The Journal of Steroid Biochemistry and Molecular Biology
Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme
Introduction
Type 2 diabetes mellitus (T2DM) is a multifactorial disease characterized by hyperglycemia and associated with obesity, peripheral insulin resistance (IR), pancreatic β- and α-cell dysfunction, and altered insulin clearance [1], [2], [3], [4], [5], [6]. At the onset of T2DM, before the development of overt hyperglycemia, the IR induces an adaptive response of pancreatic β cells that results in increased insulin secretion, leading to hyperinsulinemia [7]. Whether this compensatory hyperinsulinemia will persist depends on the ability of β cells to maintain this continuous requirement of insulin hypersecretion [2]. However, evidence also suggests that a primary persistent hyperinsulinemia, generated by environmental or genetic factors may induce IR, obesity and T2DM as consequence [8], [9].
Some therapies may also cause IR and hyperinsulinemia and glucocorticoid-based therapies that are prescribed due to their anti-inflammatory, antialergic and immunosuppressive properties are one of more relevant clinical example. In excess, glucocorticoids promote an imbalance on glucose homeostasis that include IR, glucose intolerance and, depending on the individual susceptibility, T2DM [5], [10]. The IR induced by glucocorticoid treatment is initially counteracted by compensatory insulin hypersecretion, due to increased β-cell function and proliferation [11], [12], [13], [14], [15].
Hyperinsulinemia present during obesity is also a result of increased β-cell function, but there are also evidences for a contribution of reduced hepatic insulin clearance (defined as the rate of insulin removal from plasma) in humans [16], [17], [18], [19], monkeys [1], dogs [4] and rats [20]. Decreased hepatic insulin clearance seems to precede the β-cell compensation in obese dogs, and this hepatic adaptive mechanism contributes to the augmented circulating insulin levels during obesity [4]. In accordance, glucocorticoid-treated dogs [21] and insulin-resistant non-diabetic adrenal incidentaloma (AI) patients [22] exhibit decreased hepatic insulin clearance. However, the molecular mechanisms underlying this compensatory adaptation are unknown.
Insulin clearance occurs predominantly in the liver [3], [18] and insulin degradation is mainly processed by the insulin-degrading enzyme (IDE), a 110 kDa zinc-metalloproteinase that is ubiquitously expressed [18]. Treatment of hepatic cells with glucocorticoids lead to reduction of insulin binding to IDE [23] and reduction of insulin degrading capacity [24], suggesting that glucocorticoids may regulate insulin clearance due to alterations upon the IDE expression or activity.
IDE is also a major protease involved in the degradation of the amyloid β-protein (Aβ) [25]. Reduced Aβ degradation by several proteases, including IDE, has been suggested to play a role in the onset and progression of Alzheimeŕs disease (AD) [26], [27]. In fact, the IDE knockout (IDE−/−) mice display reduced Aβ degradation in brain fractions and primary neurons, providing a molecular mechanism for the recently recognized association among hyperinsulinemia, T2DM and AD [26]. Chronic glucocorticoid treatment is associated with diminished IDE expression in the brain of macaques [27]. In accordance, astrocytes treated with glucocorticoid present reduced IDE mRNA and protein content [28].
Considering the importance of the IDE in the glycemic control and that glucocorticoid excess impairs such glucose homeostasis we investigated whether activity of hepatic IDE could be modulated in a model of hyperinsulinemia caused by dexamethasone treatment. By using two experimental models, Swiss mice and Wistar rats, we demonstrated that hyperinsulinemic rodents exhibited lower insulin clearance that was associated with lower activity of hepatic IDE, mainly in rats.
Section snippets
Ethical approval
The experiments with rats and mice were approved by the State University of Campinas Committee for Ethics in Animal Experimentation (approval ID: 2285-1).
Materials
Dexamethasone phosphate (Decadron) (Aché, Campinas, SP, Brazil), human recombinant insulin (Humulin R) (Lilly, Indianapolis, IN, USA), d-glucose (Synth, Labsynth, Diadema, SP, Brazil) and 125I-labeled insulin, used in the radioimmunoassay (RIA) (PerkinElmer, Boston, MA, USA), were used in our experiments.
Animals and experimental design
All of the experiments were performed
Glucocorticoid treatment reduced insulin sensitivity in mice and rats
It is known that in vivo glucocorticoid administration induces a decrease in insulin sensitivity in mice [32], rats [33], [34], and humans [11], [14]. Here, glucocorticoid-treated rats displayed a 56% reduction in insulin sensitivity compared to CTL groups, as observed in the ipITT (Fig. 1A and B) and indicated by the KITT (Fig. 1C). Mice submitted to the same dexamethasone regimen displayed a 36% reduction in insulin sensitivity (Fig. 1D,E), as indicated by the KITT values (Fig. 1F).
Compensatory hyperinsulinemia to the glucocorticoid-induced IR
Due to the
Discussion
The present study provides evidence that the compensatory hyperinsulinemia observed in insulin-resistant rats and mice, induced by glucocorticoid treatment, is due, at least in part, to a reduced insulin clearance that is associated with lower IDE activity in the liver in rats, with a tendency towards a reduction in mice. These findings corroborate the hypothesis that short-term and/or partial inhibition of the hepatic IDE expression may enhance the hypoglycemic action of insulin, which could
Conflict of interest
We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research was supported by Grants from Fundação de Apoio a Pesquisa do Estado de São Paulo-FAPESP (ID no. 2010-05196-2).
Authorship contributions
Conceived and designed the experiments: A.O.P.P, L.F.R., A.R. and A.C.B. Conducted experiments: A.O.P.P, J.M.C.J, S.M.F, A.P.C., F.M.M.P, J.C.S and M.A.K. Contributed with analytic tools and data analysis: A.O.P.P, L.F.R., A.R. and A.C.B. Contributed with reagents/materials: E.M.C and A.C.B. Wrote and edited paper: A.O.P.P, L.F.R., A.R and A.C.B.
Acknowledgments
We thank Mrs. Marise Brunelli for technical assistance; Mr. Bill Floriano, Mr. Washington Gomes, Mr. Juvenal Dantas, Mrs. Francine Quinelato and Mrs. Priscila Silva for animal care; and FAPESP for supporting this research.
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Contributed equally to this work.