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Fernandes A.B.,New University of Lisbon | Guarino M.P.,Portuguese Diabetes Association Education and Research Center | Macedo M.P.,New University of Lisbon
Canadian Journal of Physiology and Pharmacology | Year: 2012

Insulin sensitivity is maximal in the postprandial state, decreasing with a fasting period through a mechanism that is dependent on the integrity of the hepatic parasympathetic nerves/nitric oxide (NO) production and increased hepatic gluta-thione (GSH) levels. GSH and NO react to form S-nitrosoglutathione (GSNO), an S-nitrosothiol (RSNO) for which the in-vivo effects are still being determined. The goal of this study was to test the hypothesis that in-vivo administration of RSNOs, GSNO, or S-nitroso-N-acetylpenicillamine (SNAP) increases insulin sensitivity in fasted or fed-denervated animals, but not in fed animals, where full postprandial insulin sensitivity is achieved. Fasted, fed, or fed-denervated male Wistar rats were used as models for different insulin sensitivity conditions. The rapid insulin sensitivity test (RIST) was used to measure insulin-stimulated glucose disposal before and after drug administration (GSNO, SNAP, or 3-morpholinosydnonimine (SIN-1), intravenous (i.v.) or to the portal vein (i.p.v.)). Fast insulin sensitivity was not altered by administration of SIN-1 (neither i.v. nor i.p.v.). Intravenous infusion of RSNOs in fasted and fed hepatic denervated rats increased insulin sensitivity by 126.35% ± 35.43% and 82.7% ± 12.8%, respectively. In fed animals, RSNOs decreased insulin sensitivity indicating a negative feedback mechanism. These results suggest that RSNOs incremental effect on insulin sensitivity represent a promising therapeutical tool in insulin resistance states. Source

Fernandes A.B.,New University of Lisbon | Patarrao R.S.,New University of Lisbon | Videira P.A.,New University of Lisbon | Macedo M.P.,New University of Lisbon | Macedo M.P.,Portuguese Diabetes Association Education and Research Center
Journal of Neuroendocrinology | Year: 2011

The hepatic parasympathetic system is one of the major contributors for preserving insulin sensitivity in the postprandial state. Postprandial hepatic vagal control of whole-body glucose clearance and its effect on specific organs remains unknown. Our hypothesis is that, in the postprandial state, the hepatic parasympathetic nerves (HPN) are responsible for a considerable part of extra-hepatic tissue glucose clearance. Two groups of 9-week-old Sprague-Dawley rats were studied, comparing sham-operated versus hepatic parasympathetic denervated animals. Insulin sensitivity was evaluated in the postprandial state by the rapid insulin sensitivity test (RIST). [ 3H]2-deoxy-d-glucose was administered during the RIST. Plasma glucose rate of the disappearance and clearance by skeletal muscle, adipose tissue, liver, pancreas, heart and kidney of this radioisotope was measured. The postprandial denervated group showed a decrease insulin sensitivity of 41.4±5.2%. This group of animals showed a decrease in the rate of plasma [ 3H]2-deoxy-d-glucose disappearance and skeletal muscle, heart and kidney glucose clearance by 45%, 35% and 67%, respectively. These studies show that the major contributor of postprandial whole-body glucose clearance was skeletal muscle; in the range 69-38%, depending on HPN integrity. The results obtained in the present study indicate that HPN are crucial for postprandial action of insulin through a mechanism that is essential for maintenance of skeletal muscle, heart and kidney glucose clearance. These results suggest that hepatic parasympathetic dysfunction could lie at the genesis of type 2 diabetes complications, namely insulin resistance, nephropathy and cardiomyopathy. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd. Source

Patarrao R.S.,New University of Lisbon | Wayne Lautt W.,University of Manitoba | Afonso R.A.,New University of Lisbon | Ribeiro R.T.,Portuguese Diabetes Association Education and Research Center | And 3 more authors.
Canadian Journal of Physiology and Pharmacology | Year: 2012

The dynamic response to insulin is highly potentiated after meal ingestion, and this meal-induced insulin sensiti-zation (MIS) in healthy subjects is dependent on cholinergic mechanisms. The main objective of this study was to test the hypothesis that the reduced response to insulin observed in moderately overweight subjects, in comparison with control lean subjects, is due to MIS impairment and not to a reduction in the direct hypoglycemic action of insulin. Both lean and overweight male subjects were recruited. Insulin sensitivity (IS) was assessed by the rapid insulin sensitivity test (RIST) performed after a 24 h fast, as well as after a standardized meal. Fasting glucose disposal was similar between lean and overweight subjects. Following the meal, glucose disposal increased more extensively in lean than overweight subjects. The insulin profiles, in both fasted and fed states, were superimposable, suggesting that the absence of a factor other than insulin is responsible for the decreased postprandial insulin sensitivity observed in overweight subjects. Our data suggest that in overweight subjects, MIS contribution is decreased, which is responsible for the postprandial impaired IS observed and is suggested to be the cause, not effect, of mild adiposity. Source

Duarte N.,New University of Lisbon | Duarte N.,Instituto Gulbenkian Of Ciencia Igc | Coelho I.C.,New University of Lisbon | Coelho I.C.,Instituto Gulbenkian Of Ciencia Igc | And 7 more authors.
BioMed Research International | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most prevalent cause of liver disease worldwide and afflicts adults and children as currently associated with obesity and insulin resistance. Even though lately some advances have been made to elucidate the mechanism and causes of the disease much remains unknown about NAFLD. The aim of this paper is to discuss the present knowledge regarding the pathogenesis of the disease aiming at the initial steps of NAFLD development, when inflammation impinges on fat liver deposition. At this stage, the Kupffer cells attain a prominent role. This knowledge becomes subsequently relevant for the development of future diagnostic, prevention, and therapeutic options for the management of NAFLD. © 2015 Nádia Duarte et al. Source

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