Autoimmune activation of the GnRH receptor induces insulin resistance independent of obesity in a female rat model

Abstract

Polycystic ovary syndrome (PCOS), a metabolic and reproductive disease, is frequently associated with type 2 diabetes. We have demonstrated activating autoantibodies (AAb) directed toward the second extracellular loop (ECL2) of the gonadotropin‐releasing hormone receptor (GnRHR) are present in a significant subgroup of PCOS patients. It is unclear whether GnRHR‐AAb can induce peripheral tissue insulin resistance (IR) in animal models. Sixteen rats were divided equally into a GnRHR ECL2 peptide‐immunized group (IMM group) and a control group (CON group). Sera GnRHR‐AAb titer, luteinizing hormone (LH), and testosterone (T) were higher in IMM rats compared with CON rats. No significant difference in fasting blood glucose was observed between the two groups. However, the plasma glucose level at other time points of the IMM group was higher than that of the CON group during an intraperitoneal glucose tolerance test (IPGTT) and an insulin tolerance test (ITT) ( p < 0.01). These data support the likelihood of the GnRHR‐AAb induction of glucose intolerance and IR. Compared with the CON group, the IMM group showed a significant increase in insulin‐stimulated phosphorylation of IRS‐1 (p‐IRS‐1 S636/639) and a decrease in insulin‐stimulated phosphorylation of Akt (p‐AKT S473). Expression of the glucose transport genes including GLUT‐2 in liver and GLUT‐4 in white adipose tissue and skeletal muscle was significantly decreased in IMM rats compared with the CON rats. Serum levels of proinflammatory cytokines (TNF‐α, IL‐1α, and IL‐18) were increased, while anti‐inflammatory cytokines (IL‐4 and IL‐10) were decreased in the IMM group. Taken together, elevated GnRHR‐AAb enhanced LH, hyperandrogenism, and inflammation. These changes are likely related to the observed peripheral tissue IR through the downregulation of the insulin‐stimulated IRS/PI3K/Akt/Glut signaling pathway.

Effects of Anterior Pituitary Adenomas’ Hormones on Glucose Metabolism and Its Clinical Implications

“…126,127 LH hypersecretion leads to increased synthesis and secretion of androgens, interfering with the insulin signaling pathway (IRS-1-PI3K-Akt-Glut) in peripheral tissues. 128 It is mainly manifested as significantly increased serine phosphorylation of insulin receptor substrate-1 (IRS-1) stimulated by insulin (p-IRS-1 S636/639) and significantly decreased phosphorylation of insulin-stimulated Akt (p-AKT S473), as well as downregulated glucose transport genes including glucose transporter 2 (GLUT2) and GLUT-4. LH increases blood glucose levels via the insulin resistance mechanism described above.…”

“…132 In PCOS, 133 IL-6 can also mediate the JAK2/STAT3 signaling pathway whose activation can stimulate the expression of miR-21 and miR-155 to downregulate the expression of peroxisome proliferator-activated receptor γ(PPAR-γ) and GLUT4, thereby indirectly causing insulin resistance. 131 In addition to IL-6, the levels of tumor necrosis factor-α (TNF-α), IL-1α, and other inflammatory cytokines are significantly increased whereas IL-4, IL-10, and other anti-inflammatory cytokines are significantly decreased in women with PCOS, 128 which can further lead to insulin resistance (Figure 1).…”

Metabolic and Molecular Mechanisms of Diet and Physical Exercise in the Management of Polycystic Ovarian Syndrome

“…Recent studies showed the presence of activating autoantibodies (AAb) to the gonadotropin-releasing hormone receptor (GnRHR) [ 102 , 103 ] that seem to be associated with increased levels of testosterone and inflammatory cytokines [ 102 ]. The same antibodies, in murine models, are also responsible for increased levels of LH, TNF-α, IL-1α and IL-18, enhancing inflammation and hormonal disbalance [ 104 ].…”