β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome

Abstract

Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 mg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into b-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.

Pancreatic Islet Responses to Metabolic Trauma

“…Insulin-positive cell area was enlarged by 2.3-fold in mice exposed to corticosterone versus mice given the vehicle control. These results are consistent with the 3-fold increase in pancreatic islet volume and are likely explained by the 2.7-fold increase in markers of islet β-cell proliferation (51). Because glucocorticoid regimens can induce rapid insulin resistance in humans (46), it is plausible that the increase in pancreatic islet size and insulin output in mice and humans are adaptive responses to address the need for more circulating insulin to compensate for reduced insulin action in liver and skeletal muscle.…”

“…In a separate study, the metabolic trauma associated with oral corticosterone delivery (100 μg/mL) was extended to include increased lipid storage in liver and skeletal muscle (51). Furthermore, pancreatic islet size was increased in mice receiving oral corticosterone relative to their vehicle control counterparts.…”

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

“…Both pancreatic insulin content and islet volume increase in mice exposed to corticosterone, suggesting that the increased demand for insulin brought about by insulin resistance and increased blood glucose in this model give rise to pancreatic islet β-cell compensation (Fransson et al 2013). In this regard, GCs reduce insulin sensitivity and impair β-cell function by acting through their receptors on pancreatic β-cells (Fischer et al 1990, Matthes et al 1994, van Raalte et al 2009).…”

Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome

“…Animals were randomly assigned to either receive corticosterone (100 μg/ml, [Sigma, St Louis, MO, USA]) or vehicle (1% ethanol) via their drinking water. This corticosterone regimen is known to produce a valuable mouse model with metabolic syndrome features [20,21]. In addition, half of the mice in each group were given once daily s.c .…”