Peripheral pain is enhanced by insulin-like growth factor 1 and its receptors in a mouse model of type 2 diabetes mellitus.

BACKGROUND: Insulin-like growth factor 1 (IGF1) is a neurotrophic factor with many actions, including a possible hyperalgesic effect. This study investigated the effects of IGF1 on the overall behavior of diabetic mice and explored the possible mechanisms underlying IGF1-induced pain. METHODS: Mice were divided into five groups (db/m, db/db, vehicle-treated db/db, IGF1-treated db/db, and IGF1 + JB1-treated db/db mice). Behavioral studies were conducted using the hot plate and Von Frey tests after intraplantar injection of recombinant (r) IGF1 (50 µg/kg) and the IGF1 receptor (IGF1R) antagonist JB1 (6 µg/mouse). Morphological changes in dorsal root ganglia (DRG) were evaluated using electron microscopy. Immunofluorescence was used to detect IGF1R expression and colocalisation with pain mediators in the DRG. Changes in the expression of IGF1R, extracellular signal-regulated kinase (ERK), and ras-associated factor-1 (c-raf) in the DRG were evaluated using western blotting. RESULTS: Intraplantar injection of rIGF1 resulted in a hyperalgesic effect after 2 hours. This IGF1-induced hypersensitivity was attenuated by prior intraplantar injection of the IGF1R antagonist. There was no significant change in neuronal structure in the db/m group, whereas neuronal structure was impaired in the other four groups. Moreover, IGF1R was colocalised with pain mediators in the DRG of mice. Intraplantar injection of rIGF1 resulted in increased IGF1R, phosphorylated (p-) ERK, and c-raf expression in the DRG; prior intraplantar injection of the IGF1R antagonist attenuated rIGF1-induced increases in p-ERK and c-raf. CONCLUSIONS: The results indicate that IGF1-induced acute hyperalgesia may be associated with the IGF1R/c-raf/ERK pathway. The IGF1-induced hypersensitivity was attenuated by an IGF1R antagonist.

Endometrial Cancer Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression Increases with Body Mass Index and Is Associated with Pathologic Extent and Prognosis.

BACKGROUND: Obesity is a main risk factor for endometrial carcinoma (EC). Insulin-like growth factor 1 receptor (IGF1R) expression may influence this association. METHODS: IGF1R IHC was performed on a tissue microarray with 894 EC and scored according to the percentage and intensity of staining to create immunoreactivity scores, which were dichotomized into low and high IGF1R expression groups. Logistic regression modeling assessed associations with body mass index (BMI), age, histology, pathologic extent of disease (pT), and lymph node metastasis (pN). Overall survival (OS) and disease-free survival (DFS) were compared between IGF1R expression groups using Kaplan-Meier curves and log-rank tests. RESULTS: The proportion of patients with high IGF1R expression increased as BMI (<30, 30-39, and 40+ kg/m(2)) increased (P = 0.002). The adjusted odds of having high IGF1R expression was 1.49 [95% confidence interval (CI), 1.05-2.10, P = 0.024] for patients with BMI 30 to 39 kg/m(2) compared with <30 kg/m(2) and 1.62 (95% CI, 1.13-2.33, P = 0.009) for patients with BMI 40+ kg/m(2) compared with <30 kg/m(2). High IGF1R expression was associated with pT and pN univariately and with pT after adjusting for BMI, pN, age, and histologic subtype. DFS and OS were better with high IGF1R expression, P = 0.020 and P = 0.002, respectively, but DFS was not significant after adjusting for pT, pN, and histologic subtype of the tumor. CONCLUSIONS: There is an association between BMI and EC IGF1R expression. Higher IGF1R expression is associated with lower pT and better DFS and OS. IMPACT: These findings suggest a link between IGF1R EC expression and obesity, as well as IGF1R expression and survival.