Effects of Glucagon-Like Peptide-1 on Arteriovenous Fistula Remodelling and Vascular Smooth Muscle Cell Phenotype Switching in Diabetic Rats

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone, belonging to the incretin family. GLP-1 is secreted by the small intestine under delicate regulation in response to blood glucose concentrations. Since GLP-1 exerts stimulatory effects on insulin release through binding to the GLP-1 receptor (GLP-1R) on pancreatic beta cells, [6,7] GLP-1 analogues have been applied clinically to control hyperglycemia AbstractThis study aimed to determine the potential vascular protective effect of exendin-4, a synthetic glucagonlike peptide (GLP)-1 analogue, on the blood flow and remodelling of arteriovenous (AV) fistulas in a rat model of diabetes. AV fistulas were created in Sprague-Dawley rats with streptozotocin-induced diabetes. The animals were then randomly assigned to receive intraperitoneal injection of vehicle (saline) or exendin-4 for about 2 weeks. The blood flow and vasomotor function of the aortic limb of the fistula were measured. Concentrations of serum norepinephrine and its associate tissue signal proteins, and vascular smooth muscle cell (VSMC) contractile proteins, matrix metalloproteinase (MMP)-2, and collagen expression in the remodelled aorta were examined. Exendin-4 attenuated the contraction response to phenylephrine in isolated arterial segments from treated animals. Treatment with exendin-4 increased serum norepinephrine concentration, reduced aorta tissue α1-receptor expression, and enhanced downstream signal proteins. Additionally, exendin-4 promoted the switching of VSMCs to the synthetic phenotype, which increased tissue collagen content and suppressed tissue abundances of smooth muscle myosin heavy chain type II and desmin in diabetic animals. In conclusion, our study demonstrated that exendin-4 modulates VSMC transition to the synthetic phenotype and enhances the arterial contraction responses, thereby attenuating blood flow in the AV fistula.

Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing

“…We admit that the immune diabetic models are more compatible with type II diabetes, but streptozotocin-induced insulin-dependent chronic hyperglycemia is also a valid experimental model for wound healing, particularly when the extraglycemic effect of a drug or compound is tested. 20,49 Second, the closure of excisional wounds in this study might be affected by wound contracture rather than the true effect of re-epithelialization. Nevertheless, our results clearly showed that administration of Ex4 accelerated wound closure in diabetic rats that was comparable with controls, while the diabetic wounds remained poorly healed up to 14 d after injury.…”

“…Animals were then randomly assigned to control or Ex4 treatment group and received intraperitoneal injection of normal saline or Ex4 (0.5 mg/kg/d, Sigma Aldrich) for 14 d after operation. [18][19][20] Glp-1R analogues have been widely used in the control of blood glucose levels for the past decade, and they are most commonly administered via subcutaneous injection in type II diabetic patients. Therefore, our study design followed the clinical scenario that the application of parenteral injection of Ex4 as a supplemental hypoglycemic agent in diabetic patients may provide additional effect in the promotion of wound healing.…”