298 (5) ◽  
pp. E971-E977 ◽  
Author(s):  
Wanling Zhu ◽  
Daniel Czyzyk ◽  
Sachin A. Paranjape ◽  
Ligang Zhou ◽  
Adam Horblitt ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Glucose Concentration ◽  
Gaba Release ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Gabaergic Neurons ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
The Brain ◽  
Full Activation

Local delivery of glucose into a critical glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), can suppress glucose counterregulatory responses to systemic hypoglycemia. Here, we investigated whether this suppression was accomplished through changes in GABA output in the VMH. Sprague-Dawley rats had catheters and guide cannulas implanted. Eight to ten days later, microdialysis-microinjection probes were inserted into the VMH, and they were dialyzed with varying concentrations of glucose from 0 to 100 mM. Two groups of rats were microdialyzed with 100 mM glucose and microinjected with either the KATP channel opener diazoxide or a GABAA receptor antagonist. These animals were then subjected to a hyperinsulinemic-hypoglycemic glucose clamp. As expected, perfusion of glucose into the VMH suppressed the counterregulatory responses. Extracellular VMH GABA levels positively correlated with the concentration of glucose in the perfusate. In turn, extracellular GABA concentrations in the VMH were inversely related to the degree of counterregulatory hormone release. Of note, microinjection of either diazoxide or the GABAA receptor antagonist reversed the suppressive effects of VMH glucose delivery on counterregulatory responses. Some GABAergic neurons in the VMH respond to changes in local glucose concentration. Glucose in the VMH dose-dependently stimulates GABA release, and this in turn dose-dependently suppresses the glucagon and epinephrine responses to hypoglycemia. These data suggest that during hypoglycemia a decrease in glucose concentration within the VMH may provide an important signal that rapidly inactivates VMH GABAergic neurons, reducing inhibitory GABAergic tone, which in turn enhances the counterregulatory responses to hypoglycemia.

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