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Robert S. Sherwin - One of the best experts on this subject based on the ideXlab platform.
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Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemia counterregulation. Diabetes 52
2016Co-Authors: Monica A. Borg, William V. Tamborlane, Gerald I. Shulman, Robert S. SherwinAbstract:We have previously reported that a glucosensor inte-grating hormonal responses to hypoglycemia is located in the ventromedial hypothalamus (VMH) and that local VMH glucose perfusion blocks Counterregulatory hor-mone responses. To determine whether the by-product of glucose metabolism, lactate, can function within the VMH as an alternative for glucose, we delivered lactate locally to the VMH, during systemic hypoglycemia. For this purpose, we combined bilateral VMH microdialysis perfusion (metabolically active L-lactate or its nonme-tabolizable D-isomer) with a euglycemic-hypoglycemic clamp in conscious chronically catheterized Sprague-Dawley rats. Local VMH perfusion with L-lactate de-creased Counterregulatory Hormone responses to hypoglycemia by 80–85 % as compared with the non
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epha5 ephrina5 interactions within the ventromedial hypothalamus influence Counterregulatory Hormone release and local glutamine glutamate balance during hypoglycemia
Diabetes, 2013Co-Authors: Barbara Szepietowska, Wanling Zhu, Jan Czyzyk, Tore Eid, Robert S. SherwinAbstract:Activation of β-cell EphA5 receptors by its ligand ephrinA5 from adjacent β-cells has been reported to decrease insulin secretion during hypoglycemia. Given the similarities between islet and ventromedial hypothalamus (VMH) glucose sensing, we tested the hypothesis that the EphA5/ephrinA5 system might function within the VMH during hypoglycemia to stimulate Counterregulatory Hormone release as well. Counterregulatory responses and glutamine/glutamate concentrations in the VMH were assessed during a hyperinsulinemic-hypoglycemic glucose clamp study in chronically catheterized awake male Sprague-Dawley rats that received an acute VMH microinjection of ephrinA5-Fc, chronic VMH knockdown, or overexpression of ephrinA5 using an adenoassociated viral construct. Local stimulation of VMH EphA5 receptors by ephrinA5-Fc or ephrinA5 overexpression increased, whereas knockdown of VMH ephrinA5 reduced Counterregulatory responses during hypoglycemia. Overexpression of VMH ephrinA5 transiently increased local glutamate concentrations, whereas ephrinA5 knockdown produced profound suppression of VMH interstitial fluid glutamine concentrations in the basal state and during hypoglycemia. Changes in ephrinA5/EphA5 interactions within the VMH, a key brain glucose-sensing region, act in concert with islets to restore glucose homeostasis during acute hypoglycemia, and its effect on counterregulation may be mediated by changes in glutamate/glutamine cycling.
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key role for amp activated protein kinase in the ventromedial hypothalamus in regulating Counterregulatory Hormone responses to acute hypoglycemia
Diabetes, 2008Co-Authors: Rory J. Mccrimmon, Margaret Shaw, Xiaoning Fan, Haiying Cheng, Yuyan Ding, Monica C Vella, Ligang Zhou, Ewan C Mcnay, Robert S. SherwinAbstract:OBJECTIVE —To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia. RESEARCH DESIGN AND METHODS —Using gene silencing technology to selectively downregulate AMPK in the VMH, a key hypothalamic glucose-sensing region, we demonstrate a key role for AMPK in the detection of hypoglycemia. In vivo hyperinsulinemic-hypoglycemic (50 mg dl −1 ) clamp studies were performed in awake, chronically catheterized Sprague-Dawley rats that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPKα. RESULTS —In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon (∼60%) and epinephrine (∼40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation also required more exogenous glucose to maintain the hypoglycemia plateau and showed significant reductions in endogenous glucose production and whole-body glucose uptake. CONCLUSIONS —We conclude that AMPK in the VMH plays a key role in the detection of acute hypoglycemia and initiation of the glucose Counterregulatory response.
