Dexamethasone-induced insulin resistance and pancreatic adaptive response in aging rats are not modified by oral vanadyl sulfate treatment

Abstract

Objective: To explore the adaptive response of the endocrine pancreas in vivo and in vitro and the possible beneficial effect of the insulino-mimetic agent vanadyl sulfate (VOSO 4 ), using glucocorticoid treatment to increase insulin resistance, in aging rats. Design and Methods: Dexamethasone (Dex) (0.13 mg/kg b.w.) was administered daily for 13 days to 3-and 18-month old Sprague-Dawley rats and oral VOSO 4 was given from the 5th day. Plasma glucose, insulin and free fatty acids (FFA) concentrations were measured during these treatments and the insulin secretory response of the isolated perfused pancreas was assessed at the end of the experiment. Results and Conclusions: In both young and aging rats, particularly in the latter, hyperinsulinemia and increased in vitro insulin responsiveness to glucose were observed in response to Dex treatment, concomitant with an increase in plasma FFA concentrations. Thus, in glucocorticoid-treated animals, the b-cell adaptive response occurred in both age groups and could possibly be mediated by increased circulating FFA; however, it was insufficient to prevent hyperglycemia in 60% of aging animals. Oral VOSO 4 administration failed to correct Dex-induced alterations in glucose and lipid metabolism, although it influenced in vitro b-cell responsiveness to stimuli in aging rats.

Experimental model of glucocorticoid-induced insulin resistance

“…Several studies show that glucocorticoids induce peripheral insulin resistance, in vivo and in vitro 5,8,[23][24][25][26] , by increasing hepatic glucose output and decreasing the peripheral glucose uptake. There are evidences that ROS' production plays a fundamental role on developing insulin resistance by being responsible for the smaller capture of glucose on muscle 27 and on adipose tissue 28 .…”

“…The reduction of weight in rats 2,3 . The increase on serum glucose and serum insulin [4][5][6] . Loss in muscle mass associated to liver hypertrophy 7 .…”

The Genomic Response of Skeletal Muscle to Methylprednisolone Using Microarrays: Tailoring Data Mining to the Structure of the Pharmacogenomic Time Series

“…All remaining animals received a single 50 mg/kg dose of MPL sodium succinate (Pharmacia-Upjohn Company, Kalamazoo, MI, USA) via the cannula over 30 s. Rats (3) were sacrificed by exsanguinations under anesthesia at 0.25, 0.5, 0.75, 1, 2, 4, 5, 5. 5,6,7,8,12,18,30,48 and 72 h after dosing. The sampling time points were selected based on previous studies describing glucocorticoid response dynamics and enzyme induction in skeletal muscle and liver.…”

“…A primary substrate for gluconeogenesis is amino acid carbon derived from the net degradation of muscle protein. Glucocorticoids also cause muscle to become insulin resistant, thereby preventing the large bulk of the musculature from taking up the glucose produced by the liver and kidney [4,5,12]. When corticosteroids are used therapeutically, their effects on the musculature are accentuated, which results in muscle wasting and insulin-resistant diabetes.…”

Functional and Molecular Aspects of Glucocorticoids in the Endocrine Pancreas and Glucose Homeostasis

“…This GC-induced IR is time-, dose-and agedependent (Novelli et al, 1999;Rafacho et al, 2011) and is a common effect in GC-treated rats. This is supported by the fact that most studies showed fasting hyperinsulinemia, an indicator of IR (Lee et al, 1989;Stojanovska et al, 1990;Koranyi et al, 1992;Novelli et al, 1999;Zakrzewska et al, 1999;Barbera et al, 2001;Holness & Sugden, 2001;Karlsson et al, 2001;Severino et al, 2002;Choi et al, 2006;Giozzet et al, 2008;. This rise in circulating insulin concentrations fully compensates for peripheral IR in normal rats and prevents any increase in blood glucose concentrations (Lee et al, 1989;Koranyi et al, 1992;Ogawa et al, 1992;Novelli et al, 1999;Zakrzewska et al, 1999;Barbera et al, 2001;Holness & Sugden, 2001;Severino et al, 2002;Choi et al, 2006;Giozzet et al, 2008;, except in normal elderly rats (Novelli et al, 1999) or when the highest experimental doses (1 mg/kg.…”