TY - JOUR
T1 - Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action
AU - Afonso, Ricardo Alexandre da Silva Santos
AU - Guarino, Maria Pedro Sucena
AU - Macedo, Maria Paula Borges de Lemos
AU - Raposo, João Filipe Cancela dos Santos
PY - 2003/1/1
Y1 - 2003/1/1
N2 - We tested the hypothesis that hepatic nitric oxide (NO) and glutathione (GSH) are involved in the synthesis of a putative hormone referred to as hepatic insulin-sensitizing substance HISS. Insulin action was assessed in Wistar rats using the rapid insulin sensitivity test (RIST). Blockade of hepatic NO synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME, 1.0 mg/kg intraportal) decreased insulin sensitivity by 45.1 +/- 2.1% compared with control (from 287.3 +/- 18.1 to 155.3 +/- 10.1 mg glucose/ kg, P < 0.05). Insulin sensitivity was restored to 321.7 +/- 44.7 mg glucose/kg after administration of an NO donor, intraportal SIN-1 (5 mg/kg), which promotes GSH nitrosation, but not after intraportal. sodium nitroprusside (20 mnol.kg(-1).min(-1)), which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor 1-buthionine-[S,]sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin sensitivity by 39.1%. Insulin sensitivity after L-NAME was not significantly different between BSO- and sham-treated animals. SIN-1 did not reverse the insulin resistance induced by L-NAME in the BSO-treated group. These results support our hypothesis that NO and GSH are essential for insulin action.
AB - We tested the hypothesis that hepatic nitric oxide (NO) and glutathione (GSH) are involved in the synthesis of a putative hormone referred to as hepatic insulin-sensitizing substance HISS. Insulin action was assessed in Wistar rats using the rapid insulin sensitivity test (RIST). Blockade of hepatic NO synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME, 1.0 mg/kg intraportal) decreased insulin sensitivity by 45.1 +/- 2.1% compared with control (from 287.3 +/- 18.1 to 155.3 +/- 10.1 mg glucose/ kg, P < 0.05). Insulin sensitivity was restored to 321.7 +/- 44.7 mg glucose/kg after administration of an NO donor, intraportal SIN-1 (5 mg/kg), which promotes GSH nitrosation, but not after intraportal. sodium nitroprusside (20 mnol.kg(-1).min(-1)), which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor 1-buthionine-[S,]sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin sensitivity by 39.1%. Insulin sensitivity after L-NAME was not significantly different between BSO- and sham-treated animals. SIN-1 did not reverse the insulin resistance induced by L-NAME in the BSO-treated group. These results support our hypothesis that NO and GSH are essential for insulin action.
KW - hepatic nitric oxide synthase
KW - AFFECTS GLUCOSE-HOMEOSTASIS
KW - 3T3-L1 ADIPOCYTES
KW - DEPENDENT DIABETES-MELLITUS
KW - SOLUBLE GUANYLYL CYCLASE
KW - CYCLIC-GMP
KW - hepatic parasympathetic nerves
KW - PROTEIN-KINASE B
KW - type 2 diabetes
KW - GLUT4 TRANSLOCATION
KW - HEALTHY-SUBJECTS
KW - S-NITROSOGLUTATHIONE
KW - OXIDATIVE STRESS
U2 - 10.1152/ajpgi.00423.2002
DO - 10.1152/ajpgi.00423.2002
M3 - Article
C2 - 12466146
SN - 0193-1857
VL - 284
SP - G588-G594
JO - American Journal Of Physiology-Gastrointestinal And Liver Physiology
JF - American Journal Of Physiology-Gastrointestinal And Liver Physiology
IS - 4
ER -