Augmentedβ-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β/AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling

Abstract

Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented β-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented β-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.

Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme

“…for 5 consecutive days exhibit normal non-esterified fatty acid (NEFA) levels and normal glycemic response to a pyruvate tolerance test, compared to control mice. These parameters were both impaired in rats treated with the same glucocorticoid regimen [29]. This suggests that dexamethasone-treated mice have a more preserved insulin action on fat and liver tissues compared to rats.…”

“…This suggests that dexamethasone-treated mice have a more preserved insulin action on fat and liver tissues compared to rats. In accordance, rats treated with dexamethasone exhibit increased fat lipolysis [36] and pyruvate intolerance [29,37] that may be, at least in part, responsible for their elevated NEFA and impaired glucose tolerance [29,37]. It is important to consider that mice exhibit higher metabolic rate in relation to rats [38], and such aspect might be taken into account for the less pronounced adverse effects of dexamethasone regimen (1 mg/kg b.w.)…”

“…In fact, the increased function of islet b-cell (e.g., insulin hypersecretion), observed in mice treated with the same dexamethasone regimen [29], seems to surpass the metabolic demand caused by the reduction of insulin sensitivity, which favors for a slight reduction in blood glucose levels ( Table 1).…”

“…5) suggests that reduced IDE activity, at least in rats, is possibly not a result from transcriptional regulation, but rather a result of post-translational modulation, probably associated with the increased plasma and/or hepatic lipids and glucose in glucocorticoid-treated rodents [29,46], which are known to reduce insulin clearance [3,20,44,47,48]. The dissociation among Ide mRNA and IDE protein content/activity in the liver was recently described in an animal model of high fat diet (HFD) and in hepatoma cell-line (1c1c7) cultured with fatty acids [31], supporting the hypothesis that post-translational modulation, such as ubiquitination [49], may underlie the reduced IDE expression in liver from the dexamethasone-treated rodents.…”

“…in saline] and a control group (CTL) that received 5 consecutive daily injections of saline (1.0 ml/kg b.w.) between 0800 and 0900 h, according to previous publication [29]. To avoid overlapping of the acute and chronic glucocorticoid effects, all experiments were initiated 24 h after the last dexamethasone injection (on the sixth day).…”