Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats

Abstract

This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX) (0·13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18-and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18-and 26-monthold rats from basal values of 4·3 0·8, 4·7 0·5 and 5·6 1·0 ng/ml (means ...) respectively, rose to 11·9 1·7, 29·1 5·5 and 27·9 2·7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-monthold animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3-and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values.Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the priming effect of glucose in islets isolated from all the three age groups.In conclusion, our results show that ageing rats are unable to counteract effectively a prolonged hyperglycaemic challenge as such induced by DEX administration. This homeostatic defect can be ascribed to the age-dependent failure of the endocrine pancreas to provide enough insulin to overcome the aggravation of an antecedent state of increased peripheral insulin resistance.

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…This hyperinsulinaemia is consistent with insulin hypersecretion observed in pancreatic islets isolated from GC-treated rats (Novelli et al 1999, Karlsson et al 2001, 2010a …”

“…The plasma C-peptide values were also elevated after treatment with prednisolone in healthy men at basal conditions (Hollindgal et al 2002) and during a meal tolerance test (van Raalte et al 2010). This enhanced b-cell function was also observed in adult rats treated for up to 13 consecutive days with dexamethasone (0.125-2.0 mg/kg) based on basal hyperinsulinaemia (Novelli et al 1999, Karlsson et al 2001 or in vivo glucose challenging (Rafacho et al , 2011. This augmented b-cell function occurred in a dose- ) and time-dependent manner (Rafacho et al 2011).…”

“…Therefore, the insulinogenic index may not necessarily match the peripheral insulin demand imposed by GCs. The negative impact of GCs on glucose homeostasis is more apparent in individuals or rodents with any degree of susceptibility to glucose intolerance, such as those with low insulin sensitivity (Larsson & Ahrén 1999), low insulin response to glucose (Wajngot et al 1992), first-degree relatives of patients with type 2 diabetes (Jensen et al 2012), obesity (Besse et al 2005) and those who are older (Novelli et al 1999). In these contexts, b-cell function does not correspond to the peripheral insulin demand, and the deregulation of glucose homeostasis becomes more pronounced, reinforcing that individual background is a critical factor.…”

“…When b-cells fail to adjust to the insulin demand imposed by the GC treatment, fasting and/or postprandial hyperglycaemia may arise. The severity and progression of these alterations depend on several parameters including dosage, period and previous individual susceptibility among others (Novelli et al 1999, Jensen et al 2012. In addition to the islet's compensatory responses to IR, GCs directly affect b-cell function, which may further complicate adequate glycaemia regulation.…”

Experimental model of glucocorticoid-induced insulin resistance

“…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 .…”