Postprandial Insulin Resistance in Zucker Diabetic Fatty Rats is Associated with Parasympathetic-Nitric Oxide Axis Deficiencies

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Abstract

The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic-nitric oxide (PSN-NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN-NO axis) and direct actions of insulin. Nine-week-old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and ?-glutamyl-cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 +/- 12.9 mg/dl; LZR, 107.7 +/- 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 +/- 0.8 ng/ml; LZR, 1.5 +/- 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 +/- 7.5 mg glucose/kg; LZR, 289.2 +/- 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 +/- 7.0 mg glucose/kg; LZR, 173.3 +/- 20.5 mg glucose/kg) and the PSN-NO axis (ZDF, 24.5 +/- 3.9 mg glucose/kg; LZR, 115.9 +/- 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 +/- 11.4 mu mol/g tissue; LZR, 164.6 +/- 4.9 mu mol/g tissue) and GSH (ZDF, 4.9 +/- 0.3 mu mol/g; LZR, 5.9 +/- 0.2 mu mol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN-NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.
Original languageEnglish
Pages (from-to)1346-1355
Number of pages10
JournalJournal Of Neuroendocrinology
Volume24
Issue number10
DOIs
Publication statusPublished - 2012

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Insulin Resistance
Nitric Oxide
Insulin
Glucose
Nitric Oxide Synthase
Cysteine
Liver
Zucker Rats
Atropine
Hyperglycemia
Type 2 Diabetes Mellitus
Glutathione
Meals
Obesity

Cite this

@article{7e21f0cbe6044119af176929bde63e9f,
title = "Postprandial Insulin Resistance in Zucker Diabetic Fatty Rats is Associated with Parasympathetic-Nitric Oxide Axis Deficiencies",
abstract = "The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic-nitric oxide (PSN-NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN-NO axis) and direct actions of insulin. Nine-week-old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and ?-glutamyl-cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 +/- 12.9 mg/dl; LZR, 107.7 +/- 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 +/- 0.8 ng/ml; LZR, 1.5 +/- 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 +/- 7.5 mg glucose/kg; LZR, 289.2 +/- 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 +/- 7.0 mg glucose/kg; LZR, 173.3 +/- 20.5 mg glucose/kg) and the PSN-NO axis (ZDF, 24.5 +/- 3.9 mg glucose/kg; LZR, 115.9 +/- 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 +/- 11.4 mu mol/g tissue; LZR, 164.6 +/- 4.9 mu mol/g tissue) and GSH (ZDF, 4.9 +/- 0.3 mu mol/g; LZR, 5.9 +/- 0.2 mu mol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN-NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.",
keywords = "nitric oxide, SENSITIVITY TEST RIST, insulin action, parasympathetic nerves, LIVER, glutathione, SENSITIZATION, GLUCOSE, SKELETAL-MUSCLE, OBESE, DYSFUNCTION, Zucker diabetic fatty, postprandial state, HYPERGLYCEMIA, HYPERTENSION, GLUTATHIONE",
author = "Macedo, {Maria Paula} and Ana Fernandes and Videira, {Paula A} and Ricardo Afonso and Rita Patarr{\~a}o and Ribeiro, {Rog{\'e}rio T} and Lima, {In{\^e}s Sousa}",
year = "2012",
doi = "10.1111/j.1365-2826.2012.02341.x",
language = "English",
volume = "24",
pages = "1346--1355",
journal = "Journal Of Neuroendocrinology",
issn = "0953-8194",
publisher = "Blackwell Publishing Ltd",
number = "10",

}

TY - JOUR

T1 - Postprandial Insulin Resistance in Zucker Diabetic Fatty Rats is Associated with Parasympathetic-Nitric Oxide Axis Deficiencies

AU - Macedo, Maria Paula

AU - Fernandes, Ana

AU - Videira, Paula A

AU - Afonso, Ricardo

AU - Patarrão, Rita

AU - Ribeiro, Rogério T

AU - Lima, Inês Sousa

PY - 2012

Y1 - 2012

N2 - The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic-nitric oxide (PSN-NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN-NO axis) and direct actions of insulin. Nine-week-old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and ?-glutamyl-cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 +/- 12.9 mg/dl; LZR, 107.7 +/- 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 +/- 0.8 ng/ml; LZR, 1.5 +/- 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 +/- 7.5 mg glucose/kg; LZR, 289.2 +/- 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 +/- 7.0 mg glucose/kg; LZR, 173.3 +/- 20.5 mg glucose/kg) and the PSN-NO axis (ZDF, 24.5 +/- 3.9 mg glucose/kg; LZR, 115.9 +/- 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 +/- 11.4 mu mol/g tissue; LZR, 164.6 +/- 4.9 mu mol/g tissue) and GSH (ZDF, 4.9 +/- 0.3 mu mol/g; LZR, 5.9 +/- 0.2 mu mol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN-NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.

AB - The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic-nitric oxide (PSN-NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN-NO axis) and direct actions of insulin. Nine-week-old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and ?-glutamyl-cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 +/- 12.9 mg/dl; LZR, 107.7 +/- 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 +/- 0.8 ng/ml; LZR, 1.5 +/- 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 +/- 7.5 mg glucose/kg; LZR, 289.2 +/- 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 +/- 7.0 mg glucose/kg; LZR, 173.3 +/- 20.5 mg glucose/kg) and the PSN-NO axis (ZDF, 24.5 +/- 3.9 mg glucose/kg; LZR, 115.9 +/- 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 +/- 11.4 mu mol/g tissue; LZR, 164.6 +/- 4.9 mu mol/g tissue) and GSH (ZDF, 4.9 +/- 0.3 mu mol/g; LZR, 5.9 +/- 0.2 mu mol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN-NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.

KW - nitric oxide

KW - SENSITIVITY TEST RIST

KW - insulin action

KW - parasympathetic nerves

KW - LIVER

KW - glutathione

KW - SENSITIZATION

KW - GLUCOSE

KW - SKELETAL-MUSCLE

KW - OBESE

KW - DYSFUNCTION

KW - Zucker diabetic fatty

KW - postprandial state

KW - HYPERGLYCEMIA

KW - HYPERTENSION

KW - GLUTATHIONE

U2 - 10.1111/j.1365-2826.2012.02341.x

DO - 10.1111/j.1365-2826.2012.02341.x

M3 - Article

VL - 24

SP - 1346

EP - 1355

JO - Journal Of Neuroendocrinology

JF - Journal Of Neuroendocrinology

SN - 0953-8194

IS - 10

ER -