High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

Abstract

Here, we report a model to study ␤-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of ␤-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in ␤-cell proliferation and an increase (17%) in ␤-cell size, with significant increase in ␤-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in ␤-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory ␤-cell alterations. Augmented ␤-cell mass involves ␤-cell hyperplasia and, to a lower extent, ␤-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for ␤-cell proliferation in the dexamethasone-induced insulin resistance.␤-cell growth; glucocorticoid; hyperglycemia; hyperinsulinemia; insulin resistance PANCREATIC ␤-CELLS ARE the only significant source of insulin, which is required for maintaining appropriate metabolic homeostasis and particularly to maintain glucose levels within a narrow range. However, failure of the ␤-cell capacity (␤-cell dysfunction and/or insufficient ␤-cell mass) contributes to the pathogenesis of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) (10, 18). Physiological or pathological states such as aging, pregnancy, insulin resistance, and obesity demand an increase in circulating insulin. Several ␤-cell adaptations are observed in these conditions, including increased insulin synthesis and secretion, hyperplasia, and hypertrophy (23,28,30). ␤-Cell mass plays an essential role in limiting the amount of insulin that is secreted in these systemic conditions of increased insulin demand. Patients with T2DM show reduced ␤-cell mass as a result of impaired ␤-cell proliferation and/or increased ␤-cell apoptosis, suggesting that adequate ␤-cell mass is required for prevention of diabetes (10, 18). Although remarkable improvements in the management of diabetic patients have occurred over recent years, new therapies are still needed to further improve metabolic control of this pathology (36).Amelioration of ␤-cell function and increase in ␤-cell number are important goals in diabetes research. Pancreatic ␤-cell mass r...

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

“…The islet compensatory response is also accompanied by structural changes. It has been demonstrated that, b-cell mass increases in a time- (Rafacho et al 2011) and dose-dependent manner (Rafacho et al 2009) with GC administration, according to the correspondent degree of insulin insensitivity. Taken together, these results show that when humans or animal models are exposed to prolonged steroid treatment, they develop augmented b-cell function and mass to counteract the IR resulting from GC administration.…”

Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats

“…To study β-cell mass and cellular distribution of Pdx-1, the endocrine pancreas was excised from 4 animals in each group and processed as previously described (19)(20)(21). The relative and absolute β-cell mass as well as the islet number per pancreatic area were determined by point-counting morphometry on each pancreas section immunostained for Table 1.…”

“…Islet protein (100 µg) was used for each experiment as previously reported (20,21). Immunoblotting experiments were performed at least five times.…”

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

“…In healthy humans, it has been reported that insulin secretion is two-to fourfold increased to compensate increased insulin resistance after short-term GC administration (21)(22)(23). In rodents, GC administration has been shown to promote an increase in BCM and in insulin secretion through an increase in b-cell replication and b-cell neogenesis (18)(19)(20). On the basis of these previous studies, we hypothesized that BCM might also be increased in humans who received GC therapy.…”

“…As a result, the use of GCs is associated with a risk of development or worsening of glucose intolerance, which is well known as one of the major adverse effects of GC therapy (17). In rodents, GC-induced insulin resistance was shown to increase insulin biosynthesis and secretion and promote BCM expansion through b-cell proliferation (18)(19)(20). GC administration in humans has also been shown to augment insulin secretion (21)(22)(23); however, the effect of GC therapy on BCM in humans is unknown.…”