Defective hepatic nitric oxide action results in HISS-dependent insulin resistance in spontaneously hypertensive rats.
Peripheral insulin sensitivity is dependent on the action of Hepatic Insulin Sensitizing Substance (HISS), in which hepatic NO (HNO) plays an important role. Insulin resistance has been associated with hypertension. NO action is known to be impaired in Spontaneously Hypertensive Rat (SHR) hypertension models. We tested the hypothesis that the HNO pathway is compromised in SHR, resulting in HISS-dependent insulin resistance. Wistar rats (Wis) were the normotensive controls. Insulin sensitivity was evaluated through the Rapid Insulin Sensitivity Test (RIST), a modified euglycemic clamp. A clamp was performed in basal state (control RIST), followed by ipv administration of the NO synthase (NOS) competitive antagonist L-NMMA (0.73 mg/kg) and a RIST post L-NMMA. HISS-dependent insulin sensitivity was assessed by subtracting the RIST post-L-NMMA from the control RIST and is represented as the resultant insulin sensitivity inhibition. In SHR ipv L-NMMA induced 26+/-5% insulin sensitivity inhibition (187.5+/-15.3 mg glucose/kg, n=6; P<0.05), whereas in Wis, ipv L-NMMA induced 53.8+/-5.9% insulin sensitivity inhibition (138.2+/-14.7 mg glucose/kg, n=6, P<0.05), significantly higher than in SHR (P<0.01). Our results suggest that functional HNO is essential to achieve maximal insulin sensitivity and that HNO action is compromised in hypertension, resulting in HISS-dependent insulin resistance.
Afonso
Ricardo Alexandre
RA
Departamento de Fisiologia - FCM-UNL, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal.
Ribeiro
Rogério Tavares
RT
Macedo
Maria Paula
MP
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D019323:omega-N-Methylarginine / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase