During long term treatment with glucocorticoids (GCs), many patients develop various degrees of glucose intolerance, some progressing into frank diabetes, a condition commonly known clinically as “steroid diabetes” [
1]. Additionally, worsening of glycemic control in patients with known type 2 diabetes mellitus (T2DM) on GC therapy is also a clinically well-known phenomenon. The reasons for the impaired glucose tolerance are probably multifactorial, and the precise nature of the mechanisms contributing remains elusive. The insulin-producing pancreatic beta-cell may be extra susceptible to GC excess, since both iatrogenic Cushing syndrome and GC-induced diabetes in animal models are associated with loss of glucose-stimulated insulin secretion (GSIS), and GC immunosuppressive treatment adversely affects islet transplantation outcome [
2]. In animal models susceptible to GC treatment, dexamethasone exposure causes GLUT-2 degradation, thereby impeding beta-cell glucose sensing [
3] and increases islet glucose cycling as a consequence of augmented glucose-6-phosphatase activity [
4,
5].
In vitro, GCs exert several negative effects on beta-cell function including reduced GSIS and increased alpha-2 adrenergic receptor response [
6], increased activity of K
v1.5 channel (repolarizing potassium channel) [
7], endoplasmic reticulum dysfunction [
8], and increased beta-cell apoptosis [
9,
10]. Since the human insulin gene contains GC-sensitive transcriptional elements [
11], it may be susceptive to deleterious effects of GCs. Beta-cell susceptibility to GCs may also be relevant in the natural unfolding of diabetes, since mice overexpressing the GC receptor restricted to the beta-cell develop early beta-cell failure, glucose intolerance and later in life overt diabetes [
4,
5]. Humans with impaired beta-cell function (low insulin responders) are predisposed to become overtly diabetic during GC therapy [
12]. Clinically, 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. However, such regime may result in undesirable side effects. The risk of incurring hypoglycemia, weight gain and adiposity -- on top of what is the result of GC therapy -- is a significant drawback of insulin treatment. Recently, another class of antidiabetic agents, incretin-based therapy, has been made available [
13,
14]. This novel treatment modality is based upon activation of the receptor for glucagon-like peptide 1 (GLP-1), which leads to enhanced GSIS, glucagon suppression and other antidiabetic effects [
13,
14]. GLP-1 is synthesized in enteroendocrine L-cells and is released post-prandially in proportion to caloric intake. Especially carbohydrate and fat seem to be effective stimuli for GLP-1 secretion [
15]. GLP-1 drugs, in contrast to insulin, are devoid of risk for hypoglycemia and weight gain. Exendin-4, the first generation GLP-1 receptor (GLP-1R) agonist was recently shown to improve beta-cell function in healthy men treated for two days with prednisolone [
16]. Similarly, 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]. Although 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. In the present work, 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.