Impairment of the insulin-degrading enzyme (IDE) is associated with obesity and type 2 diabetes mellitus (T2DM). Here, we used 4-mo-old male C57BL/6 interleukin-6 (IL-6) knockout mice (KO) to investigate the role of this cytokine on IDE expression and activity. IL-6 KO mice displayed lower insulin clearance in the liver and skeletal muscle, compared with wild type (WT), due to reduced IDE expression and activity. We also observed that after 3-h incubation, IL-6, 50 and 100 ng ml⁻¹, increased the expression of IDE in HEPG2 and C2C12 cells, respectively. In addition, during acute exercise, the inhibition of IL-6 prevented an increase in insulin clearance and IDE expression and activity, mainly in the skeletal muscle. Finally, IL-6 and IDE concentrations were significantly increased in plasma from humans, after an acute exercise, compared to pre-exercise values. Although the increase in plasma IDE activity was only marginal, a positive correlation between IL-6 and IDE activity, and between IL-6 and IDE protein expression, was observed. Our outcomes indicate a novel function of IL-6 on the insulin metabolism expanding the possibilities for new potential therapeutic strategies, focused on insulin degradation, for the treatment and/or prevention of diseases related to hyperinsulinemia, such as obesity and T2DM.

Type 1 diabetes (T1D) is provoked by an autoimmune assault against pancreatic β cells. Exercise training enhances β‐cell mass in T1D. Here, we investigated how exercise signals β cells in T1D condition. For this, we used several approaches. Wild‐type and IL‐6 knockout (KO) C57BL/6 mice were exercised. Afterward, islets from control and trained mice were exposed to inflammatory cytokines (IL‐1β plus IFN‐γ). Islets from control mice and β‐cell lines (INS‐1E and MIN6) were incubated with serum from control or trained mice or medium obtained from 5‐aminoimidazole‐4 carboxamide 1‐β‐ d ‐ribofuranoside (AICAR)‐treated C2C12 skeletal muscle cells. Subsequently, islets and β cells were exposed to IL‐1β plus IFN‐γ. Proteins were assessed by immunoblotting, apoptosis was determined by DNA‐binding dye propidium iodide fluorescence, and NO* was estimated by nitrite. Exercise reduced 25, 75, and 50% of the IL‐1β plus IFN‐γ‐induced iNOS, nitrite, and cleaved caspase‐3 content, respectively, in pancreatic islets. Serum from trained mice and medium from AICAR‐treated C2C12 cells reduced β‐cell death, induced by IL‐1β plus IFN‐γ treatment, in 15 and 38%, respectively. This effect was lost in samples treated with IL‐6 inhibitor or with serum from exercised IL‐6 KO mice. In conclusion, muscle contraction signals β‐cell survival in T1D through IL‐6.—Paula, F.M.M., Leite, N. C., Vanzela, E. C., Kurauti, M. A., Freitas‐Dias, R., Carneiro, E. M., Boschero, A. C., Zoppi, C. C. Exercise increases pancreatic β‐cell viability in a model of type 1 diabetes through IL‐6 signaling. FASEB J. 29, 1805‐1816 (2015). www.fasebj.org

Introduction: Low-intensity endurance training (ET) performed with blood flow restriction (BFR) can improve muscle strength, cross-sectional area (CSA) and cardiorespiratory capacity. Whether muscle strength and CSA as well as cardiorespiratory capacity (i.e., V˙O_2max) and underlying molecular processes regulating such respective muscle adaptations are comparable to resistance and ET is unknown. Purpose: To determine the respective chronic (i.e., 8 wk) functional, morphological, and molecular responses of ET-BFR training compared with conventional, unrestricted resistance training (RT) and ET. Methods: Thirty healthy young men were randomly assigned to one of three experimental groups: ET-BFR (n = 10, 4 d·wk⁻¹, 30-min cycling at 40% of V˙O_2max), RT (n = 10, 4 d·wk⁻¹, 4 sets of 10 repetitions leg press at 70% of one repetition maximum with 60 s rest) or ET (n = 10, 4 d·wk⁻¹, 30-min cycling at 70% of V˙O_2max) for 8 wk. Measures of quadriceps CSA, leg press one repetition maximum, and V˙O_2max as well as muscle biopsies were obtained before and after intervention. Results: Both RT and ET-BFR increased muscle strength and hypertrophy responses. ET-BFR also increased V˙O_2max, total cytochrome c oxidase subunit 4 isoform 1 abundance and vascular endothelial growth factor mRNA abundance despite the lower work load compared to ET. Conclusions: Eight weeks of ET-BFR can increase muscle strength and induce similar muscle hypertrophy responses to RT while V˙O_2max responses also increased postintervention even with a significantly lower work load compared with ET. Our findings provide new insight to some of the molecular mechanisms mediating adaptation responses with ET-BFR and the potential for this training protocol to improve muscle and cardiorespiratory capacity.

Background/Aims: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease’s (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. Methods: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. Results: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. Conclusion: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

Type 1 diabetes (T1D) is characterized by impairment in beta-cell mass and insulin levels, resulting in hyperglycemia and diabetic complications. Since diagnosis, appropriate control of glycaemia in T1D requires insulin administration, which can result in side effects, such as hypoglycemia. In this sense, some bile acids have emerged as new therapeutic targets to treat T1D and T2D, as well as metabolic diseases. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA) reduces the incidence of T1D development and improves glucose homeostasis in obese and T2D mice. However, its effects in early-stage of T1D have not been well explored. Therefore, we have assessed the effects of TUDCA on the glycemic control of mice with early-stage T1D. To achieve this, C57BL/6 mice received intraperitoneal administration of streptozotocin (STZ, 40 mg/kg) for 5 days. Once diabetes was confirmed in the STZ mice, they received TUDCA treatment (300 mg/kg) or phosphate buffered saline (PBS) for 24 days. After 15 days of treatment, the STZ+TUDCA mice showed a 43% reduction in blood glucose, compared with the STZ group. This reduction was likely due to an increase in insulinemia. This increase in insulinemia may be explained, at least in part, by a reduction in hepatic IDE activity and, consequently, reduction on insulin clearance, as well as an increase in beta-cell mass and a higher beta-cell number per islet. Also, the groups did not present any alterations in insulin sensitivity. All together, these effects contributed to the improvement of glucose metabolism in T1D mice, pointing TUDCA as a potential therapeutic agent for the glycemic control in early-stage of T1D.