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activation of amp activated protein kinase within the ventromedial hypothalamus amplifies Counterregulatory Hormone responses in rats with defective counterregulation
Diabetes, 2006Co-Authors: Rory J. Mccrimmon, Wanling Zhu, Margaret Shaw, Xiaoning Fan, Haiying Cheng, Yuyan Ding, Ewan C Mcnay, Owen Chan, Robert S. SherwinAbstract:Defective Counterregulatory responses (CRRs) to hypoglycemia are associated with a marked increase in the risk of severe hypoglycemia. The mechanisms leading to the development of defective CRRs remain largely unknown, although they are associated with antecedent hypoglycemia. Activation of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) amplifies the Counterregulatory increase in glucose production during acute hypoglycemia. To examine whether activation of AMPK in the VMH restores defective CRR, controlled hypoglycemia (∼2.8 mmol/l) was induced in a group of 24 Sprague-Dawley rats, all of which had undergone a 3-day model of recurrent hypoglycemia before the clamp study. Before the acute study, rats were microinjected to the VMH with either 5-aminoimidazole-4-carboxamide (AICAR; n = 12), to activate AMPK, or saline ( n = 12). In a subset of rats, an infusion of H 3 -glucose was additionally started to calculate glucose turnover. Stimulation of AMPK within the VMH was found to amplify hormonal CRR and increase endogenous glucose production. In addition, analysis of tissue from both whole hypothalamus and VMH showed that recurrent hypoglycemia induces an increase in the gene expression of AMPK α 1 and α 2 . These findings suggest that the development of novel drugs designed to selectively activate AMPK in the VMH offer a future therapeutic potential for individuals with type 1 diabetes who have defective CRRs to hypoglycemia.
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activation of atp sensitive k channels in the ventromedial hypothalamus amplifies Counterregulatory Hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats
Diabetes, 2005Co-Authors: Rory J. Mccrimmon, Wanling Zhu, Xiaoning Fan, Yuyan Ding, Ewan C Mcnay, Owen Chan, Mark L Evans, Dorte Xenia Gram, Robert S. SherwinAbstract:The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic beta-cell, ATP-sensitive K+ channels (K ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K ATP channels during systemic hypoglycemia would amplify hormonal Counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (approximately 2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU x kg(-1) x min(-1)) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon Counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the Counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective Counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation.
Timothy W Jones - One of the best experts on this subject based on the ideXlab platform.
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effect of sensor augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes a randomized clinical trial
JAMA, 2013Co-Authors: Trang T Ly, Jennifer A Nicholas, Adam Retterath, Elizabeth A Davis, Timothy W JonesAbstract:Importance Hypoglycemia is a critical obstacle to the care of patients with type 1 diabetes. Sensor-augmented insulin pump with automated low-glucose insulin suspension has the potential to reduce the incidence of major hypoglycemic events. Objective To determine the incidence of severe and moderate hypoglycemia with sensor-augmented pump with low-glucose suspension compared with standard insulin pump therapy. Design, Setting, and Participants A randomized clinical trial involving 95 patients with type 1 diabetes, recruited from December 2009 to January 2012 in Australia. Interventions Patients were randomized to insulin pump only or automated insulin suspension for 6 months. Main Outcomes and Measures The primary outcome was the combined incidence of severe (hypoglycemic seizure or coma) and moderate hypoglycemia (an event requiring assistance for treatment). In a subgroup, Counterregulatory Hormone responses to hypoglycemia were assessed using the hypoglycemic clamp technique. Results Of the 95 patients randomized, 49 were assigned to the standard-pump (pump-only) therapy and 46 to the low-glucose suspension group. The mean (SD) age was 18.6 (11.8) years; duration of diabetes, 11.0 (8.9) years; and duration of pump therapy, 4.1 (3.4) years. The baseline rate of severe and moderate hypoglycemic events in the pump-only group was 20.7 vs 129.6 events per 100 patient months in the low-glucose suspension group. After 6 months of treatment, the event rates decreased from 28 to 16 in the pump-only group vs 175 to 35 in the low-glucose suspension group. The adjusted incidence rate per 100 patient-months was 34.2 (95% CI, 22.0-53.3) for the pump-only group vs 9.5 (95% CI, 5.2-17.4) for the low-glucose suspension group. The incidence rate ratio was 3.6 (95% CI, 1.7-7.5; P Conclusions and Relevance Sensor-augmented pump therapy with automated insulin suspension reduced the combined rate of severe and moderate hypoglycemia in patients with type 1 diabetes. Trial Registration anzctr.org.auIdentifier:ACTRN12610000024044
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Improving Epinephrine Responses in Hypoglycemia Unawareness With Real-Time Continuous Glucose Monitoring in Adolescents With Type 1 Diabetes
