IGFBP-1 is associated with IRS signaling upregulation and contributes to metabolic recovery post-Roux-en-Y bypass.

OBJECTIVE: To investigate whether increased IGFBP-1 following Roux-en-Y gastric bypass (RYGB) surgery is associated with upregulation of IRS-1 and its downstream PI3K/AKT/GSK-3β signaling components, thereby contributing to the glucose-lowering mechanism of metabolic surgery.

METHODS: Wild-type C57BL/6 mice (WT) and C57BL/6-Igfbpem1 IGFBP-1 knockout mice (KO) were used, along with an induced diabetes model (high-fat diet for 6 weeks followed by low-dose streptozotocin for 5 days prior to surgery). Preoperatively and at 1 to 8 weeks postoperatively, body weight, fasting blood glucose, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR, calculated from fasting glucose and insulin at week 8) were assessed. Plasma samples were collected and stored at -80 °C. Mice were euthanized at eight weeks postoperatively, and tissues were collected. ELISA was used to measure plasma IGFBP-1, IRS-1, PI3K, AKT, GSK-3β. Real-time PCR was performed to assess mRNA expression of these targets in multiple tissues. This work is reported in accordance with the ARRIVE guidelines.

RESULTS: Following RYGB, body weight, fasting blood glucose, and HOMA-IR improved significantly. IGFBP-1 levels were significantly elevated post-surgery, along with marked upregulation of IRS-1, PI3K, and AKT, and downregulation of GSK-3β in WT mice. These changes were absent in KO mice. Histomorphometric analysis demonstrated that RYGB reversed multi-organ pathological changes (cardiomyocyte hypertrophy, hepatic steatosis, glomerular enlargement, adipocyte hypertrophy) in WT mice but only partially in KO mice.

CONCLUSION: Metabolic surgery upregulates IGFBP-1 expression. Elevated IGFBP-1 is associated with upregulation of the IRS/PI3K/AKT/GSK-3β signaling axis and improved insulin sensitivity. IGFBP-1 is necessary for achieving complete normalization of glucose homeostasis and multi-tissue repair after RYGB.