Abstract
BackgroundGlucocorticoid excess is commonly associated with diabetogenic effects, including insulin resistance and glucose intolerance. The effects of the long-term glucagon-like peptide 1 receptor agonist treatment on the metabolic syndrome-like conditions are not yet fully elucidated. Thus, we aimed to test whether long-term liraglutide treatment could be effective as a therapy to counteract the metabolic dysfunctions induced by chronic glucocorticoid exposure.MethodsMice were given corticosterone or vehicle via their drinking water for five consecutive weeks. In addition, mice were treated with once-daily injections of either PBS or liraglutide.ResultsLiraglutide treatment slowed progression towards obesity and ectopic fat deposition in liver that otherwise occurred in corticosterone-treated mice. The drug reduced the increment in serum insulin caused by corticosterone, but did not affect the reduction of insulin sensitivity. Furthermore, liraglutide improved glucose control in mice exposed to corticosterone as evident by a delay in the progression towards post-prandial hyperglycemia and enhanced glucose clearance during a glucose tolerance test. Glucose-stimulated C-peptide levels were higher in those mice that had received liraglutide and corticosterone compared to mice that had been treated with corticosterone alone, indicating a positive role of liraglutide for beta-cell function. Morphometric analysis revealed increased beta- and alpha-cell masses that were associated with more Ki67-positive islet cells in corticosterone-treated mice irrespective of whether they were co-treated with liraglutide or not. Liraglutide had no discernible effect on alpha-cell mass.ConclusionLiraglutide can be beneficial for subjects at risk of developing metabolic complications as a result of glucocorticoid excess.
Highlights
Glucocorticoid excess is commonly associated with diabetogenic effects, including insulin resistance and glucose intolerance
Once-daily injections of liraglutide slow the progression towards obesity and ectopic fat deposition in liver that otherwise occurs during administration of corticosterone to mice
Morphometric analysis revealed that the relative and absolute beta-cell mass was significantly increased in pancreata obtained from corticosterone-treated mice irrespective of whether they were co-treated with liraglutide or not (Figures 4C-E)
Summary
Glucocorticoid excess is commonly associated with diabetogenic effects, including insulin resistance and glucose intolerance. Steroid diabetes or worsened glycemic control in diabetic subjects is usually treated with insulin injections, oftentimes mixtures containing a high proportion of a direct acting insulin analogue to curb prandial glycemia. Such regime may result in undesirable side effects. Matsuo et al reported on four cases of patients with type 2 diabetes with worsened glycemic control due to GCs who were successfully treated with exendin-4 administration [17] These studies indicate beneficial glycemic effects of GLP-1 receptor activation after GC treatment, they neither address the ability of these drugs to counteract the long-term effects of GC treatment. We aimed at addressing this issue in an animal model of steroid diabetes by using liraglutide, an efficacious second generation GLP-1 analogue in clinical use [18,19] and to study the mechanisms behind any protective effect exerted by liraglutide
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