2013Co-Authors: Jacqueline Hewitt, Raymond J Davey, Timothy W JonesAbstract:OBJECTIVE — To determine whether real-time continuous glucose monitoring (CGM) with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and improve the Counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness. RESEARCH DESIGN AND METHODS — Adolescents with type 1 diabetes with hypoglycemia unawareness underwent hyperinsulinemic hypoglycemic clamp studies at baseline to determine their Counterregulatory Hormone responses to hypoglycemia. Subjects were then randomized to either standard therapy or real-time CGM for 4 weeks. The clamp study was then repeated. RESULTS — The epinephrine response during hypoglycemia after the intervention was greater in the CGM group than in the standard therapy group. CONCLUSIONS — A greater epinephrine response during hypoglycemia suggests that realtime CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes. Hypoglycemia unawareness is define
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improving epinephrine responses in hypoglycemia unawareness with real time continuous glucose monitoring in adolescents with type 1 diabetes
Diabetes Care, 2011Co-Authors: Jacqueline K Hewitt, Elizabeth A Davis, Raymond J Davey, Ee Mun Lim, Timothy W JonesAbstract:OBJECTIVE To determine whether real-time continuous glucose monitoring (CGM) with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and improve the Counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness. RESEARCH DESIGN AND METHODS Adolescents with type 1 diabetes with hypoglycemia unawareness underwent hyperinsulinemic hypoglycemic clamp studies at baseline to determine their Counterregulatory Hormone responses to hypoglycemia. Subjects were then randomized to either standard therapy or real-time CGM for 4 weeks. The clamp study was then repeated. RESULTS The epinephrine response during hypoglycemia after the intervention was greater in the CGM group than in the standard therapy group. CONCLUSIONS A greater epinephrine response during hypoglycemia suggests that real-time CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes.
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decreased epinephrine responses to hypoglycemia during sleep
The New England Journal of Medicine, 1998Co-Authors: Timothy W Jones, Elizabeth A Davis, Paul A Porte, Robe S Sherwi, Pete Oleary, Fiona Fraze, G C Yrne, Stephe M Stick, William V. TamborlaneAbstract:Background In patients with type I diabetes mellitus, hypoglycemia occurs commonly during sleep and is frequently asymptomatic. This raises the question of whether sleep is associated with reduced Counterregulatory-Hormone responses to hypoglycemia. Methods We studied the Counterregulatory-Hormone responses to insulin-induced hypoglycemia in eight adolescent patients with type I diabetes and six age-matched normal subjects when they were awake during the day, asleep at night, and awake at night. In each study, the plasma glucose concentration was stabilized for 60 minutes at approximately 100 mg per deciliter (5.6 mmol per liter) and then reduced to 50 mg per deciliter (2.8 mmol per liter) and maintained at that concentration for 40 minutes. Plasma free insulin, epinephrine, norepinephrine, cortisol, and growth Hormone were measured frequently during each study. Sleep was monitored by polysomnography. Results The plasma glucose and free insulin concentrations were similar in both groups during all studies...
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Gender influences Counterregulatory Hormone responses to hypoglycemia
Metabolism: clinical and experimental, 1993Co-Authors: Michael P Diamond, Timothy W Jones, William V. Tamborlane, Lynn Hallarman, Sonia Caprio, Meredith C. Diamond, Mario Addabbo, Robert S. SherwinAbstract:It has been generally assumed that Counterregulatory Hormone responses to hypoglycemia are not influenced by gender. To test this assumption, we analyzed three separate hypoglycemic insulin clamp studies in age-matched, healthy, non-obese females (n = 33) and males (n = 37). In one study (12 females, 17 males), plasma glucose level was rapidly decreased to about 57 mg/dL for 100 minutes with a 0.65-mU/kg/min insulin infusion. Despite an identical decrease in glucose level, the increase in epinephrine (361 ± 64 v 188 ± 38 pg/mL, P < .05), norepinephrine (132 ± 28 v 47 ± 19 pg/mL, P < .01), and growth Hormone ([GH] 16.0 ± 3.8 v 4.9 ± 1.9 ng/mL, P < .05) levels, but not glucagon or cortisol levels, were significantly greater in males than in females, respectively. In the second study (10 females, eight males), a 5.0-mU/kg/min insulin infusion was used to decrease glucose levels to 55 mg/dL for 180 minutes. Epinephrine (P < .05) and GH (P < .01) responses were greater in males than in females. In a third study (11 females, 12 males), plasma glucose level was gradually decreased to about 50 mg/dL over 240 minutes. Again epinephrine (P < .01), norepinephrine (P < .01), GH (P < .05), and cortisol (P < .01) responses were nearly twofold greater in males (P < .01). Multivariate analysis of all 70 subjects identified gender as the most significant factor contributing to the epinephrine (P < .001) and norepinephrine (P < .005) responses, and also as a significant contributor to the GH response (P < .05). Moreover, the glucose levels that triggered an increase in epinephrine, norepinephrine, and cortisol were each about 9 mg/dL higher in males (P < .05). We conclude that, with respect to males, females have decreased Counterregulatory hormonal responses to hypoglycemia. This sexual dimorphism may be in part due to an alteration in the glucose threshold for Hormone release.
