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.