Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

Abstract

Osteoarthritis (OA) and osteoporosis (OP) are common among older women, especially postmenopausal women. Glucosamine (GlcN) is a common medication for OA, but it may induce insulin resistance and β-cell dysfunction, especially if ovarian hormones are lacking. Raloxifene (RLX) is a selective estrogen receptor modulator and also an OP drug. Previously, we found that estrogen could improve GlcN-induced insulin resistance in ovariectomized (OVX) rats. Here, we further hypothesized that RLX, similarly to estrogen, can ameliorate GlcN-induced insulin resistance in OVX rats. We used GlcN to induce insulin resistance in OVX rats as a model for evaluating the protective effects of RLX in vivo. We used a pancreatic β-cell line, MIN-6, to study the mechanisms underlying the effect of RLX in GlcN-induced β-cell dysfunction in vitro. Increases in fasting plasma glucose, insulin, and homeostasis model assessments of insulin resistance in OVX Sprague Dawley rats treated with GlcN were reversed by RLX treatment (n = 8 in each group). Skeletal muscle GLUT-4 increased, liver PEPCK decreased, pancreatic islet hypertrophy, and β-cell apoptosis in OVX rats treated with GlcN was ameliorated by RLX. The negative effects of GlcN on insulin secretion and cell viability in MIN-6 cells were related to the upregulation of reticulum (ER) stress-associated proteins (C/EBP homologous protein, phospho-extracellular signal-regulated kinase, phospho-c-JunN-terminal kinase), the expression of which was reduced by RLX. Pretreatment with estrogen receptor antagonists reversed the protective effects of RLX. GlcN can induce insulin resistance, β-cell dysfunction, and apoptosis in OVX rats and increase ER stress-related proteins in β-cells, whereas RLX can reverse these adverse effects. The effects of RLX act mainly through estrogen receptor α; therefore, RLX may be a candidate drug for postmenopausal women with OA and OP.

High‐fat diet‐induced obesity augments the deleterious effects of estrogen deficiency on bone: Evidence from ovariectomized mice

“…Interestingly, we observed that OVX mice maintained glucose tolerance by increasing β cell area and function. Similar findings were reported in a recent study on OVX rats (Chen et al, 2021 ). Furthermore, the impaired glucose tolerance observed in HFD‐SHAM was partially caused by diminished capacity of the β cell to secrete insulin even though β cell area was increased as evidenced by HOMA‐β.…”

Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

“…The percentages of TUNEL-positive cells in osteocytes relative to 4′,6-diamidino-2-phenylindole (DAPI)-stained cells were calculated, and an analysis was conducted using a Leica immunofluorescence system (Leica Microsystems, Wetzlar, Germany). Photographs from three independent experiments were taken for each experimental group [ 25 , 32 ].…”

Special Issue: Emerging Paradigms in Insulin Resistance

“…In addition to changes in bone fragility, osteoarthritis (OA), insulin resistance, and T2D are more common in postmenopausal women than in premenopausal women. To address whether a current drug used to treat OA could also be effective against insulin resistance, Chen et al, used raloxifene in glucosamine exposed, ovariectomized rats [ 25 ]. Raloxifine is an estrogen receptor modulator, and by virtue of its ability to activate transcriptional targets of the estrogen receptor, may be effective against the inflammation associated with OA and T2D.…”