Karen P Briski - One of the best experts on this subject based on the ideXlab platform.
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neuroestradiol regulation of ventromedial hypothalamic nucleus 5 amp activated protein kinase activity and Counterregulatory Hormone secretion in hypoglycemic male versus female rats
AIMS neuroscience, 2021Co-Authors: Main Uddin, Karen P BriskiAbstract:Hypoglycemia activates the ultra-sensitive energy gauge 5'-AMP-activated protein kinase (AMPK) in ventromedial hypothalamic nucleus (VMN) gluco-regulatory neurons. The VMN is exemplified by high levels of expression of the enzyme aromatase, which converts testosterone to estradiol. This study examined the hypothesis that neuroestradiol imposes sex-dimorphic control of VMN AMPK activity during eu- and/or hypoglycemia. VMN tissue corresponding to distinct rostro-caudal segments was obtained by micropunch dissection from testes-intact male and estradiol-replaced ovariectomized female rats that were infused intracerebroventricularly with the aromatase inhibitor letrozole (Lz) before subcutaneous insulin (INS) injection. In euglycemic rats, Lz treatment elevated (male) or decreased (female) middle VMN phosphoAMPK content, with concurrent effects on total AMPK expression. Lz prevented hypoglycemic up-regulation of the mean pAMPK/AMPK ratio in rostral and middle segments of the male VMN, and significantly inhibited this proportion throughout the VMN of hypoglycemic female rats. Lz prevented glucagon secretion in hypoglycemic rats of each sex, and abolished hypoglycemic hypercorticosteronemia in males. Results show that neuroestradiol regulation of VMN AMPK activity during euglycemia is region-specific and gender-divergent, e.g. inhibitory in males versus stimulatory in females. Intra-VMN distribution of hypoglycemia-activated AMPK varies between sexes, but in each sex, locally-generated estradiol is critical for sensor reactivity to this stimulus. Coincident Lz attenuation of VMN AMPK and counter-regulatory Hormone responses to hypoglycemia infers a possible cause-and-effect association. Further effort is needed to elucidate the cellular and molecular mechanisms that underlie sex-dimorphic neuroestradiol control of VMN total AMPK and phosphoAMPK expression during distinct metabolic states.
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caudal fourth ventricular administration of the ampk activator 5 aminoimidazole 4 carboxamide riboside regulates glucose and Counterregulatory Hormone profiles dorsal vagal complex metabolosensory neuron function and hypothalamic fos expression
Journal of Neuroscience Research, 2013Co-Authors: Baher A Ibrahim, Pratistha Tamrakar, Amit D Gujar, Ajeesh Koshy Cherian, Karen P BriskiAbstract:This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, Counterregulatory Hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction. © 2013 Wiley Periodicals, Inc.
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caudal fourth ventricular administration of the ampk activator 5 aminoimidazole 4 carboxamide riboside regulates glucose and Counterregulatory Hormone profiles dorsal vagal complex metabolosensory neuron function and hypothalamic fos expression
Journal of Neuroscience Research, 2013Co-Authors: Baher A Ibrahim, Pratistha Tamrakar, Amit D Gujar, Ajeesh Koshy Cherian, Karen P BriskiAbstract:This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, Counterregulatory Hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction.
William V. Tamborlane - One of the best experts on this subject based on the ideXlab platform.
