Absence of Estrogen Receptor Alpha in T Regulatory Cells Results in Decreased Skeletal Muscle Glucose Uptake in Western Diet-Fed Female Mice

Presentation Number: SAT 575
Date of Presentation: April 1st, 2017

Guido Lastra1, Susan C McKarns2, James R. Sowers3 and Camila Manrique Acevedo*1
1University of Missouri, Columbia, MO, 2University of Missouri - Columbia, Columbia, MO, 3Harry S Truman VA Hospital and University of Missouri, Columbia, MO

Abstract

Insulin resistance, manifested in skeletal muscle as decreased insulin-mediated glucose uptake, is a key event in the pathogenesis of type 2 diabetes mellitus. Furthermore, inflammation has been hypothesized as an important event in the origin of insulin resistance in skeletal muscle. In these regards, T regulatory cells (Tregs) suppress inflammation and ameliorate insulin resistance. Interestingly, signaling through estrogen receptor alpha (ERα) has been postulated to modulate Tregs function. Consequently, using a novel rodent model lacking ERα in Treg cells (TregERαKO) we tested the hypothesis that in conditions of WD-feeding, abrogation of ERα signaling in Tregs in female mice results in worsened whole-body and skeletal muscle-specific insulin sensitivity. Female TregERαKO mice and ERαFloxed (ERαFl2) littermate controls were fed a WD for 16 weeks. WD consisted of high fat (46%) and high carbohydrate as sucrose (17.5%) and high fructose corn syrup (17.5%). At the end of the intervention, rodents underwent hyperinsulinemic-euglycemic clamps (n=7-9 per group). Body weight was not significantly different between the 2 different cohorts (35.1 ± 1.6 vs. 36.9 ± 1.8 mg, ERαFl2 vs. TregERαKO respectively p=0.448). Although TregERα deletion did not significantly impact whole-body insulin sensitivity (glucose infusion rate at steady state: 20 ± 2 vs. 17 ± 2 mg/Kg/min, ERαFl2 vs. TregERαKO respectively, p=0.22), TregERαKO mice had during the clamp a significantly lower rate of glucose disappearance (Rd) (33 ± 2 vs. 25 ± 2 mg/kg/min, ERαFl2 and TregERαKO respectively p<0.05) in parallel with a lower rate of endogenous glucose production (14 ± 1 vs. 11 ± 1 mg/kg/min, ERαFl2 and TregERαKO respectively p<0.05). Insulin-stimulated glucose uptake was significantly lower in gastrocnemius muscle (8.7±0.8 vs.6.2±0.5 mmol/100g tissue/min/, ERαFl2 and TregERαKO respectively p<0.05) and in vastus lateralis (8.6±0.4 vs.6.1±0.7 mmol/100g tissue/min/, ERαFl2 and TregERαKO respectively p<0.05) in the TregERαKO cohort, consistent with skeletal muscle insulin resistance. Conclusions: In female mice fed a WD lack of ERα signaling in Tregs results in lower rate of glucose disappearance along with decreased skeletal muscle glucose uptake. The lower rate of glucose production likely accounts for the lack of a significant impact on whole-body insulin sensitivity. Further studies are needed to ascertain the relative contribution of each tissue in the pathogenesis of type 2 diabetes in females.

 

Nothing to Disclose: GL, SCM, JRS, CM