Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

Xavier Fioramonti; Nicolas Marsollier; Zhentao Song; Kurt A. Fakira; Reema M. Patel; Stacey Brown; Thibaut Duparc; Arnaldo Pica-Mendez; Nicole M. Sanders; Claude Knauf; Philippe Valet; Rory J. McCrimmon; Annie Beuve; Christophe Magnan; Vanessa H. Routh

doi:10.2337/db09-0421

Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

Xavier Fioramonti, Nicolas Marsollier, Zhentao Song, Kurt A. Fakira, Reema M. Patel, Stacey Brown, Thibaut Duparc, Arnaldo Pica-Mendez, Nicole M. Sanders, Claude Knauf, Philippe Valet, Rory J. McCrimmon, Annie Beuve, Christophe Magnan, Vanessa H. Routh

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Abstract

OBJECTIVE-The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.

RESEARCH DESIGN AND METHODS-The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.

RESULTS-Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebro-ventricular and VMH injection of the nonselective NOS inhibitor N-G-monomethyl-L-arginine (L-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH L-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.

CONCLUSIONS-We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy. Diabetes 59:519-528, 2010

Original language	English
Pages (from-to)	519-528
Number of pages	10
Journal	Diabetes
Volume	59
Issue number	2
DOIs	https://doi.org/10.2337/db09-0421
Publication status	Published - Feb 2010

Keywords

CEREBRAL-BLOOD-FLOW
GLUCOSE-INHIBITED NEURONS
INSULIN-INDUCED HYPOGLYCEMIA
DEPENDENT DIABETES-MELLITUS
ACTIVATED PROTEIN-KINASE
ARCUATE NUCLEUS
HORMONE-RELEASE
EXCITED NEURONS
NEUROPEPTIDE-Y
HEART-RATE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db09-0421

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Fioramonti, X., Marsollier, N., Song, Z., Fakira, K. A., Patel, R. M., Brown, S., Duparc, T., Pica-Mendez, A., Sanders, N. M., Knauf, C., Valet, P., McCrimmon, R. J., Beuve, A., Magnan, C., & Routh, V. H. (2010). Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation. Diabetes, 59(2), 519-528. https://doi.org/10.2337/db09-0421

@article{a181fcfb4bd341b8bd1956cacf830634,

title = "Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation",

abstract = "OBJECTIVE-The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.RESEARCH DESIGN AND METHODS-The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.RESULTS-Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebro-ventricular and VMH injection of the nonselective NOS inhibitor N-G-monomethyl-L-arginine (L-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH L-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.CONCLUSIONS-We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy. Diabetes 59:519-528, 2010",

keywords = "CEREBRAL-BLOOD-FLOW, GLUCOSE-INHIBITED NEURONS, INSULIN-INDUCED HYPOGLYCEMIA, DEPENDENT DIABETES-MELLITUS, ACTIVATED PROTEIN-KINASE, ARCUATE NUCLEUS, HORMONE-RELEASE, EXCITED NEURONS, NEUROPEPTIDE-Y, HEART-RATE",

author = "Xavier Fioramonti and Nicolas Marsollier and Zhentao Song and Fakira, {Kurt A.} and Patel, {Reema M.} and Stacey Brown and Thibaut Duparc and Arnaldo Pica-Mendez and Sanders, {Nicole M.} and Claude Knauf and Philippe Valet and McCrimmon, {Rory J.} and Annie Beuve and Christophe Magnan and Routh, {Vanessa H.}",

year = "2010",

month = feb,

doi = "10.2337/db09-0421",

language = "English",

volume = "59",

pages = "519--528",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "2",

}

Fioramonti, X, Marsollier, N, Song, Z, Fakira, KA, Patel, RM, Brown, S, Duparc, T, Pica-Mendez, A, Sanders, NM, Knauf, C, Valet, P, McCrimmon, RJ, Beuve, A, Magnan, C & Routh, VH 2010, 'Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation', Diabetes, vol. 59, no. 2, pp. 519-528. https://doi.org/10.2337/db09-0421

TY - JOUR

T1 - Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

AU - Fioramonti, Xavier

AU - Marsollier, Nicolas

AU - Song, Zhentao

AU - Fakira, Kurt A.

AU - Patel, Reema M.

AU - Brown, Stacey

AU - Duparc, Thibaut

AU - Pica-Mendez, Arnaldo

AU - Sanders, Nicole M.

AU - Knauf, Claude

AU - Valet, Philippe

AU - McCrimmon, Rory J.

AU - Beuve, Annie

AU - Magnan, Christophe

AU - Routh, Vanessa H.

PY - 2010/2

Y1 - 2010/2

N2 - OBJECTIVE-The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.RESEARCH DESIGN AND METHODS-The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.RESULTS-Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebro-ventricular and VMH injection of the nonselective NOS inhibitor N-G-monomethyl-L-arginine (L-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH L-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.CONCLUSIONS-We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy. Diabetes 59:519-528, 2010

AB - OBJECTIVE-The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.RESEARCH DESIGN AND METHODS-The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.RESULTS-Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebro-ventricular and VMH injection of the nonselective NOS inhibitor N-G-monomethyl-L-arginine (L-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH L-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.CONCLUSIONS-We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy. Diabetes 59:519-528, 2010

KW - CEREBRAL-BLOOD-FLOW

KW - GLUCOSE-INHIBITED NEURONS

KW - INSULIN-INDUCED HYPOGLYCEMIA

KW - DEPENDENT DIABETES-MELLITUS

KW - ACTIVATED PROTEIN-KINASE

KW - ARCUATE NUCLEUS

KW - HORMONE-RELEASE

KW - EXCITED NEURONS

KW - NEUROPEPTIDE-Y

KW - HEART-RATE

U2 - 10.2337/db09-0421

DO - 10.2337/db09-0421

M3 - Article

C2 - 19934009

SN - 0012-1797

VL - 59

SP - 519

EP - 528

JO - Diabetes

JF - Diabetes

IS - 2

ER -

Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

Abstract

Keywords

UN SDGs

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