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Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemia counterregulation. Diabetes 52
2016Co-Authors: Monica A. Borg, William V. Tamborlane, Gerald I. Shulman, Robert S. SherwinAbstract:We have previously reported that a glucosensor inte-grating hormonal responses to hypoglycemia is located in the ventromedial hypothalamus (VMH) and that local VMH glucose perfusion blocks Counterregulatory hor-mone responses. To determine whether the by-product of glucose metabolism, lactate, can function within the VMH as an alternative for glucose, we delivered lactate locally to the VMH, during systemic hypoglycemia. For this purpose, we combined bilateral VMH microdialysis perfusion (metabolically active L-lactate or its nonme-tabolizable D-isomer) with a euglycemic-hypoglycemic clamp in conscious chronically catheterized Sprague-Dawley rats. Local VMH perfusion with L-lactate de-creased Counterregulatory Hormone responses to hypoglycemia by 80–85 % as compared with the non
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blunted Counterregulatory Hormone responses to hypoglycemia in young children and adolescents with well controlled type 1 diabetes response to graveling warren and frier
Diabetes Care, 2010Co-Authors: Eva Tsalikian, William V. TamborlaneAbstract:We thank Graveling et al. (1) for their thoughtful comments regarding our article (2). In their letter, they argue that our conclusion was not supported by the study data because the achieved level of hypoglycemia was not adequate. They point out that the mean nadir plasma glucose level in our subjects was ∼60 mg/dl, whereas plasma glucose concentrations <60 mg/dl are often required to elicit …
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blunted Counterregulatory Hormone responses to hypoglycemia in young children and adolescents with well controlled type 1 diabetes
Diabetes Care, 2009Co-Authors: Eva Tsalikian, William V. Tamborlane, Nelly Mauras, Bruce A Buckingham, Stuart A Weinzimer, Dongyuan Xing, Dorothy M Becker, Rosanna Fialloscharer, Michael W Steffes, Ravinder J SinghAbstract:We thank Graveling et al. (1) for their thoughtful comments regarding our article (2). In their letter, they argue that our conclusion was not supported by the study data because the achieved level of hypoglycemia was not adequate. They point out that the mean nadir plasma glucose level in our subjects was ∼60 mg/dl, whereas plasma glucose concentrations <60 mg/dl are often required to elicit …
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Oral glucose augments the Counterregulatory Hormone response during insulin-induced hypoglycemia in humans.
The Journal of clinical endocrinology and metabolism, 2001Co-Authors: Rubina A. Heptulla, William V. Tamborlane, Tony Y.-z., Fran Rife, Robert S. SherwinAbstract:It has been suggested that the Counterregulatory Hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 ± 2 mg/dL (3.08 mmol/L). As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, ther...
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decreased epinephrine responses to hypoglycemia during sleep
The New England Journal of Medicine, 1998Co-Authors: Timothy W Jones, Elizabeth A Davis, Paul A Porte, Robe S Sherwi, Pete Oleary, Fiona Fraze, G C Yrne, Stephe M Stick, William V. TamborlaneAbstract:Background In patients with type I diabetes mellitus, hypoglycemia occurs commonly during sleep and is frequently asymptomatic. This raises the question of whether sleep is associated with reduced Counterregulatory-Hormone responses to hypoglycemia. Methods We studied the Counterregulatory-Hormone responses to insulin-induced hypoglycemia in eight adolescent patients with type I diabetes and six age-matched normal subjects when they were awake during the day, asleep at night, and awake at night. In each study, the plasma glucose concentration was stabilized for 60 minutes at approximately 100 mg per deciliter (5.6 mmol per liter) and then reduced to 50 mg per deciliter (2.8 mmol per liter) and maintained at that concentration for 40 minutes. Plasma free insulin, epinephrine, norepinephrine, cortisol, and growth Hormone were measured frequently during each study. Sleep was monitored by polysomnography. Results The plasma glucose and free insulin concentrations were similar in both groups during all studies...
Baher A Ibrahim - One of the best experts on this subject based on the ideXlab platform.
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caudal fourth ventricular administration of the ampk activator 5 aminoimidazole 4 carboxamide riboside regulates glucose and Counterregulatory Hormone profiles dorsal vagal complex metabolosensory neuron function and hypothalamic fos expression
Journal of Neuroscience Research, 2013Co-Authors: Baher A Ibrahim, Pratistha Tamrakar, Amit D Gujar, Ajeesh Koshy Cherian, Karen P BriskiAbstract:This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, Counterregulatory Hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction. © 2013 Wiley Periodicals, Inc.
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caudal fourth ventricular administration of the ampk activator 5 aminoimidazole 4 carboxamide riboside regulates glucose and Counterregulatory Hormone profiles dorsal vagal complex metabolosensory neuron function and hypothalamic fos expression
Journal of Neuroscience Research, 2013Co-Authors: Baher A Ibrahim, Pratistha Tamrakar, Amit D Gujar, Ajeesh Koshy Cherian, Karen P BriskiAbstract:This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, Counterregulatory Hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction.
